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Sample records for a-t heterozygous breast

  1. Irradiated HMEC from A-T Heterozygous Breast Tissue

    NASA Technical Reports Server (NTRS)

    Richmond, Robert; Bors, Karen; Cruz, Angela; Pettengil, Olive; Curreri, Peter A. (Technical Monitor)

    2002-01-01

    Women who are heterozygous for ataxia-telangiectasia (A-T) carry a single defective ATM gene in chromosome 11 q22-23, and have been statistically determined with high significance within a defined database to be approximately 5-fold more susceptible for developing breast cancer than their noma1 counterpart. Breast cancer susceptibility of these A-T heterozygotes has been hypothesized to include consequence of response to damage caused by low levels of ionizing radiation. Prophylactic mastectomy specimens were donated by a 41 year-old obligate A-T heterozygote who was located prior to her elective surgery through an existing pedigree. Harvest of that breast tissue provided an isolate of long-term growth human mammary epithelial cells (HMEC), designated WH612/3. An isolate of presumed normal long-term growth HMEC, designated 48R, was obtained from Dr. Martha Stampfer (Lawrence Berkeley Laboratory, University of California), and the A-T heterozygous HMEC were transformed with E6 and E7 oncogenes of human papilloma virus Type-16 in the laboratory of Dr. Ray White (Hunt- Cancer Institute, University of Utah) for use in this study. The objective of this study is to study the expression of end points that may bear on cancer outcome following irradiation of HMEC. Specific end points are cell survival, cell cycle, p53 expression, and apoptosis. Survival curves, immunostaining, and flow cytometery are used to examine these end points. Radiation-induced cell killing shows less shoulder development in the survival curve for WH61U3 compared to 48R HMEC, suggesting less repair of damage in the former HMEC. Additional information is included in the original extended abstract.

  2. Cancer Risk-Assessment of Radiation Damage in Ataxia Telangiectasia Heterozygous Human Breast Epithelial Cell Cultures

    NASA Technical Reports Server (NTRS)

    Applewhite, Lisa C.

    2002-01-01

    This paper describes the study of the markers of cellular changes that are found during the onset of carcinogenesis. Several of the biological factors are markers of stress response, oncoprotein expression, and differentiation factors. Oxidative stress response agents such as heat shock proteins (HSPs) protect cells from oxidative stresses such as ionizing radiation. The onocoprotein HER-2/neu, a specific breast cancer marker, indicates early onset of cancer. Additional structural and morphogenetic markers of differentiation were considered in order to determine initial cellular changes at the initial onset of cancer. As an additional consideration, all-trans retinoic acid (RA), a differentiation agent, was considered because of its known role in regulating normal differentiation and inhibiting tumor proliferation via specific nuclear receptors. This paper discusses study and results of the preliminary analyses of gamma irradiation of AT heterozygous human breast epithelial cells (WH). Comparisons are also made of the effects various RA concentrations post-irradiation.

  3. Radiation Dose-effects on Cell Cycle, Apoptosis, and Marker Expression of Ataxia Telangiectasia-Heterozygous Human Breast Epithelial Cells

    NASA Technical Reports Server (NTRS)

    Cruz, A.; Bors, K.; Jansen, H.; Richmond, R.

    2003-01-01

    Ataxia-telangiectasia (A-T) is a radiation-sensitive genetic condition. AT-heterozygous human mammary epithelial cells (HMEC) were irradiated using a Cs137 source in order to compare cell cycle, apoptosis, and marker expression responses across 3 radiation doses. No differences in cell cycle and apoptosis were found with any of the radiation doses used (30, 60, and 90 rads) compared with the unirradiated control (0 rad). At the same doses, however, differences were found in marker expression, such as keratin 18 (kl8), keratin 14 (k14), insulin-like growth factor I receptor (IGF-IR), and connexin 43 (cx43). This may indicate that radiation sensitivity in the heterozygous state may be initiated through signal transduction responses.

  4. Nonhomologous Pairing in Mice Heterozygous for a t Haplotype Can Produce Recombinant Chromosomes with Duplications and Deletions

    PubMed Central

    Sarvetnick, Nora; Fox, Howard S.; Mann, Elizabeth; Mains, Paul E.; Elliott, Rosemary W.; Silver, Lee M.

    1986-01-01

    We have investigated the structure and properties of a chromosomal product recovered from a rare recombination event between a t haplotype and a wild-type form of mouse chromosome 17. Our embryological and molecular studies indicate that this chromosome (twLub2 ) is characterized by both a deletion and duplication of adjacent genetic material. The deletion appears to be responsible for a dominant lethal maternal effect and a recessive embryonic lethality. The duplication provides an explanation for the twLub2 suppression of the dominant T locus phenotype. A reanalysis of previously described results with another chromosome 17 variant called TtOrl indicates a structure for this chromosome that is reciprocal to that observed for twLub2. We have postulated the existence of an inversion over the proximal portion of all complete t haplotypes in order to explain the generation of the partial t haplotypes t wLub2 and TtOrl. This proximal inversion and the previously described distal inversion are sufficient to account for all of the recombination properties that are characteristic of complete t haplotypes. The structures determined for twLub2 and TtOrl indicate that rare recombination can occur between nonequivalent genomic sequences within the inverted proximal t region when wild-type and t chromosomes are paired in a linear, nonhomologous configuration. PMID:3732789

  5. Compound heterozygous mutations in SLC30A2/ZnT2 results in low milk zinc concentrations: a novel mechanism for zinc deficiency in a breast-fed infant.

    PubMed

    Itsumura, Naoya; Inamo, Yasuji; Okazaki, Fumiko; Teranishi, Fumie; Narita, Hiroshi; Kambe, Taiho; Kodama, Hiroko

    2013-01-01

    Zinc concentrations in breast milk are considerably higher than those of the maternal serum, to meet the infant's requirements for normal growth and development. Thus, effective mechanisms ensuring secretion of large amounts of zinc into the milk operate in mammary epithelial cells during lactation. ZnT2 was recently found to play an essential role in the secretion of zinc into milk. Heterozygous mutations of human ZnT2 (hZnT2), including H54R and G87R, in mothers result in low (>75% reduction) secretion of zinc into the breast milk, and infants fed on the milk develop transient neonatal zinc deficiency. We identified two novel missense mutations in the SLC30A2/ZnT2 gene in a Japanese mother with low milk zinc concentrations (>90% reduction) whose infant developed severe zinc deficiency; a T to C transition (c.454T>C) at exon 4, which substitutes a tryptophan residue with an arginine residue (W152R), and a C to T transition (c.887C>T) at exon 7, which substitutes a serine residue with a leucine residue (S296L). Biochemical characterization using zinc-sensitive DT40 cells indicated that the W152R mutation abolished the abilities to transport zinc and to form a dimer complex, indicating a loss-of-function mutation. The S296L mutation retained both abilities but was extremely destabilized. The two mutations were found on different alleles, indicating that the genotype of the mother with low milk zinc was compound heterozygous. These results show novel compound heterozygous mutations in the SLC30A2/ZnT2 gene causing zinc deficiency in a breast-fed infant.

  6. Compound Heterozygous Mutations in SLC30A2/ZnT2 Results in Low Milk Zinc Concentrations: A Novel Mechanism for Zinc Deficiency in a Breast-Fed Infant

    PubMed Central

    Itsumura, Naoya; Inamo, Yasuji; Okazaki, Fumiko; Teranishi, Fumie; Narita, Hiroshi; Kambe, Taiho; Kodama, Hiroko

    2013-01-01

    Zinc concentrations in breast milk are considerably higher than those of the maternal serum, to meet the infant's requirements for normal growth and development. Thus, effective mechanisms ensuring secretion of large amounts of zinc into the milk operate in mammary epithelial cells during lactation. ZnT2 was recently found to play an essential role in the secretion of zinc into milk. Heterozygous mutations of human ZnT2 (hZnT2), including H54R and G87R, in mothers result in low (>75% reduction) secretion of zinc into the breast milk, and infants fed on the milk develop transient neonatal zinc deficiency. We identified two novel missense mutations in the SLC30A2/ZnT2 gene in a Japanese mother with low milk zinc concentrations (>90% reduction) whose infant developed severe zinc deficiency; a T to C transition (c.454T>C) at exon 4, which substitutes a tryptophan residue with an arginine residue (W152R), and a C to T transition (c.887C>T) at exon 7, which substitutes a serine residue with a leucine residue (S296L). Biochemical characterization using zinc-sensitive DT40 cells indicated that the W152R mutation abolished the abilities to transport zinc and to form a dimer complex, indicating a loss-of-function mutation. The S296L mutation retained both abilities but was extremely destabilized. The two mutations were found on different alleles, indicating that the genotype of the mother with low milk zinc was compound heterozygous. These results show novel compound heterozygous mutations in the SLC30A2/ZnT2 gene causing zinc deficiency in a breast-fed infant. PMID:23741301

  7. A novel loss-of-function heterozygous BRCA2 c.8946_8947delAG mutation found in a Chinese woman with family history of breast cancer.

    PubMed

    Ma, Jing; Yang, Jichun; Jian, Wenjing; Wang, Xianming; Xiao, Deyong; Xia, Wenjun; Xiong, Likuan; Ma, Duan

    2017-04-01

    Breast cancer is the most frequent female malignancy worldwide. Among them, some cases have hereditary susceptibility in two leading genes, BRCA1 and BRCA2. Heterozygous germ line mutations in them are related with increased risk of breast, ovarian and other cancer, following autosomal dominant inheritance mode. For purpose of early finding, early diagnosis and early treatment, mutation detecting of BRCA1/2 genes was performed in unselected 300 breast or ovarian patients and unaffected women using next-generation sequencing and then confirmed by Sanger sequencing. A non-previously reported heterozygous mutation c.8946_8947delAG (p.D2983FfsX34) of BRCA2 gene was identified in an unaffected Chinese woman with family history of breast cancer (her breast cancer mother, also carrying this mutation). The BRCA2-truncated protein resulted from the frame shift mutation was found to lose two putative nuclear localization signals and a Rad51-binding motif in the extreme C-terminal region by bioinformatic prediction. And then in vitro experiments showed that nearly all the mutant protein was unable to translocate to the nucleus to perform DNA repair activity. This novel mutant BRCA2 protein is dysfunction. We classify the mutation into disease causing and conclude that it is the risk factor for breast cancer in this family. So, conducting the same mutation test and providing genetic counseling for this family is practically meaningful and significant. Meanwhile, the identification of this new mutation enriches the Breast Cancer Information Core database, especially in China.

  8. Simultaneous Vascular Targeting and Tumor Targeting of Cerebral Breast Cancer Metastases Using a T-Cell Receptor Mimic Antibody

    DTIC Science & Technology

    2014-05-01

    in May 2013, the difference between nude mice (which lack T- cells , but still have a partially functional adaptive and innate immune system) and NSG...Mangada J, Greiner DL, Handgretinger R. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human...Targeting of Cerebral Breast Cancer Metastases Using a T- Cell Receptor Mimic Antibody PRINCIPAL INVESTIGATOR: Ulrich Bickel

  9. ATM, radiation, and the risk of second primary breast cancer.

    PubMed

    Bernstein, Jonine L; Concannon, Patrick

    2017-10-01

    It was first suggested more than 40 years ago that heterozygous carriers for the human autosomal recessive disorder Ataxia-Telangiectasia (A-T) might also be at increased risk for cancer. Subsequent studies have identified the responsible gene, Ataxia-Telangiectasia Mutated (ATM), characterized genetic variation at this locus in A-T and a variety of different cancers, and described the functions of the ATM protein with regard to cellular DNA damage responses. However, an overall model of how ATM contributes to cancer risk, and in particular, the role of DNA damage in this process, remains lacking. This review considers these questions in the context of contralateral breast cancer (CBC). Heterozygous carriers of loss of function mutations in ATM that are A-T causing, are at increased risk of breast cancer. However, examination of a range of genetic variants, both rare and common, across multiple cancers, suggests that ATM may have additional effects on cancer risk that are allele-dependent. In the case of CBC, selected common alleles at ATM are associated with a reduced incidence of CBC, while other rare and predicted deleterious variants may act jointly with radiation exposure to increase risk. Further studies that characterize germline and somatic ATM mutations in breast cancer and relate the detected genetic changes to functional outcomes, particularly with regard to radiation responses, are needed to gain a complete picture of the complex relationship between ATM, radiation and breast cancer.

  10. The risk for developing cancer in Israeli ATM, BLM, and FANCC heterozygous mutation carriers.

    PubMed

    Laitman, Yael; Boker-Keinan, Lital; Berkenstadt, Michal; Liphsitz, Irena; Weissglas-Volkov, Daphna; Ries-Levavi, Liat; Sarouk, Ifat; Pras, Elon; Friedman, Eitan

    2016-03-01

    Cancer risks in heterozygous mutation carriers of the ATM, BLM, and FANCC genes are controversial. To shed light on this issue, cancer rates were evaluated by cross referencing asymptomatic Israeli heterozygous mutation carriers in the ATM, BLM, and FANCC genes with cancer diagnoses registered at the Israeli National Cancer Registry (INCR). Comparison of observed to expected Standardized Incidence Rates (SIR) was performed. Overall, 474 individuals participated in the study: 378 females; 25 Arab and 31 Jewish ATM carriers, 152 BLM carriers, and 170 FANCC carriers (all Ashkenazim). Age range at genotyping was 19-53 years (mean + SD 30.6 + 5 years). In addition, 96 males were included; 5, 34, and 57 ATM, BLM, and FANCC mutation carriers, respectively. Over 5-16 years from genotyping (4721 person/years), 15 new cancers were diagnosed in mutation carriers: 5 breast, 4 cervical, 3 melanomas, and one each bone sarcoma, pancreatic, and colorectal cancer. No single cancer diagnosis was more prevalent then expected in all groups combined or per gene analyzed. Specifically breast cancer SIR was 0.02-0.77. We conclude that Israeli ATM, BLM, and FANCC heterozygous mutation carriers are not at an increased risk for developing cancer. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Heterozygous TGFBR2 mutations in Marfan syndrome

    PubMed Central

    Mizuguchi, Takeshi; Collod-Beroud, Gwenaëlle; Akiyama, Takushi; Abifadel, Marianne; Harada, Naoki; Morisaki, Takayuki; Allard, Delphine; Varret, Mathilde; Claustres, Mireille; Morisaki, Hiroko; Ihara, Makoto; Kinoshita, Akira; Yoshiura, Koh-ichiro; Junien, Claudine; Kajii, Tadashi; Jondeau, Guillaume; Ohta, Tohru; Kishino, Tatsuya; Furukawa, Yoichi; Nakamura, Yusuke; Niikawa, Norio; Boileau, Catherine; Matsumoto, Naomichi

    2004-01-01

    Marfan syndrome (MFS) is an extracellular matrix disorder with cardinal manifestations in the eye, skeleton, and cardiovascular systems and associated with defects in the fibrillin gene (FBN1) at 15q21.1 1. We previously mapped the second locus for MFS (MFS type 2, MFS2, OMIM *154705), at 3p24.2-p25 in a large French family (MS1)2. Identification of a 3p24.1 chromosomal breakpoint disrupting the TGF-beta receptor 2 gene (TGFBR2) in a Japanese MFS patient led us to consider TGFBR2 as the MSF2 gene. We found a Q508Q mutation of TGFBR2 that resulted in abnormal splicing and segregated with MFS2 in MS1. Three other missense mutations were found in four unrelated probands and were shown by luciferase-assays to lead to loss of function of the TGF-β signaling activity on extracellular matrix formation. These results show that heterozygous mutations in TGFBR2, a putative tumor suppressor gene implicated in several malignancies, are also associated with inherited connective-tissue disorders. PMID:15235604

  12. A new compound heterozygous CFTR mutation in a Chinese family with cystic fibrosis.

    PubMed

    Xie, Yingjun; Huang, Xueqiong; Liang, Yujian; Xu, Lingling; Pei, Yuxin; Cheng, Yucai; Zhang, Lidan; Tang, Wen

    2017-11-01

    Cystic fibrosis (CF) is the most common autosomal recessive disease among Caucasians but is rarer in the Chinese population, because mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. To elucidate the causative role of a novel compound heterozygous mutation of CF. In this study, clinical samples were obtained from two siblings with recurrent airway infections, clubbed fingers, salt-sweat and failure to gain weight in a non-consanguineous Chinese family. Next-generation sequencing was performed on the 27 coding exons of CFTR in both children, with confirmation by Sanger sequencing. Next-generation sequencing showed the same compound heterozygous CFTR mutation (c.865A>T p.Arg289X and c.3651_3652insAAAT p.Tyr1219X) in both children. As this mutation is consistent with the clinical manifestations of CF and no other mutations were detected after scanning the gene sequence, we suggest that the CF phenotype is caused by compound heterozygosity for c.865A>T and c.3651_3652insAAAT. As c865A>T is not currently listed in the "Cystic Fibrosis Mutation Database", this information about CF in a Chinese population is of interest. © 2015 John Wiley & Sons Ltd.

  13. FAK-heterozygous mice display enhanced tumour angiogenesis.

    PubMed

    Kostourou, Vassiliki; Lechertier, Tanguy; Reynolds, Louise E; Lees, Delphine M; Baker, Marianne; Jones, Dylan T; Tavora, Bernardo; Ramjaun, Antoine R; Birdsey, Graeme M; Robinson, Stephen D; Parsons, Maddy; Randi, Anna M; Hart, Ian R; Hodivala-Dilke, Kairbaan

    2013-01-01

    Genetic ablation of endothelial focal adhesion kinase (FAK) can inhibit pathological angiogenesis, suggesting that loss of endothelial FAK is sufficient to reduce neovascularization. Here we show that reduced stromal FAK expression in FAK-heterozygous mice unexpectedly enhances both B16F0 and CMT19T tumour growth and angiogenesis. We further demonstrate that cell proliferation and microvessel sprouting, but not migration, are increased in serum-stimulated FAK-heterozygous endothelial cells. FAK-heterozygous endothelial cells display an imbalance in FAK phosphorylation at pY397 and pY861 without changes in Pyk2 or Erk1/2 activity. By contrast, serum-stimulated phosphorylation of Akt is enhanced in FAK-heterozygous endothelial cells and these cells are more sensitive to Akt inhibition. Additionally, low doses of a pharmacological FAK inhibitor, although too low to affect FAK autophosphorylation in vitro, can enhance angiogenesis ex vivo and tumour growth in vivo. Our results highlight a potential novel role for FAK as a nonlinear, dose-dependent regulator of angiogenesis where heterozygous levels of FAK enhance angiogenesis.

  14. FAK-heterozygous mice display enhanced tumour angiogenesis

    PubMed Central

    Kostourou, Vassiliki; Lechertier, Tanguy; Reynolds, Louise E.; Lees, Delphine M.; Baker, Marianne; Jones, Dylan T.; Tavora, Bernardo; Ramjaun, Antoine R.; Birdsey, Graeme M.; Robinson, Stephen D.; Parsons, Maddy; Randi, Anna M.; Hart, Ian R; Hodivala-Dilke, Kairbaan

    2013-01-01

    Genetic ablation of endothelial Focal Adhesion Kinase (FAK) can inhibit pathological angiogenesis, suggesting that loss of endothelial FAK is sufficient to reduce neovascularisation. Here we show that reduced stromal-FAK expression in FAK-heterozygous mice unexpectedly enhances both B16F0 and CMT19T tumour growth and angiogenesis. We further demonstrate that cell proliferation and microvessel sprouting, but not migration, are increased in serum-stimulated FAK-heterozygous endothelial cells. FAK-heterozygous endothelial cells display an imbalance in FAK phosphorylation at pY397 and pY861 without changes in Pyk2 or Erk1/2 activity. By contrast, serum-stimulated phosphorylation of Akt is enhanced in FAK-heterozygous endothelial cells and these cells are more sensitive to Akt inhibition. Additionally, low doses of a pharmacological FAK inhibitor, although too low to affect FAK autophosphorylation in vitro, can enhance angiogenesis ex vivo and tumor growth in vivo. Our results highlight a potential novel role for FAK as a non-linear, dose-dependent regulator of angiogenesis where heterozygous levels of FAK enhance angiogenesis. PMID:23799510

  15. Behavioral and Electrophysiological Characterization of Dyt1 Heterozygous Knockout Mice

    PubMed Central

    Yokoi, Fumiaki; Chen, Huan-Xin; Dang, Mai Tu; Cheetham, Chad C.; Campbell, Susan L.; Roper, Steven N.; Sweatt, J. David; Li, Yuqing

    2015-01-01

    DYT1 dystonia is an inherited movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Most of the patients have a trinucleotide deletion (ΔGAG) corresponding to a glutamic acid in the C-terminal region (torsinAΔE). Dyt1 ΔGAG heterozygous knock-in (KI) mice, which mimic ΔGAG mutation in the endogenous gene, exhibit motor deficits and deceased frequency of spontaneous excitatory post-synaptic currents (sEPSCs) and normal theta-burst-induced long-term potentiation (LTP) in the hippocampal CA1 region. Although Dyt1 KI mice show decreased hippocampal torsinA levels, it is not clear whether the decreased torsinA level itself affects the synaptic plasticity or torsinAΔE does it. To analyze the effect of partial torsinA loss on motor behaviors and synaptic transmission, Dyt1 heterozygous knock-out (KO) mice were examined as a model of a frame-shift DYT1 mutation in patients. Consistent with Dyt1 KI mice, Dyt1 heterozygous KO mice showed motor deficits in the beam-walking test. Dyt1 heterozygous KO mice showed decreased hippocampal torsinA levels lower than those in Dyt1 KI mice. Reduced sEPSCs and normal miniature excitatory post-synaptic currents (mEPSCs) were also observed in the acute hippocampal brain slices from Dyt1 heterozygous KO mice, suggesting that the partial loss of torsinA function in Dyt1 KI mice causes action potential-dependent neurotransmitter release deficits. On the other hand, Dyt1 heterozygous KO mice showed enhanced hippocampal LTP, normal input-output relations and paired pulse ratios in the extracellular field recordings. The results suggest that maintaining an appropriate torsinA level is important to sustain normal motor performance, synaptic transmission and plasticity. Developing therapeutics to restore a normal torsinA level may help to prevent and treat the symptoms in DYT1 dystonia. PMID:25799505

  16. Behavioral and electrophysiological characterization of Dyt1 heterozygous knockout mice.

    PubMed

    Yokoi, Fumiaki; Chen, Huan-Xin; Dang, Mai Tu; Cheetham, Chad C; Campbell, Susan L; Roper, Steven N; Sweatt, J David; Li, Yuqing

    2015-01-01

    DYT1 dystonia is an inherited movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Most of the patients have a trinucleotide deletion (ΔGAG) corresponding to a glutamic acid in the C-terminal region (torsinA(ΔE)). Dyt1 ΔGAG heterozygous knock-in (KI) mice, which mimic ΔGAG mutation in the endogenous gene, exhibit motor deficits and deceased frequency of spontaneous excitatory post-synaptic currents (sEPSCs) and normal theta-burst-induced long-term potentiation (LTP) in the hippocampal CA1 region. Although Dyt1 KI mice show decreased hippocampal torsinA levels, it is not clear whether the decreased torsinA level itself affects the synaptic plasticity or torsinA(ΔE) does it. To analyze the effect of partial torsinA loss on motor behaviors and synaptic transmission, Dyt1 heterozygous knock-out (KO) mice were examined as a model of a frame-shift DYT1 mutation in patients. Consistent with Dyt1 KI mice, Dyt1 heterozygous KO mice showed motor deficits in the beam-walking test. Dyt1 heterozygous KO mice showed decreased hippocampal torsinA levels lower than those in Dyt1 KI mice. Reduced sEPSCs and normal miniature excitatory post-synaptic currents (mEPSCs) were also observed in the acute hippocampal brain slices from Dyt1 heterozygous KO mice, suggesting that the partial loss of torsinA function in Dyt1 KI mice causes action potential-dependent neurotransmitter release deficits. On the other hand, Dyt1 heterozygous KO mice showed enhanced hippocampal LTP, normal input-output relations and paired pulse ratios in the extracellular field recordings. The results suggest that maintaining an appropriate torsinA level is important to sustain normal motor performance, synaptic transmission and plasticity. Developing therapeutics to restore a normal torsinA level may help to prevent and treat the symptoms in DYT1 dystonia.

  17. Heterozygous RTEL1 mutations are associated with familial pulmonary fibrosis.

    PubMed

    Kannengiesser, Caroline; Borie, Raphael; Ménard, Christelle; Réocreux, Marion; Nitschké, Patrick; Gazal, Steven; Mal, Hervé; Taillé, Camille; Cadranel, Jacques; Nunes, Hilario; Valeyre, Dominique; Cordier, Jean François; Callebaut, Isabelle; Boileau, Catherine; Cottin, Vincent; Grandchamp, Bernard; Revy, Patrick; Crestani, Bruno

    2015-08-01

    Pulmonary fibrosis is a fatal disease with progressive loss of respiratory function. Defective telomere maintenance leading to telomere shortening is a cause of pulmonary fibrosis, as mutations in the telomerase component genes TERT (reverse transcriptase) and TERC (RNA component) are found in 15% of familial pulmonary fibrosis (FPF) cases. However, so far, about 85% of FPF remain genetically uncharacterised.Here, in order to identify new genetic causes of FPF, we performed whole-exome sequencing, with a candidate-gene approach, of 47 affected subjects from 35 families with FPF without TERT and TERC mutations.We identified heterozygous mutations in regulator of telomere elongation helicase 1 (RTEL1) in four families. RTEL1 is a DNA helicase with roles in DNA replication, genome stability, DNA repair and telomere maintenance. The heterozygous RTEL1 mutations segregated as an autosomal dominant trait in FPF, and were predicted by structural analyses to severely affect the function and/or stability of RTEL1. In agreement with this, RTEL1-mutated patients exhibited short telomeres in comparison with age-matched controls.Our results provide evidence that heterozygous RTEL1 mutations are responsible for FPF and, thereby, extend the clinical spectrum of RTEL1 deficiency. Thus, RTEL1 enlarges the number of telomere-associated genes implicated in FPF. Copyright ©ERS 2015.

  18. Classical phenotype of Laron syndrome in a girl with a heterozygous mutation and heterozygous polymorphism of the growth hormone receptor gene.

    PubMed

    Shevah, Orit; Galli-Tsinopoulou, Assimina; Rubinstein, Menachem; Nousia-Arvanitakis, Sanda; Laron, Zvi

    2004-03-01

    We describe here a 19 month-old girl with classical Laron syndrome (LS). Molecular analysis of the GH receptor gene in the patient and her parents was performed. The patient was found to be heterozygous for a mutation in exon 4 (R43X) and heterozygous for a polymorphism in exon 6 (Gly168Gly). Her mother was also heterozygous for R43X but homozygous for the polymorphism. In the father, a heterozygous polymorphism was found. Contrary to previous assumptions that only homozygous patients express the typical phenotype, this patient shows all the classical features of LS, despite being a heterozygote for a pathological defect.

  19. Atm heterozygous mice are more sensitive to radiation-induced cataracts than are their wild-type counterparts

    PubMed Central

    Worgul, Basil V.; Smilenov, Lubomir; Brenner, David J.; Junk, Anna; Zhou, Wei; Hall, Eric J.

    2002-01-01

    It is important to know whether the human population includes genetically predisposed radiosensitive subsets. In vitro studies have shown that cells from individuals homozygous for ataxia telangiectasia (A-T) are much more radiosensitive than cells from unaffected individuals. Although cells heterozygous for the ATM gene (ATM+/−) may be slightly more radiosensitive in vitro, it remained to be determined whether the greater susceptibility of ATM+/− cells translates into an increased sensitivity for late effects in vivo, though there is a suggestion that radiotherapy patients that are heterozygous for the ATM gene may be more at risk of developing late normal tissue damage. We chose cataractogenesis in the lens as a means to assay for the effects of ATM deficiency in a late-responding tissue. One eye of wild-type, Atm heterozygous and homozygous knockout mice was exposed to 0.5-, 1.0-, 2.0-, or 4.0-Gy x rays. The animals were followed weekly for cataract development by conventional slit-lamp biomicroscopy. Cataract development in the animals of all three groups was strongly dependent on dose. The lenses of homozygous mice were the first to opacify at any given dose. Most important in the present context is that cataracts appeared earlier in the heterozygous versus wild-type animals. The data suggest that ATM heterozygotes in the human population may also be radiosensitive. This may influence the choice of individuals destined to be exposed to higher than normal doses of radiation, such as astronauts, and may also suggest that radiotherapy patients who are ATM heterozygotes could be predisposed to increased late normal tissue damage. PMID:12119422

  20. Atm heterozygous mice are more sensitive to radiation-induced cataracts than are their wild-type counterparts

    NASA Technical Reports Server (NTRS)

    Worgul, Basil V.; Smilenov, Lubomir; Brenner, David J.; Junk, Anna; Zhou, Wei; Hall, Eric J.

    2002-01-01

    It is important to know whether the human population includes genetically predisposed radiosensitive subsets. In vitro studies have shown that cells from individuals homozygous for ataxia telangiectasia (A-T) are much more radiosensitive than cells from unaffected individuals. Although cells heterozygous for the ATM gene (ATM(+/-)) may be slightly more radiosensitive in vitro, it remained to be determined whether the greater susceptibility of ATM(+/-) cells translates into an increased sensitivity for late effects in vivo, though there is a suggestion that radiotherapy patients that are heterozygous for the ATM gene may be more at risk of developing late normal tissue damage. We chose cataractogenesis in the lens as a means to assay for the effects of ATM deficiency in a late-responding tissue. One eye of wild-type, Atm heterozygous and homozygous knockout mice was exposed to 0.5-, 1.0-, 2.0-, or 4.0-Gy x rays. The animals were followed weekly for cataract development by conventional slit-lamp biomicroscopy. Cataract development in the animals of all three groups was strongly dependent on dose. The lenses of homozygous mice were the first to opacify at any given dose. Most important in the present context is that cataracts appeared earlier in the heterozygous versus wild-type animals. The data suggest that ATM heterozygotes in the human population may also be radiosensitive. This may influence the choice of individuals destined to be exposed to higher than normal doses of radiation, such as astronauts, and may also suggest that radiotherapy patients who are ATM heterozygotes could be predisposed to increased late normal tissue damage.

  1. Heterozygous defects in PAX6 gene and congenital hypopituitarism.

    PubMed

    Takagi, Masaki; Nagasaki, Keisuke; Fujiwara, Ikuma; Ishii, Tomohiro; Amano, Naoko; Asakura, Yumi; Muroya, Koji; Hasegawa, Yukihiro; Adachi, Masanori; Hasegawa, Tomonobu

    2015-01-01

    The prevalence of congenital hypopituitarism (CH) attributable to known transcription factor mutations appears to be rare and other causative genes for CH remain to be identified. Due to the sporadic occurrence of CH, de novo chromosomal rearrangements could be one of the molecular mechanisms participating in its etiology, especially in syndromic cases. To identify the role of copy number variations (CNVs) in the etiology of CH and to identify novel genes implicated in CH. We enrolled 88 (syndromic: 30; non-syndromic: 58) Japanese CH patients. We performed an array comparative genomic hybridization screening in the 30 syndromic CH patients. For all the 88 patients, we analyzed PAX6 by PCR-based sequencing. We identified one heterozygous 310-kb deletion of the PAX6 enhancer region in one patient showing isolated GH deficiency (IGHD), cleft palate, and optic disc cupping. We also identified one heterozygous 6.5-Mb deletion encompassing OTX2 in a patient with bilateral anophthalmia and multiple pituitary hormone deficiency. We identified a novel PAX6 mutation, namely p.N116S in one non-syndromic CH patient showing IGHD. The p.N116S PAX6 was associated with an impairment of the transactivation capacities of the PAX6-binding elements. This study showed that heterozygous PAX6 mutations are associated with CH patients. PAX6 mutations may be associated with diverse clinical features ranging from severely impaired ocular and pituitary development to apparently normal phenotype. Overall, this study identified causative CNVs with a possible role in the etiology of CH in <10% of syndromic CH patients. © 2015 European Society of Endocrinology.

  2. Heterozygous familial hypercholesterolemia: an underrecognized cause of early cardiovascular disease.

    PubMed

    Yuan, George; Wang, Jian; Hegele, Robert A

    2006-04-11

    Heterozygous familial hypercholesterolemia (HeFH) is a monogenic disorder that affects about 1 in 500 people, with a higher prevalence in certain subpopulations such as people of Quebecois, Christian Lebanese and Dutch South Afrikaner extraction. HeFH is characterized by cholesterol deposits affecting the corneas, eyelids and extensor tendons; elevated plasma concentrations of low-density lipoprotein (LDL) cholesterol; and accelerated vascular disease, especially coronary artery disease (CAD). Although HeFH is genetically heterogeneous, it is most often caused by heterozygous mutations in the LDLR gene encoding the LDL receptor. We describe a man who was diagnosed with HeFH after he had a myocardial infarction at 33 years of age. By DNA sequence analysis, he was found to have a heterozygous splicing mutation in his LDLR gene. This discovery expanded the growing mutational spectrum in patients with HeFH in Ontario. Given that HeFH is a treatable cause of early vascular disease, it is important that this condition be recognized, diagnosed and treated in affected patients; but as yet, there is no consensus on the best approach. Diagnostic criteria based on family history and clinical presentation have been proposed for patients with suspected HeFH. Biochemical or molecular screening might be considered to detect new cases of HeFH in populations with a relatively high HeFH prevalence and a relatively small number of possible causative mutations. So far, however, the most cost-effective and efficient systematic strategy to detect previously undiagnosed cases of HeFH is still cascade testing: clinical and biochemical screening of close relatives of the proband patient diagnosed with HeFH. Pharmacologic treatment of HeFH is cost-effective.

  3. Heterozygous familial hypercholesterolemia: an underrecognized cause of early cardiovascular disease

    PubMed Central

    Yuan, George; Wang, Jian; Hegele, Robert A.

    2006-01-01

    Heterozygous familial hypercholesterolemia (HeFH) is a monogenic disorder that affects about 1 in 500 people, with a higher prevalence in certain subpopulations such as people of Quebecois, Christian Lebanese and Dutch South Afrikaner extraction. HeFH is characterized by cholesterol deposits affecting the corneas, eyelids and extensor tendons; elevated plasma concentrations of low-density lipoprotein (LDL) cholesterol; and accelerated vascular disease, especially coronary artery disease (CAD). Although HeFH is genetically heterogeneous, it is most often caused by heterozygous mutations in the LDLR gene encoding the LDL receptor. We describe a man who was diagnosed with HeFH after he had a myocardial infarction at 33 years of age. By DNA sequence analysis, he was found to have a heterozygous splicing mutation in his LDLR gene. This discovery expanded the growing mutational spectrum in patients with HeFH in Ontario. Given that HeFH is a treatable cause of early vascular disease, it is important that this condition be recognized, diagnosed and treated in affected patients; but as yet, there is no consensus on the best approach. Diagnostic criteria based on family history and clinical presentation have been proposed for patients with suspected HeFH. Biochemical or molecular screening might be considered to detect new cases of HeFH in populations with a relatively high HeFH prevalence and a relatively small number of possible causative mutations. So far, however, the most cost-effective and efficient systematic strategy to detect previously undiagnosed cases of HeFH is still cascade testing: clinical and biochemical screening of close relatives of the proband patient diagnosed with HeFH. Pharmacologic treatment of HeFH is cost-effective. PMID:16606962

  4. Primary microcephaly caused by novel compound heterozygous mutations in ASPM

    PubMed Central

    Okamoto, Nobuhiko; Kohmoto, Tomohiro; Naruto, Takuya; Masuda, Kiyoshi; Imoto, Issei

    2018-01-01

    Autosomal recessive primary microcephaly (microcephaly primary hereditary, MCPH) is a genetically heterogeneous rare developmental disorder that is characterized by prenatal onset of abnormal brain growth, which leads to intellectual disability of variable severity. We report a 5-year-old male who presented with a severe form of primary microcephaly. Targeted panel sequencing revealed compound heterozygous truncating mutations of the abnormal spindle-like microcephaly-associated (ASPM) gene, which confirmed the MCPH5 diagnosis. A novel NM_018136.4: c.9742_9745del (p.Lys3248Serfs*13) deletion mutation was identified. PMID:29644084

  5. Primary microcephaly caused by novel compound heterozygous mutations in ASPM.

    PubMed

    Okamoto, Nobuhiko; Kohmoto, Tomohiro; Naruto, Takuya; Masuda, Kiyoshi; Imoto, Issei

    2018-01-01

    Autosomal recessive primary microcephaly (microcephaly primary hereditary, MCPH) is a genetically heterogeneous rare developmental disorder that is characterized by prenatal onset of abnormal brain growth, which leads to intellectual disability of variable severity. We report a 5-year-old male who presented with a severe form of primary microcephaly. Targeted panel sequencing revealed compound heterozygous truncating mutations of the abnormal spindle-like microcephaly-associated ( ASPM ) gene, which confirmed the MCPH5 diagnosis. A novel NM_018136.4: c.9742_9745del (p.Lys3248Serfs*13) deletion mutation was identified.

  6. [Molecular characterization of heterozygous beta-thalassemia in Lanzarote, Spain].

    PubMed

    Calvo-Villas, José Manuel; de la Iglesia Iñigo, Silvia; Ropero Gradilla, Paloma; Zapata Ramos, María Francisca; Cuesta Tovar, Jorge; Sicilia Guillén, Francisco

    2008-04-05

    The aim of this study was to determine the molecular defects of heterozygous beta thalassaemia and to ascertain their distribution in Lanzarote. Molecular characterization was achieved by real time polymerase chain reaction (RT-PCR LightCycler, Roche), PCR-ARMS (PCR-amplification reaction mutations system) and DNA sequencing on an automated DNA sequencer. Two hundred forty-three heterozygous beta thalassaemia carriers were included between July 1991 and February 2007. RT-PCR detected the molecular defect in 81% of the beta thalassaemia chromosomes analyzed [113 codon CD 39 (C --> T); 41 IVS-1-nt-110 (G --> A), 25 IVS 1-nt-1 (G --> A) and 19 IVS 1-nt-6 (T --> C)]. The remaining 12 molecular defects included the deletion 619 bp (7.8%) and the mutations -28 (A --> G), IVS1-nt-2 (T --> G), CD 41/42 (-TTCT), CD 8/9 (+G), CD 51 (-C), CD 22 (G --> T) and CD 24 (T --> A), CD 67 (-TG) and the novel mutation CD 20/21-TGGA. The distribution of the mutations is similar to that found in the Mediterranean area. The increasing migratory flow received in the Canary Islands may explain the emergence of new mutations not reported before in our area.

  7. Clinical and functional characterization of a patient carrying a compound heterozygous pericentrin mutation and a heterozygous IGF1 receptor mutation.

    PubMed

    Müller, Eva; Dunstheimer, Desiree; Klammt, Jürgen; Friebe, Daniela; Kiess, Wieland; Kratzsch, Jürgen; Kruis, Tassilo; Laue, Sandy; Pfäffle, Roland; Wallborn, Tillmann; Heidemann, Peter H

    2012-01-01

    Intrauterine and postnatal longitudinal growth is controlled by a strong genetic component that regulates a complex network of endocrine factors integrating them with cellular proliferation, differentiation and apoptotic processes in target tissues, particularly the growth centers of the long bones. Here we report on a patient born small for gestational age (SGA) with severe, proportionate postnatal growth retardation, discreet signs of skeletal dysplasia, microcephaly and moyamoya disease. Initial genetic evaluation revealed a novel heterozygous IGF1R p.Leu1361Arg mutation affecting a highly conserved residue with the insulin-like growth factor type 1 receptor suggestive for a disturbance within the somatotropic axis. However, because the mutation did not co-segregate with the phenotype and functional characterization did not reveal an obvious impairment of the ligand depending major IGF1R signaling capabilities a second-site mutation was assumed. Mutational screening of components of the somatotropic axis, constituents of the IGF signaling system and factors involved in cellular proliferation, which are described or suggested to provoke syndromic dwarfism phenotypes, was performed. Two compound heterozygous PCNT mutations (p.[Arg585X];[Glu1774X]) were identified leading to the specification of the diagnosis to MOPD II. These investigations underline the need for careful assessment of all available information to derive a firm diagnosis from a sequence aberration.

  8. Clinical and Functional Characterization of a Patient Carrying a Compound Heterozygous Pericentrin Mutation and a Heterozygous IGF1 Receptor Mutation

    PubMed Central

    Klammt, Jürgen; Friebe, Daniela; Kiess, Wieland; Kratzsch, Jürgen; Kruis, Tassilo; Laue, Sandy; Pfäffle, Roland; Wallborn, Tillmann; Heidemann, Peter H.

    2012-01-01

    Intrauterine and postnatal longitudinal growth is controlled by a strong genetic component that regulates a complex network of endocrine factors integrating them with cellular proliferation, differentiation and apoptotic processes in target tissues, particularly the growth centers of the long bones. Here we report on a patient born small for gestational age (SGA) with severe, proportionate postnatal growth retardation, discreet signs of skeletal dysplasia, microcephaly and moyamoya disease. Initial genetic evaluation revealed a novel heterozygous IGF1R p.Leu1361Arg mutation affecting a highly conserved residue with the insulin-like growth factor type 1 receptor suggestive for a disturbance within the somatotropic axis. However, because the mutation did not co-segregate with the phenotype and functional characterization did not reveal an obvious impairment of the ligand depending major IGF1R signaling capabilities a second-site mutation was assumed. Mutational screening of components of the somatotropic axis, constituents of the IGF signaling system and factors involved in cellular proliferation, which are described or suggested to provoke syndromic dwarfism phenotypes, was performed. Two compound heterozygous PCNT mutations (p.[Arg585X];[Glu1774X]) were identified leading to the specification of the diagnosis to MOPD II. These investigations underline the need for careful assessment of all available information to derive a firm diagnosis from a sequence aberration. PMID:22693602

  9. Atypical Progeroid Syndrome due to Heterozygous Missense LMNA Mutations

    PubMed Central

    Garg, Abhimanyu; Subramanyam, Lalitha; Agarwal, Anil K.; Simha, Vinaya; Levine, Benjamin; D'Apice, Maria Rosaria; Novelli, Giuseppe; Crow, Yanick

    2009-01-01

    Context: Hutchinson-Gilford progeria syndrome (HGPS) and mandibuloacral dysplasia are well-recognized allelic autosomal dominant and recessive progeroid disorders, respectively, due to mutations in lamin A/C (LMNA) gene. Heterozygous LMNA mutations have also been reported in a small number of patients with a less well-characterized atypical progeroid syndrome (APS). Objective: The objective of the study was to investigate the underlying genetic and molecular basis of the phenotype of patients presenting with APS. Results: We report 11 patients with APS from nine families, many with novel heterozygous missense LMNA mutations, such as, P4R, E111K, D136H, E159K, and C588R. These and previously reported patients now reveal a spectrum of clinical features including progeroid manifestations such as short stature, beaked nose, premature graying, partial alopecia, high-pitched voice, skin atrophy over the hands and feet, partial and generalized lipodystrophy with metabolic complications, and skeletal anomalies such as mandibular hypoplasia and mild acroosteolysis. Skin fibroblasts from these patients when assessed for lamin A/C expression using epifluorescence microscopy revealed variable nuclear morphological abnormalities similar to those observed in patients with HGPS. However, these nuclear abnormalities in APS patients could not be rescued with 48 h treatment with farnesyl transferase inhibitors, geranylgeranyl transferase inhibitors or trichostatin-A, a histone deacetylase inhibitor. Immunoblots of cell lysates from fibroblasts did not reveal prelamin A accumulation in any of these patients. Conclusions: APS patients have a few overlapping but some distinct clinical features as compared with HGPS and mandibuloacral dysplasia. The pathogenesis of clinical manifestations in APS patients seems not to be related to accumulation of mutant farnesylated prelamin A. PMID:19875478

  10. Novel treatment options for the management of heterozygous familial hypercholesterolemia.

    PubMed

    Polychronopoulos, Georgios; Tziomalos, Konstantinos

    2017-12-01

    Even though statins represent the mainstay of treatment of heterozygous familial hypercholesterolemia (FH), their low-density lipoprotein cholesterol (LDL-C) lowering efficacy is finite and most patients with FH will not achieve LDL-C targets with statin monotherapy. Addition of ezetimibe with or without bile acid sequestrants will also not lead to treatment goals in many of these patients, particularly in those with established cardiovascular disease. In this selected subgroup of the FH population, proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors provide substantial reductions in LDL-C levels, reduce cardiovascular morbidity and appear to be safe. Mipomersen, an antisense single-strand oligonucleotide that inhibits the production of apoB by binding to the mRNA that encodes the synthesis of apoB, and lomitapide, an inhibitor of microsomal triglyceride transfer protein, also reduce LDL-C levels but are currently indicated only for the management of homozygous FH. Areas covered: In the present review, the role of PCSK9 inhibitors, mipomersen and lomitapide in the management of FH is briefly discussed. Other LDL-C-lowering agents under evaluation include inclisiran, a small interference RNA molecule that induces long-term inhibition of PSCK9 synthesis, anacetrapib, a cholesterol ester-transfer protein inhibitor, ETC-1002 (bempedoic acid), an inhibitor of adenosine triphosphate citrate lyase, and gemcabene, which reduces hepatic apolipoprotein C-III mRNA. The safety and efficacy of these agents are also reviewed. Expert Commentary: Even though several novel treatment options for heterozygous FH are under development, it remains to be shown whether these treatments will also reduce cardiovascular morbidity in these high-risk patients.

  11. Cell and Molecular Biology of Ataxia Telangiectasia Heterozygous Human Mammary Epithelial Cells Irradiated in Culture

    NASA Technical Reports Server (NTRS)

    Richmond, Robert C.

    2001-01-01

    Autologous isolates of cell types from obligate heterozygotes with the autosomal disorder ataxia-telangiectasia (A-T)were used to begin a tissue culture model for assessing pathways of radiation-induced cancer formation in this target tissue. This was done by establishing cultures of stromal fibroblasts and long-term growth human mammary epithelial cells (HMEC) in standard 2-dimensional tissue culture in order to establish expression of markers detailing early steps of carcinogenesis. The presumptive breast cancer susceptibility of A-T heterozygotes as a sequel to damage caused by ionizing radiation provided reason to study expression of markers in irradiated HMEC. Findings from our study with HMEC have included determination of differences in specific protein expression amongst growth phase (e.g., log vs stationary) and growth progression (e.g., pass 7 vs pass 9), as well as differences in morphologic markers within populations of irradiated HMEC (e.g., development of multinucleated cells).

  12. Association of Allelic Interaction of Single Nucleotide Polymorphisms of Influx and Efflux Transporters Genes With Nonhematologic Adverse Events of Docetaxel in Breast Cancer Patients.

    PubMed

    Jabir, Rafid Salim; Ho, Gwo Fuang; Annuar, Muhammad Azrif Bin Ahmad; Stanslas, Johnson

    2018-05-04

    Nonhematologic adverse events (AEs) of docetaxel constitute an extra burden in the treatment of cancer patients and necessitate either a dose reduction or an outright switch of docetaxel for other regimens. These AEs are frequently associated with genetic polymorphisms of genes encoding for proteins involved docetaxel disposition. Therefore, we investigated that association in Malaysian breast cancer patients. A total of 110 Malaysian breast cancer patients were enrolled in the present study, and their blood samples were investigated for different single nucleotide polymorphisms using polymerase chain reaction restriction fragment length polymorphism. AEs were evaluated using the Common Terminology Criteria for Adverse Events, version 4.0. Fatigue, nausea, oral mucositis, and vomiting were the most common nonhematologic AEs. Rash was associated with heterozygous and mutant genotypes of ABCB1 3435C>T (P < .05). Moreover, patients carrying the GG genotype of ABCB1 2677G>A/T reported more fatigue than those carrying the heterozygous genotype GA (P < .05). The presence of ABCB1 3435-T, ABCC2 3972-C, ABCC2 1249-G, and ABCB1 2677-G alleles was significantly associated with nausea and oral mucositis. The coexistence of ABCB1 3435-C, ABCC2 3972-C, ABCC2 1249-G, and ABCB1 2677-A was significantly associated with vomiting (P < .05). The prevalence of nonhematologic AEs in breast cancer patients treated with docetaxel has been relatively high. The variant allele of ABCB1 3435C>T polymorphism could be a potential predictive biomarker of docetaxel-induced rash, and homozygous wild-type ABCB1 2677G>A/T might predict for a greater risk of fatigue. In addition, the concurrent presence of specific alleles could be predictive of vomiting, nausea, and oral mucositis. Copyright © 2018 Elsevier Inc. All rights reserved.

  13. Evidence for Mitotic Recombination in W(ei)/+ Heterozygous Mice

    PubMed Central

    Panthier, J. J.; Guenet, J. L.; Condamine, H.; Jacob, F.

    1990-01-01

    A number of alleles at coat color loci of the house mouse give rise to areas of wild-type pigmentation on the coats of otherwise mutant animals. Such unstable alleles include both recessive and dominant mutations. Among the latter are several alleles at the W locus. In this report, phenotypic reversions of the W(ei) allele at the W locus were studied Mice heterozygous in repulsion for both W(ei) and buff (bf) [i.e. W(ei)+/+bf] were examined for the occurrence of phenotypic reversion events. Buff (bf) is a recessive mutation, which lies 21 cM from W on the telomeric side of chromosome 5 and is responsible for the khaki colored coat of nonagouti buff homozygotes (a/a; bf/bf). Two kinds of fully pigmented reversion spots were recovered on the coats of a/a; W(ei)+/+bf mice: either solid black or khaki colored. Furthermore phenotypic reversions of W(ei)/+ were enhanced significantly following X-irradiation of 9.25-day-old W(ei)/+ embryos (P < 0.04). These observations are consistent with the suggestion of a role for mitotic recombination in the origin of these phenotypic reversions. In addition these results rise the intriguing possibility that some W mutations may enhance mitotic recombination in the house mouse. PMID:2341029

  14. Norepinephrine Transporter Heterozygous Knockout Mice Exhibit Altered Transport and Behavior

    PubMed Central

    Fentress, HM; Klar, R; Krueger, JK; Sabb, T; Redmon, SN; Wallace, NM; Shirey-Rice, JK; Hahn, MK

    2013-01-01

    The norepinephrine (NE) transporter (NET) regulates synaptic NE availability for noradrenergic signaling in the brain and sympathetic nervous system. Although genetic variation leading to a loss of NET expression has been implicated in psychiatric and cardiovascular disorders, complete NET deficiency has not been found in people, limiting the utility of NET knockout mice as a model for genetically-driven NET dysfunction. Here, we investigate NET expression in NET heterozygous knockout male mice (NET+/−), demonstrating that they display an ~50% reduction in NET protein levels. Surprisingly, these mice display no significant deficit in NET activity, assessed in hippocampal and cortical synaptosomes. We found that this compensation in NET activity was due to enhanced activity of surface-resident transporters, as opposed to surface recruitment of NET protein or compensation through other transport mechanisms, including serotonin, dopamine or organic cation transporters. We hypothesize that loss of NET protein in the NET+/− mouse establishes an activated state of existing, surface NET proteins. NET+/− mice exhibit increased anxiety in the open field and light-dark box and display deficits in reversal learning in the Morris Water Maze. These data suggest recovery of near basal activity in NET+/− mice appears to be insufficient to limit anxiety responses or support cognitive performance that might involve noradrenergic neurotransmission. The NET+/− mice represent a unique model to study the loss and resultant compensatory changes in NET that may be relevant to behavior and physiology in human NET deficiency disorders. PMID:24102798

  15. Stress testing response in women heterozygous for familial hypercholesterolemia.

    PubMed

    Kolovou, Genovefa D; Damaskos, Dimitris S; Anagnostopoulou, Katherine K; Salpea, Klelia D; Dritsas, Athanasios; Giannakopoulou, Vasiliki; Vasiliadis, Ioannis K; Cokkinos, Dennis V

    2007-10-31

    We evaluated 62 exercise treadmill tests (ETTs) in equal numbers of heterozygous for familial hypercholesterolemia (hFH) and healthy (HLY) women, matched for age, baseline systolic and diastolic blood pressure (BP) and baseline heart rate (HR), using the Bruce protocol. Both groups had similar rate pressure product (RPP) and workload in metabolic equivalents (METs) (27,563+/-3124 vs. 29,090+/-4077, p=0.103 and 11.2+/-1.7 vs. 11.5+/-1.8, p=0.473, respectively). Women with hFH had lower delta (difference of peak to baseline) and peak exercise systolic and diastolic BP (systolic: 48+/-12 vs. 58+/-17 mmHg, p=0.010 and 167+/-19 vs. 177+/-17 mmHg, p=0.042, respectively; diastolic: 11+/-7 vs. 15+/-7 mmHg, p=0.028 and 85+/-7 vs. 91+/-7 mmHg, p<0.001, respectively). Furthermore, women with hFH had higher delta percentage (%) of HR, compared to HLY; (106+/-25 vs. 95+/-20, p=0.047). In conclusion, hFH women possibly have an inadequate rise in systolic BP during ETT. Diastolic BP increased more in the HLY than in the hFH group, but still remained within normal limits. These findings may reflect preclinical changes of atherosclerosis in hFH women, however further research should be undertaken.

  16. Heterozygous ABCC8 mutations are a cause of MODY.

    PubMed

    Bowman, P; Flanagan, S E; Edghill, E L; Damhuis, A; Shepherd, M H; Paisey, R; Hattersley, A T; Ellard, S

    2012-01-01

    The ABCC8 gene encodes the sulfonylurea receptor 1 (SUR1) subunit of the pancreatic beta cell ATP-sensitive potassium (K(ATP)) channel. Inactivating mutations cause congenital hyperinsulinism (CHI) and activating mutations cause transient neonatal diabetes (TNDM) or permanent neonatal diabetes (PNDM) that can usually be treated with sulfonylureas. Sulfonylurea sensitivity is also a feature of HNF1A and HNF4A MODY, but patients referred for genetic testing with clinical features of these types of diabetes do not always have mutations in the HNF1A/4A genes. Our aim was to establish whether mutations in the ABCC8 gene cause MODY that is responsive to sulfonylurea therapy. We sequenced the ABCC8 gene in 85 patients with a BMI <30 kg/m², no family history of neonatal diabetes and who were deemed sensitive to sulfonylureas by the referring clinician or were sulfonylurea-treated. All had tested negative for mutations in the HNF1A and HNF4A genes. ABCC8 mutations were found in seven of the 85 (8%) probands. Four patients were heterozygous for previously reported mutations and four novel mutations, E100K, G214R, Q485R and N1245D, were identified. Only four probands fulfilled MODY criteria, with two diagnosed after 25 years and one patient, who had no family history of diabetes, as a result of a proven de novo mutation. ABCC8 mutations can cause MODY in patients whose clinical features are similar to those with HNF1A/4A MODY. Therefore, sequencing of ABCC8 in addition to the known MODY genes should be considered if such features are present, to facilitate optimal clinical management of these patients.

  17. Dental Abnormalities Caused by Novel Compound Heterozygous CTSK Mutations.

    PubMed

    Xue, Y; Wang, L; Xia, D; Li, Q; Gao, S; Dong, M; Cai, T; Shi, S; He, L; Hu, K; Mao, T; Duan, X

    2015-05-01

    Cathepsin K (CTSK) is an important protease responsible for degrading type I collagen, osteopontin, and other bone matrix proteins. The mutations in the CTSK gene can cause pycnodysostosis (OMIM 265800), a rare autosomal recessive bone dysplasia. Patients with pycnodysostosis have been reported to present specific dental abnormalities; however, whether these dental abnormalities are related to dysfunctional CTSK has never been reported. Here we investigated the histologic changes of cementum and alveolar bone in a pycnodysostosis patient, caused by novel compound heterozygous mutations in the CTSK gene (c.87 G>A p.W29X and c.848 A>G p.Y283C). The most impressive manifestations in tooth were extensive periradicular high-density clumps with unclear periodontal space by orthopantomography examination and micro-computed tomography scanning analysis. Hematoxylin/eosin and toluidine blue staining and atomic force microscopy analysis showed that the cementum became significantly thickened, softened, and full of cementocytes. The disorganized bone structure was the main character of alveolar bone. The p.W29X mutation may represent the loss-of-function allele with an earlier termination codon in the precursor CTSK polypeptide. Residue Y283 is highly conserved among papain-like cysteine proteases. Three-dimensional structure modeling analysis found that the loss of the hydroxybenzene residue in the Y283C mutation would interrupt the hydrogen network and possibly affect the self-cleavage of the CTSK enzyme. Furthermore, p.Y283C mutation did not affect the mRNA and protein levels of overexpressed CTSK in COS-7 system but did reduce CTSK enzyme activity. In conclusion, the histologic and ultrastructural changes of cementum and alveolar bone might be affected by CTSK mutation via reduction of its enzyme activity (clinical trial registration: ChiCTR-TNC-10000876). © International & American Associations for Dental Research 2015.

  18. Norepinephrine transporter heterozygous knockout mice exhibit altered transport and behavior.

    PubMed

    Fentress, H M; Klar, R; Krueger, J J; Sabb, T; Redmon, S N; Wallace, N M; Shirey-Rice, J K; Hahn, M K

    2013-11-01

    The norepinephrine (NE) transporter (NET) regulates synaptic NE availability for noradrenergic signaling in the brain and sympathetic nervous system. Although genetic variation leading to a loss of NET expression has been implicated in psychiatric and cardiovascular disorders, complete NET deficiency has not been found in people, limiting the utility of NET knockout mice as a model for genetically driven NET dysfunction. Here, we investigate NET expression in NET heterozygous knockout male mice (NET(+/-) ), demonstrating that they display an approximately 50% reduction in NET protein levels. Surprisingly, these mice display no significant deficit in NET activity assessed in hippocampal and cortical synaptosomes. We found that this compensation in NET activity was due to enhanced activity of surface-resident transporters, as opposed to surface recruitment of NET protein or compensation through other transport mechanisms, including serotonin, dopamine or organic cation transporters. We hypothesize that loss of NET protein in the NET(+/-) mouse establishes an activated state of existing surface NET proteins. The NET(+/-) mice exhibit increased anxiety in the open field and light-dark box and display deficits in reversal learning in the Morris water maze. These data suggest that recovery of near basal activity in NET(+/-) mice appears to be insufficient to limit anxiety responses or support cognitive performance that might involve noradrenergic neurotransmission. The NET(+/-) mice represent a unique model to study the loss and resultant compensatory changes in NET that may be relevant to behavior and physiology in human NET deficiency disorders. © 2013 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  19. Could Heterozygous Beta Thalassemia Provide Protection Against Multiple Sclerosis?

    PubMed Central

    Cikrikcioglu, Mehmet Ali; Ozcan, Muhammed Emin; Halac, Gulistan; Gultepe, Ilhami; Celik, Kenan; Sekin, Yahya; Eser, Elif Ece; Burhan, Sebnem; Cetin, Guven; Uysal, Omer

    2016-01-01

    Background Heterozygous beta thalassemia (HBT) has been proposed to increase the risk of developing autoimmune disease. Our aim in this study was to examine the prevalence of HBT among multiple sclerosis (MS) patients. Material/Methods HBT frequency was investigated in our MS group (243 patients with MS). Hemoglobin electrophoresis (HE) was carried out if MS patients had a mean corpuscular volume of (MCV) <80 fL and a mean corpuscular hemoglobin level of (MCH) <27 pg/L according to a complete blood count (CBC). If MCV was lower than 80 fL, MCH was lower than 27 pg/L, and Hemoglobin A2 equal to or higher than 3.5%, a diagnosis of HBT was established. The frequency of patients with HBT in our MS patient group was statistically compared with the prevalence of HBT in the city of Istanbul, where our MS patients lived. Results The HBT prevalence was 0.823% (2 patients) in the MS patient group. The prevalence of HBT in Istanbul has been reported to be 4.5%. According to the z-test, the HBT prevalence in our MS patient group was significantly lower than that in Istanbul (Z=6.3611, two-sided p value <0.0001, 95% confidence interval of prevalence of HBT in our MS patient group: 0.000998–0.029413). Conclusions Contrary to our hypothesis at the outset of study, the reduced HBT prevalence in the MS group compared to HBT frequency in the city of Istanbul might indicate that HBT is protective against MS. PMID:27941710

  20. HbA1c levels in individuals heterozygous for hemoglobin variants.

    PubMed

    Tavares, Ricardo Silva; Souza, Fábio Oliveira de; Francescantonio, Isabel Cristina Carvalho Medeiros; Soares, Weslley Carvalho; Mesquita, Mauro Meira

    2017-04-01

    To evaluate the levels of glycated hemoglobin (HbA1c) in patients heterozygous for hemoglobin variants and compare the results of this test with those of a control group. This was an experimental study based on the comparison of HbA1c tests in two different populations, with a test group represented by individuals heterozygous for hemoglobin variants (AS and AC) and a control group consisting of people with electrophoretic profile AA. The two populations were required to meet the following inclusion criteria: Normal levels of fasting glucose, hemoglobin, urea and triglycerides, bilirubin > 20 mg/dL and non-use of acetylsalicylic acid. 50 heterozygous subjects and 50 controls were evaluated between August 2013 and May 2014. The comparison of HbA1c levels between heterozygous individuals and control subjects was performed based on standard deviation, mean and G-Test. The study assessed a test group and a control group, both with 39 adults and 11 children. The mean among heterozygous adults for HbA1c was 5.0%, while the control group showed a rate of 5.74%. Heterozygous children presented mean HbA1c at 5.11%, while the controls were at 5.78%. G-Test yielded p=0.93 for children and p=0.89 for adults. Our study evaluated HbA1c using ion exchange chromatography resins, and the patients heterozygous for hemoglobin variants showed no significant difference from the control group.

  1. Breast pain

    MedlinePlus

    Pain - breast; Mastalgia; Mastodynia; Breast tenderness ... There are many possible causes for breast pain. For example, changes in the level of of hormones during menstruation or pregnancy often cause breast pain. Some swelling and tenderness just before ...

  2. Heterozygous Hb Hope [beta136(H14)Gly --> Asp] in association with heterozygous beta0-thalassemia with apparent homozygous expression, in a Spanish patient.

    PubMed

    Beneitez, David; Carrera, Alícia; Duran-Suárez, Joan Ramón; Paz, Victoria; León, Antonio; García Talavera, Juan

    2006-01-01

    Hb Hope [beta136(H14)Gly --> Asp (GGT --> GAT)] has been found alone or in combination with other globin gene mutations in several African-American families, as well as in Japanese, Thai, Laotian, Cuban and Mauritanian families. We report the hematological and molecular characteristics of a heterozygous association of Hb Hope with beta0-thalassemia (thal) in a Spanish patient, in whom the level of expression of abnormal hemoglobin (Hb) by cation exchange high performance liquid chromatography (HPLC) and electrophoresis suggested initially a homozygous expression of the abnormal Hb, although sequencing of the polymerase chain reaction (PCR)-amplified beta-globin gene demonstrated a heterozygous genotype for Hb Hope. To the best of our knowledge, this is the first description of a case of Hb Hope in a Spanish family.

  3. PINK1 heterozygous mutations induce subtle alterations in dopamine-dependent synaptic plasticity

    PubMed Central

    Madeo, G.; Schirinzi, T.; Martella, G.; Latagliata, E.C.; Puglisi, F.; Shen, J.; Valente, E.M.; Federici, M.; Mercuri, N.B.; Puglisi-Allegra, S.; Bonsi, P.; Pisani, A.

    2014-01-01

    Background Homozygous or compound heterozygous mutations in the PTEN-induced kinase 1 (PINK1) gene are causative of autosomal recessive, early onset PD. Single heterozygous mutations have been repeatedly detected in a subset of patients as well as in non-affected subjects, and their significance has long been debated. Several neurophysiological studies from non-manifesting PINK1 heterozygotes have shown the existence of neural plasticity abnormalities, indicating the presence of specific endophenotypic traits in the heterozygous state. Methods In the present study, we performed a functional analysis of corticostriatal synaptic plasticity in heterozygous PINK1 knock-out (PINK1+/−) mice by a multidisciplinary approach. Results We found that, despite a normal motor behavior, repetitive activation of cortical inputs to striatal neurons failed to induce long-term potentiation (LTP), whereas long-term depression (LTD) was normal. Although nigral dopaminergic neurons exhibited normal morphological and electrophysiological properties with normal responses to dopamine receptor activation, we measured a significantly lower dopamine release in the striatum of PINK1+/−, compared to control mice, suggesting that a decrease in stimulus-evoked dopamine overflow acts as a major determinant for the LTP deficit. Accordingly, pharmacological agents capable of increasing the availability of dopamine in the synaptic cleft restored a normal LTP in heterozygous mice. Moreover, MAO-B inhibitors rescued a physiological LTP and a normal dopamine release. Conclusions Our results provide novel evidence for striatal plasticity abnormalities even in the heterozygous disease state. These alterations might be considered an endophenotype to this monogenic form of PD, and a valid tool to characterize early disease stage and design possible disease-modifying therapies. PMID:24167038

  4. Characterization of Heterozygous HTRA1 Mutations in Taiwanese Patients With Cerebral Small Vessel Disease.

    PubMed

    Lee, Yi-Chung; Chung, Chih-Ping; Chao, Nai-Chen; Fuh, Jong-Ling; Chang, Feng-Chi; Soong, Bing-Wing; Liao, Yi-Chu

    2018-07-01

    Homozygous and compound heterozygous mutations in the high temperature requirement serine peptidase A1 gene ( HTRA1 ) cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. However, heterozygous HTRA1 mutations were recently identified to be associated with autosomal dominant cerebral small vessel disease (SVD). The present study aims at investigating the clinical features, frequency, and spectrum of HTRA1 mutations in a Taiwanese cohort with SVD. Mutational analyses of HTRA1 were performed by Sanger sequencing in 222 subjects, selected from a cohort of 337 unrelated patients with SVD after excluding those harboring a NOTCH3 mutation. The influence of these mutations on HTRA1 protease activities was characterized. Seven novel heterozygous mutations in HTRA1 were identified, including p.Gly120Asp, p.Ile179Asn, p.Ala182Profs*33, p.Ile256Thr, p.Gly276Ala, p.Gln289Ter, and p.Asn324Thr, and each was identified in 1 single index patient. All mutations significantly compromise the HTRA1 protease activities. For the 7 index cases and another 2 affected siblings carrying a heterozygous HTRA1 mutation, the common clinical presentations include lacunar infarction, intracerebral hemorrhage, cognitive decline, and spondylosis at the fifth to sixth decade of life. Among the 9 patients, 4 have psychiatric symptoms as delusion, depression, and compulsive behavior, 3 have leukoencephalopathy in anterior temporal poles, and 2 patients have alopecia. Heterozygous HTRA1 mutations account for 2.08% (7 of 337) of SVD in Taiwan. The clinical and neuroradiological features of HTRA1 -related SVD and sporadic SVD are similar. These findings broaden the mutational spectrum of HTRA1 and highlight the pathogenic role of heterozygous HTRA1 mutations in SVD. © 2018 American Heart Association, Inc.

  5. A novel heterozygous RIT1 mutation in a patient with Noonan syndrome, leukopenia, and transient myeloproliferation-a review of the literature.

    PubMed

    Nemcikova, Michaela; Vejvalkova, Sarka; Fencl, Filip; Sukova, Martina; Krepelova, Anna

    2016-04-01

    Noonan syndrome (NS) is a genetic condition presenting with typical facies, cardiac defects, short stature, variable developmental deficit, cryptorchidism, skeletal, and other abnormalities. Germline mutations in genes involved in the RAS/MAPK signaling have been discovered to underlie NS. Recently, missense mutations in RIT1 have been reported as causative for individuals with clinical signs of NS. We report on a 2.5-year-old boy with NS phenotype with a novel heterozygous change in the RIT1 gene. The patient was born prematurely from pregnancy monitored for polyhydramnios. At 7 months of age, non-immune neutropenia and splenomegaly have been observed. During the severe pneumonia at 10 months, significant progression of hepatosplenomegaly, leukopenia with monocytosis (15-29 %), and thrombocytopenia occurred. Bone marrow evaluation showed myeloid hyperplasia and monocytosis, suggestive of myeloproliferative syndrome. Clinical phenotype (facial dysmorphism, soft hair, short neck, broad chest, widely spaced nipples, mild pectus carinatum, deep palmar creases, unilateral cryptorchidism), and moderate pulmonary valve stenosis with mild psychomotor delay were indicative of NS. DNA analysis identified a de novo heterozygous variant c.69A >T, p.(Lys23Asn) in exon 2 of the RIT1 gene, presumed to be causative. We present a patient with a clinical suspicion of NS carrying a novel substitution in RIT1 and hematologic findings not being observed in RIT1 positive patients to date. Thus, the case broadens variability of hematologic symptoms in RIT1 positive NS individuals. • Noonan syndrome is a common genetically heterogeneous disorder of autosomal dominant inheritance characterized by craniofacial dysmorphism, short stature, congenital heart defects, variable cognitive deficit, and other anomalies. What is new: • We report on a 2.5-year-old male patient with clinical signs of NS and hematologic abnormalities, in whom a novel heterozygous substitution in RIT1 with probable

  6. [CHEK2-mutation in Dutch breast cancer families: expanding genetic testing for breast cancer].

    PubMed

    Adank, Muriel A; Hes, Frederik J; van Zelst-Stams, Wendy A G; van den Tol, M Petrousjka; Seynaeve, Caroline; Oosterwijk, Jan C

    2015-01-01

    In the majority of breast cancer families, DNA testing does not show BRCA1 or BRCA2 mutations and the genetic cause of breast cancer remains unexplained. Routine testing for the CHEK2*1100delC mutation has recently been introduced in breast cancer families in the Netherlands. The 1100delC mutation in the CHEK2-gene may explain the occurrence of breast cancer in about 5% of non-BRCA1/2 families in the Netherlands. In the general population the CHEK2*1100delC mutation confers a slightly increased breast cancer risk, but in a familial breast cancer setting this risk is between 35-55% for first degree female carriers. Female breast cancer patients with the CHEK2*1100delC mutation are at increased risk of contralateral breast cancer and may have a less favourable prognosis. Female heterozygous CHEK2*1100delC mutation carriers are offered annual mammography and specialist breast surveillance between the ages of 35-60 years. Prospective research in CHEK2-positive families is essential in order to develop more specific treatment and screening strategies.

  7. Mixed Sequence Reader: A Program for Analyzing DNA Sequences with Heterozygous Base Calling

    PubMed Central

    Chang, Chun-Tien; Tsai, Chi-Neu; Tang, Chuan Yi; Chen, Chun-Houh; Lian, Jang-Hau; Hu, Chi-Yu; Tsai, Chia-Lung; Chao, Angel; Lai, Chyong-Huey; Wang, Tzu-Hao; Lee, Yun-Shien

    2012-01-01

    The direct sequencing of PCR products generates heterozygous base-calling fluorescence chromatograms that are useful for identifying single-nucleotide polymorphisms (SNPs), insertion-deletions (indels), short tandem repeats (STRs), and paralogous genes. Indels and STRs can be easily detected using the currently available Indelligent or ShiftDetector programs, which do not search reference sequences. However, the detection of other genomic variants remains a challenge due to the lack of appropriate tools for heterozygous base-calling fluorescence chromatogram data analysis. In this study, we developed a free web-based program, Mixed Sequence Reader (MSR), which can directly analyze heterozygous base-calling fluorescence chromatogram data in .abi file format using comparisons with reference sequences. The heterozygous sequences are identified as two distinct sequences and aligned with reference sequences. Our results showed that MSR may be used to (i) physically locate indel and STR sequences and determine STR copy number by searching NCBI reference sequences; (ii) predict combinations of microsatellite patterns using the Federal Bureau of Investigation Combined DNA Index System (CODIS); (iii) determine human papilloma virus (HPV) genotypes by searching current viral databases in cases of double infections; (iv) estimate the copy number of paralogous genes, such as β-defensin 4 (DEFB4) and its paralog HSPDP3. PMID:22778697

  8. Age-Dependent Deficits in Fear Learning in Heterozygous BDNF Knock-Out Mice

    ERIC Educational Resources Information Center

    Endres, Thomas; Lessmann, Volkmar

    2012-01-01

    Beyond its trophic function, the neurotrophin BDNF (brain-derived neurotrophic factor) is well known to crucially mediate synaptic plasticity and memory formation. Whereas recent studies suggested that acute BDNF/TrkB signaling regulates amygdala-dependent fear learning, no impairments of cued fear learning were reported in heterozygous BDNF…

  9. HetMappsS: Heterozygous mapping strategy for high resolution Genotyping-by-Sequencing Markers

    USDA-ARS?s Scientific Manuscript database

    Reduced representation genotyping approaches, such as genotyping-by-sequencing (GBS), provide opportunities to generate high-resolution genetic maps at a low per-sample cost. However, missing data and non-uniform sequence coverage can complicate map creation in highly heterozygous species. To facili...

  10. EDNRB mutations cause Waardenburg syndrome type II in the heterozygous state.

    PubMed

    Issa, Sarah; Bondurand, Nadege; Faubert, Emmanuelle; Poisson, Sylvain; Lecerf, Laure; Nitschke, Patrick; Deggouj, Naima; Loundon, Natalie; Jonard, Laurence; David, Albert; Sznajer, Yves; Blanchet, Patricia; Marlin, Sandrine; Pingault, Veronique

    2017-05-01

    Waardenburg syndrome (WS) is a genetic disorder characterized by sensorineural hearing loss and pigmentation anomalies. The clinical definition of four WS types is based on additional features due to defects in structures mostly arising from the neural crest, with type I and type II being the most frequent. While type I is tightly associated to PAX3 mutations, WS type II (WS2) remains partly enigmatic with mutations in known genes (MITF, SOX10) accounting for only 30% of the cases. We performed exome sequencing in a WS2 index case and identified a heterozygous missense variation in EDNRB. Interestingly, homozygous (and very rare heterozygous) EDNRB mutations are already described in type IV WS (i.e., in association with Hirschsprung disease [HD]) and heterozygous mutations in isolated HD. Screening of a WS2 cohort led to the identification of an overall of six heterozygous EDNRB variations. Clinical phenotypes, pedigrees and molecular segregation investigations unraveled a dominant mode of inheritance with incomplete penetrance. In parallel, cellular and functional studies showed that each of the mutations impairs the subcellular localization of the receptor or induces a defective downstream signaling pathway. Based on our results, we now estimate EDNRB mutations to be responsible for 5%-6% of WS2. © 2017 Wiley Periodicals, Inc.

  11. Prenatal diagnosis of fetal glutaric aciduria type 1 with rare compound heterozygous mutations in GCDH gene.

    PubMed

    Peng, Hsiu-Huei; Shaw, Sheng-Wen; Huang, Kuan-Gen

    2018-02-01

    Glutaric aciduria type 1 is a rare disease, with the estimated prevalence about 1 in 100,000 newborns. GCDH gene mutation can lead to glutaric acid and 3- OH glutaric acid accumulation, with clinical manifestation of neuronal damage, brain atrophy, microencephalic macrocephaly, decreased coordination of swallowing, poor muscle coordination, spasticity, and severe dystonic movement disorder. A 22-year-old female, Gravida 4 Para 2, is pregnancy at 13 weeks of gestational age. Her first child is normal, however, the second child was diagnosed as glutaric aciduria type I after birth. She came to our hospital for prenatal genetic counselling of her fetus at 13 weeks of gestational age. We performed GCDH gene mutation analysis of maternal blood showed IVS 3 + 1 G > A heterozygous mutation, GCDH gene mutation analysis of paternal blood showed c. 1240 G > A heterozygous mutation, and the second child has compound heterozygous IVS 3 + 1 G > A and c. 1240 G > A mutations. Later, we performed amniocentesis at 16 weeks of gestational age for chromosome study and GCDH gene mutation analysis for the fetus. The fetal chromosome study showed normal karyotype, however, GCDH gene mutation analysis showed compound heterozygous IVS 3 + 1 G > A and c. 1240 G > A mutations. The couple decided to termination of pregnancy thereafter. Glutaric acidemia type 1 is an autosomal recessive disorder because of pathogenic mutations in the GCDH gene. Early diagnosis and therapy of glutaric acidemia type 1 can reduce the risk of neuronal damage and acute dystonia. We report a case of prenatal diagnosis of fetal glutaric aciduria type 1 with rare compound heterozygous GCDH gene mutation at IVS 3 + 1 G > A and c. 1240 G > A mutations, which provide better genetic counselling for the couples. Copyright © 2018. Published by Elsevier B.V.

  12. Identification of compound heterozygous patients with primary hyperoxaluria type 1: clinical evaluations and in silico investigations.

    PubMed

    Kanoun, Houda; Jarraya, Faiçal; Maalej, Bayen; Lahiani, Amina; Mahfoudh, Hichem; Makni, Fatma; Hachicha, Jamil; Fakhfakh, Faiza

    2017-10-02

    Primary hyperoxaluria type 1 (PH1) is an autosomal recessive inherited disorder of glyoxylate metabolism in which excessive oxalates are formed by the liver and excreted by the kidneys. Calcium oxalate crystallizes in the urine, leading to urolithiasis, nephrocalcinosis, and consequent renal failure if treatment is not initiated promptly. Mutations in the AGXT gene which encodes the hepatic peroxisomal enzyme alanine:glyoxylate aminotransferase are responsible of PH1. In the present work, we aimed to analyze AGXT gene and in silico investigations performed in four patients with PH1 among two non consanguineous families. Exhaustive gene sequencing was performed after PCR amplification of coding exons and introns boundaries. Bioinformatic tools were used to predict the impact of AGXT variants on gene expression as well as on the protein structure and function. Direct sequencing of all exons of AGXT gene revealed the emergence of multiple mutations in compound heterozygous state in the two studied families. Two patients were compound heterozygous for the c.731 T > C, c.32C > T, c.1020A > G and c.33_34insC and presented clinically with recurrent urinary tract infection, multiple urolithiasis and nephrocalcinosis under the age of 1 year and a persistent hyperoxaluria at the age of diagnosis. The two other patients presenting a less severe phenotypes were heterozygous for c.731 T > C and homozygous for the c.32C > T and c.1020A > G or compound heterozygous for c.26C > A and c.65A > G variants. In Summary, we provided relevance regarding the compound heterozygous mutations in non consanguineous PH1 families with variable severity.

  13. Breast lump

    MedlinePlus

    ... with milk). These cysts can occur with breastfeeding. Breast abscess . These typically occur if you are breastfeeding or ... Breast infections are treated with antibiotics. Sometimes a breast abscess needs to be drained with a needle or ...

  14. Ignoring heterozygous sites biases phylogenomic estimates of divergence times: implications for the evolutionary history of microtus voles.

    PubMed

    Lischer, Heidi E L; Excoffier, Laurent; Heckel, Gerald

    2014-04-01

    Phylogenetic reconstruction of the evolutionary history of closely related organisms may be difficult because of the presence of unsorted lineages and of a relatively high proportion of heterozygous sites that are usually not handled well by phylogenetic programs. Genomic data may provide enough fixed polymorphisms to resolve phylogenetic trees, but the diploid nature of sequence data remains analytically challenging. Here, we performed a phylogenomic reconstruction of the evolutionary history of the common vole (Microtus arvalis) with a focus on the influence of heterozygosity on the estimation of intraspecific divergence times. We used genome-wide sequence information from 15 voles distributed across the European range. We provide a novel approach to integrate heterozygous information in existing phylogenetic programs by repeated random haplotype sampling from sequences with multiple unphased heterozygous sites. We evaluated the impact of the use of full, partial, or no heterozygous information for tree reconstructions on divergence time estimates. All results consistently showed four deep and strongly supported evolutionary lineages in the vole data. These lineages undergoing divergence processes split only at the end or after the last glacial maximum based on calibration with radiocarbon-dated paleontological material. However, the incorporation of information from heterozygous sites had a significant impact on absolute and relative branch length estimations. Ignoring heterozygous information led to an overestimation of divergence times between the evolutionary lineages of M. arvalis. We conclude that the exclusion of heterozygous sites from evolutionary analyses may cause biased and misleading divergence time estimates in closely related taxa.

  15. A novel heterozygous SOX2 mutation causing congenital bilateral anophthalmia, hypogonadotropic hypogonadism and growth hormone deficiency.

    PubMed

    Macchiaroli, Annamaria; Kelberman, Daniel; Auriemma, Renata Simona; Drury, Suzanne; Islam, Lily; Giangiobbe, Sara; Ironi, Gabriele; Lench, Nicholas; Sowden, Jane C; Colao, Annamaria; Pivonello, Rosario; Cavallo, Luciano; Gasperi, Maurizio; Faienza, Maria Felicia

    2014-01-25

    Heterozygous de novo mutations in SOX2 have been reported in approximately 10-20% of patients with unilateral or bilateral anophthalmia or microphthalmia. An additional phenotype of hypopituitarism, with anterior pituitary hypoplasia and hypogonadotropic hypogonadism, has been reported in patients carrying SOX2 alterations. We report a novel heterozygous mutation in the SOX2 gene in a male affected with congenital bilateral anophthalmia, hypogonadotrophic hypogonadism and growth hormone deficiency. The mutation we describe is a cytosine deletion in position 905 (c905delC) which causes frameshift and an aberrant C-terminal domain. Our report highlights the fact that subjects affected with eye anomalies and harboring SOX2 mutations are at high risk for gonadotropin deficiency, which has important implications for their clinical management. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4

    PubMed Central

    Deenick, Elissa K.; Niemela, Julie E.; Avery, Danielle T.; Schickel, Jean-Nicolas; Tran, Dat Q.; Stoddard, Jennifer; Zhang, Yu; Frucht, David M.; Dumitriu, Bogdan; Scheinberg, Phillip; Folio, Les R.; Frein, Cathleen A.; Price, Susan; Koh, Christopher; Heller, Theo; Seroogy, Christine M.; Huttenlocher, Anna; Rao, V. Koneti; Su, Helen C.; Kleiner, David; Notarangelo, Luigi D.; Rampertaap, Yajesh; Olivier, Kenneth N.; McElwee, Joshua; Hughes, Jason; Pittaluga, Stefania; Oliveira, Joao B.; Meffre, Eric; Fleisher, Thomas A.; Holland, Steven M.; Lenardo, Michael J.; Tangye, Stuart G.; Uzel, Gulbu

    2015-01-01

    Cytotoxic T lymphocyte antigen–4 (CTLA-4) is an inhibitory receptor found on immune cells. The consequences of mutations in CTLA4 in humans are unknown. We identified germline heterozygous mutations in CTLA4 in subjects with severe immune dysregulation from four unrelated families. Whereas Ctla4 heterozygous mice have no obvious phenotype, human CTLA4 haploinsufficiency caused dysregulation of FoxP3+ regulatory T (Treg) cells, hyperactivation of effector T cells, and lymphocytic infiltration of target organs. Patients also exhibited progressive loss of circulating B cells, associated with an increase of predominantly autoreactive CD21lo B cells and accumulation of B cells in nonlymphoid organs. Inherited human CTLA4 haploinsufficiency demonstrates a critical quantitative role for CTLA-4 in governing T and B lymphocyte homeostasis. PMID:25213377

  17. X-linked adrenoleukodystrophy in heterozygous female patients: women are not just carriers.

    PubMed

    Lourenço, Charles Marques; Simão, Gustavo Novelino; Santos, Antonio Carlos; Marques, Wilson

    2012-07-01

    X-linked adrenoleukodystrophy (X-ALD) is a recessive X-linked disorder associated with marked phenotypic variability. Female carriers are commonly thought to be normal or only mildly affected, but their disease still needs to be better described and systematized. To review and systematize the clinical features of heterozygous women followed in a Neurogenetics Clinic. We reviewed the clinical, biochemical, and neuroradiological data of all women known to have X-ADL. The nine women identified were classified into three groups: with severe and aggressive diseases; with slowly progressive, spastic paraplegia; and with mildly decreased vibratory sensation, brisk reflexes, and no complaints. Many of these women did not have a known family history of X-ALD. Heterozygous women with X-ADL have a wide spectrum of clinical manifestations, ranging from mild to severe phenotypes.

  18. Late-onset nonketotic hyperglycinemia with a heterozygous novel point mutation of the GLDC gene.

    PubMed

    Brenton, J Nicholas; Rust, Robert S

    2014-05-01

    Atypical nonketotic hyperglycinemia is characterized by heterogeneous phenotypes that often include nonspecific behavioral problems, cognitive deficits, and developmental delays. We describe a girl with late-onset nonketotic hyperglycinemia presenting at 5 years of age with hypotonia, chorea, ataxia, and alterations in consciousness in the setting of febrile illness. Serum amino acid analysis was mildly elevated; however, urine amino acid analysis was instrumental in demonstrating marked hyperglycinuria. Mutation testing showed a heterozygous novel sequence change/point mutation in the glycine decarboxylase gene. This patient illustrates the importance of obtaining urine amino acids in individuals whose clinical manifestations are suspicious for any form of nonketotic hyperglycinemia, because this testing may provide more prominent evidence of elevations in glycine. She also illustrates the potential for a heterozygous mutation to result in manifestations of an atypical form of nonketotic hyperglycinemia. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Clinical Phenotype in a Toddler with a Novel Heterozygous Mutation of the Vitamin D Receptor

    PubMed Central

    Dingle, Elena

    2017-01-01

    We present the clinical phenotype of a toddler who presented with vitamin D-resistant rickets, with one of the highest initial levels of alkaline phosphatase and parathyroid hormone (PTH) levels reported in the literature. The toddler had novel compound heterozygous mutations in the ligand-binding site of the vitamin D receptor and had an excellent response to calcitriol (1,25(OH)2D). PMID:28620554

  20. Novel CLCN7 compound heterozygous mutations in intermediate autosomal recessive osteopetrosis

    PubMed Central

    Okamoto, Nana; Kohmoto, Tomohiro; Naruto, Takuya; Masuda, Kiyoshi; Komori, Takahide; Imoto, Issei

    2017-01-01

    Osteopetrosis is a heritable disorder of the skeleton that is characterized by increased bone density on radiographs caused by defects in osteoclast formation and function. Mutations in >10 genes are identified as causative for this clinically and genetically heterogeneous disease in humans. We report two novel missense variations in a compound heterozygous state in the CLCN7 gene, detected through targeted exome sequencing, in a 15-year-old Japanese female with intermediate autosomal recessive osteopetrosis. PMID:28819563

  1. Novel CLCN7 compound heterozygous mutations in intermediate autosomal recessive osteopetrosis.

    PubMed

    Okamoto, Nana; Kohmoto, Tomohiro; Naruto, Takuya; Masuda, Kiyoshi; Komori, Takahide; Imoto, Issei

    2017-01-01

    Osteopetrosis is a heritable disorder of the skeleton that is characterized by increased bone density on radiographs caused by defects in osteoclast formation and function. Mutations in >10 genes are identified as causative for this clinically and genetically heterogeneous disease in humans. We report two novel missense variations in a compound heterozygous state in the CLCN7 gene, detected through targeted exome sequencing, in a 15-year-old Japanese female with intermediate autosomal recessive osteopetrosis.

  2. Clinical Phenotype in a Toddler with a Novel Heterozygous Mutation of the Vitamin D Receptor.

    PubMed

    Brar, Preneet Cheema; Dingle, Elena; Pappas, John; Raisingani, Manish

    2017-01-01

    We present the clinical phenotype of a toddler who presented with vitamin D-resistant rickets, with one of the highest initial levels of alkaline phosphatase and parathyroid hormone (PTH) levels reported in the literature. The toddler had novel compound heterozygous mutations in the ligand-binding site of the vitamin D receptor and had an excellent response to calcitriol (1,25(OH)2D).

  3. Novel compound heterozygous mutations in SERPINH1 cause rare autosomal recessive osteogenesis imperfecta type X.

    PubMed

    Song, Y; Zhao, D; Xu, X; Lv, F; Li, L; Jiang, Y; Wang, O; Xia, W; Xing, X; Li, M

    2018-03-09

    We identified novel compound heterozygous mutations in SERPINH1 in a Chinese boy suffering from recurrent fractures, femoral deformities, and growth retardation, which resulted in extremely rare autosomal recessive OI type X. Long-term treatment of BPs was effective in increasing BMD Z-score, reducing fracture incidence and reshaping vertebrae compression. Osteogenesis imperfecta (OI) is a heritable bone disorder characterized by low bone mineral density, recurrent fractures, and progressive bone deformities. Mutation in serpin peptidase inhibitor clade H, member 1 (SERPINH1), which encodes heat shock protein 47 (HSP47), leads to rare autosomal recessive OI type X. We aimed to detect the phenotype and the pathogenic mutation of OI type X in a boy from a non-consanguineous Chinese family. We investigated the pathogenic mutations and analyzed their relationship with the phenotype in the patient using next-generation sequencing (NGS) and Sanger sequencing. Moreover, the efficacy of long-term bisphosphonate treatment in this patient was evaluated. The patient suffered from multiple fractures, low bone mass, and bone deformities in the femur, without dentinogenesis imperfecta or hearing loss. Compound heterozygous variants were found in SERPINH1 as follows: c.149 T>G in exon 2 and c.1214G>A in exon 5. His parents were heterozygous carriers of each of these mutations, respectively. Bisphosphonates could be helpful in increasing BMD Z-score, reducing bone fracture risk and reshaping the compressed vertebral bodies of this patient. We reported novel compound heterozygous mutations in SERPINH1 in a Chinese OI patient for the first time, which expanded the spectrum of phenotype and genotype of extremely rare OI type X.

  4. Breast Exam

    MedlinePlus

    ... can cause changes in your breasts, including breast cancer. A breast self-exam for breast awareness isn't a reliable way to screen for ... instructions and technique with your doctor. The American Cancer Society recommends ... have their techniques periodically evaluated by their doctors. ...

  5. Risk of asthma in heterozygous carriers for cystic fibrosis: A meta-analysis.

    PubMed

    Nielsen, Anne Orholm; Qayum, Sadaf; Bouchelouche, Pierre Nourdine; Laursen, Lars Christian; Dahl, Ronald; Dahl, Morten

    2016-09-01

    Patients with cystic fibrosis (CF) have a higher prevalence of asthma than the background population, however, it is unclear whether heterozygous CF carriers are susceptible to asthma. Given this, a meta-analysis is necessary to determine the veracity of the association of CF heterozygosity with asthma. We screened the medical literature from 1966 to 2015 and performed a meta-analysis to determine the risk of asthma in CF heterozygotes vs. non-carriers. Aggregating data from 15 studies, the odds ratio for asthma in CF heterozygotes compared with non-carriers was significantly elevated at 1.61 (95% CI: 1.18-2.21). When analyzing the studies considered of high quality in which asthma was diagnosed by a physician, the patients were >18years, or study size was ≥500, the trend remained the same, that heterozygous carriers of CF had elevated risk for asthma. The results show that heterozygous carriers for CF have a higher risk of asthma than non-carriers. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  6. Neurochemical and behavioral characterization of neuronal glutamate transporter EAAT3 heterozygous mice.

    PubMed

    González, Luis F; Henríquez-Belmar, Francisca; Delgado-Acevedo, Claudia; Cisternas-Olmedo, Marisol; Arriagada, Gloria; Sotomayor-Zárate, Ramón; Murphy, Dennis L; Moya, Pablo R

    2017-09-19

    Obsessive-compulsive disorder (OCD) is a severe neuropsychiatric condition affecting 1-3% of the worldwide population. OCD has a strong genetic component, and the SLC1A1 gene that encodes neuronal glutamate transporter EAAT3 is a strong candidate for this disorder. To evaluate the impact of reduced EAAT3 expression in vivo, we studied male EAAT3 heterozygous and wild-type littermate mice using a battery of behavioral paradigms relevant to anxiety (open field test, elevated plus maze) and compulsivity (marble burying), as well as locomotor activity induced by amphetamine. Using high-performance liquid chromatography, we also determined tissue neurotransmitter levels in cortex, striatum and thalamus-brain areas that are relevant to OCD. Compared to wild-type littermates, EAAT3 heterozygous male mice have unaltered baseline anxiety-like, compulsive-like behavior and locomotor activity. Administration of acute amphetamine (5 mg/kg intraperitoneally) increased locomotion with no differences across genotypes. Tissue levels of glutamate, GABA, dopamine and serotonin did not vary between EAAT3 heterozygous and wild-type mice. Our results indicate that reduced EAAT3 expression does not impact neurotransmitter content in the corticostriatal circuit nor alter anxiety or compulsive-like behaviors.

  7. Altered social cognition in male BDNF heterozygous mice and following chronic methamphetamine exposure.

    PubMed

    Manning, Elizabeth E; van den Buuse, Maarten

    2016-05-15

    Growing clinical evidence suggests that persistent psychosis which occurs in methamphetamine users is closely related to schizophrenia. However, preclinical studies in animal models have focussed on psychosis-related behaviours following methamphetamine, and less work has been done to assess endophenotypes relevant to other deficits observed in schizophrenia. Altered social behaviour is a feature of both the negative symptoms and cognitive deficits in schizophrenia, and significantly impacts patient functioning. We recently found that brain-derived neurotrophic factor (BDNF) heterozygous mice show disrupted sensitization to methamphetamine, supporting other work suggesting an important role of this neurotrophin in the pathophysiology of psychosis and the neuronal response to stimulant drugs. In the current study, we assessed social and cognitive behaviours in methamphetamine-treated BDNF heterozygous mice and wildtype littermate controls. Following chronic methamphetamine exposure male wildtype mice showed a 50% reduction in social novelty preference. Vehicle-treated male BDNF heterozygous mice showed a similar impairment in social novelty preference, with a trend for no further disruption by methamphetamine exposure. Female mice were unaffected in this task, and no groups showed any changes in sociability or short-term spatial memory. These findings suggest that chronic methamphetamine alters behaviour relevant to disruption of social cognition in schizophrenia, supporting other studies which demonstrate a close resemblance between persistent methamphetamine psychosis and schizophrenia. Together these findings suggest that dynamic regulation of BDNF signalling is necessary to mediate the effects of methamphetamine on behaviours relevant to schizophrenia. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Impaired fear extinction learning in adult heterozygous BDNF knock-out mice.

    PubMed

    Psotta, Laura; Lessmann, Volkmar; Endres, Thomas

    2013-07-01

    Brain-derived neurotrophic factor (BDNF) is a crucial regulator of neuroplasticity, which underlies learning and memory processes in different brain areas. To investigate the role of BDNF in the extinction of amygdala-dependent cued fear memories, we analyzed fear extinction learning in heterozygous BDNF knock-out mice, which possess a reduction of endogenous BDNF protein levels to ~50% of wild-type animals. Since BDNF expression has been shown to decline with aging of animals, we tested the performance in extinction learning of these mice at 2 months (young adults) and 7 months (older adults) of age. The present study shows that older adult heterozygous BDNF knock-out mice, which have a chronic 50% lack of BDNF, also possess a deficit in the acquisition of extinction memory, while extinction learning remains unaffected in young adult heterozygous BDNF knock-out mice. This deficit in extinction learning is accompanied by a reduction of BDNF protein in the hippocampus, amygdala and the prefrontal cortex. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Two middle-age-onset hemochromatosis patients with heterozygous mutations in the hemojuvelin gene in a Chinese family.

    PubMed

    Li, Shufeng; Xue, Jun; Chen, Baojun; Wang, Qiwei; Shi, Minke; Xie, Xiaojing; Zhang, Liang

    2014-04-01

    Hereditary hemochromatosis is a disorder characterized by enhanced intestinal absorption of dietary iron. Here, we report a heterozygous genotype at two mutation sites in hemojuvelin (HJV) present in two brothers with middle-age-onset hemochromatosis in a Chinese family. To date, only homozygous or compound heterozygous states of HJV gene have been reported as associated with iron overload. However, the patients here were heterozygous for two mutations in one HJV allele in cis: a premature termination mutation (962G>A and 963C>A; C321X) and a mutation in the signal peptide (18G>C; Q6H). Previously unrecognized environmental or other genetic factors may have interacted with the heterozygous genotype in these patients.

  10. Breast reconstruction - implants

    MedlinePlus

    Breast implants surgery; Mastectomy - breast reconstruction with implants; Breast cancer - breast reconstruction with implants ... it harder to find a tumor if your breast cancer comes back. Getting breast implants does not take ...

  11. Breast Abscess

    PubMed Central

    Ajao, Oluwole G.; Ajao, Adebola O.

    1979-01-01

    Breast abscess is a relatively important disease in the tropics, and yet this condition has received little attention in the literature. Breast abscess encourages artificial feeding, which in many instances may be responsible for gastroenteritis in infants. This occurs when foods are not properly prepared by mothers of low socioeconomic class with inadequate sanitation. Breast abscess occurs primarily in the lactating breast and is most commonly located in the upper half of the breast. The organism most commonly present in the pus is Staphylococcus aureus. When the abscess is localized, it may present with all the clinical features of a breast carcinoma. PMID:522185

  12. Breast Gangrene

    PubMed Central

    2011-01-01

    Background Breast gangrene is rare in surgical practice. Gangrene of breast can be idiopathic or secondary to some causative factor. Antibiotics and debridement are used for management. Acute inflammatory infiltrate, severe necrosis of breast tissue, necrotizing arteritis, and venous thrombosis is observed on histopathology. The aim of was to study patients who had breast gangrene. Methods A prospective study of 10 patients who had breast gangrene over a period of 6 years were analyzed Results All the patients in the study group were female. Total of 10 patients were encountered who had breast gangrene. Six patients presented with breast gangrene on the right breast whereas four had on left breast. Out of 10 patients, three had breast abscess after teeth bite followed by gangrene, one had iatrogenic trauma by needle aspiration of erythematous area of breast under septic conditions. Four had history of application of belladonna on cutaneous breast abscess and had then gangrene. All were lactating female. Amongst the rest two were elderly, one of which was a diabetic who had gangrene of breast and had no application of belladonna. All except one had debridement under cover of broad spectrum antibiotics. Three patients had grafting to cover the raw area. Conclusion Breast gangrene occurs rarely. Etiology is variable and mutifactorial. Teeth bite while lactation and the iatrogenic trauma by needle aspiration of breast abscess under unsterlised conditions could be causative. Uncontrolled diabetes can be one more causative factor for the breast gangrene. Belladonna application as a topical agent could be inciting factor. Sometimes gangrene of breast can be idiopathic. Treatment is antibiotics and debridement. PMID:21854557

  13. Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.

    PubMed

    Patel, Kashyap A; Kettunen, Jarno; Laakso, Markku; Stančáková, Alena; Laver, Thomas W; Colclough, Kevin; Johnson, Matthew B; Abramowicz, Marc; Groop, Leif; Miettinen, Päivi J; Shepherd, Maggie H; Flanagan, Sarah E; Ellard, Sian; Inagaki, Nobuya; Hattersley, Andrew T; Tuomi, Tiinamaija; Cnop, Miriam; Weedon, Michael N

    2017-10-12

    Finding new causes of monogenic diabetes helps understand glycaemic regulation in humans. To find novel genetic causes of maturity-onset diabetes of the young (MODY), we sequenced MODY cases with unknown aetiology and compared variant frequencies to large public databases. From 36 European patients, we identify two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants are enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio = 131, P = 1 × 10 -4 ). We find similar results in non-Finnish European (n = 348, odds ratio = 43, P = 5 × 10 -5 ) and Finnish (n = 80, odds ratio = 22, P = 1 × 10 -6 ) replication cohorts. RFX6 heterozygotes have reduced penetrance of diabetes compared to common HNF1A and HNF4A-MODY mutations (27, 70 and 55% at 25 years of age, respectively). The hyperglycaemia results from beta-cell dysfunction and is associated with lower fasting and stimulated gastric inhibitory polypeptide (GIP) levels. Our study demonstrates that heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.Maturity-onset diabetes of the young (MODY) is the most common subtype of familial diabetes. Here, Patel et al. use targeted DNA sequencing of MODY patients and large-scale publically available data to show that RFX6 heterozygous protein truncating variants cause reduced penetrance MODY.

  14. Heterozygous Che-1 KO mice show deficiencies in object recognition memory persistence.

    PubMed

    Zalcman, Gisela; Corbi, Nicoletta; Di Certo, Maria Grazia; Mattei, Elisabetta; Federman, Noel; Romano, Arturo

    2016-10-06

    Transcriptional regulation is a key process in the formation of long-term memories. Che-1 is a protein involved in the regulation of gene transcription that has recently been proved to bind the transcription factor NF-κB, which is known to be involved in many memory-related molecular events. This evidence prompted us to investigate the putative role of Che-1 in memory processes. For this study we newly generated a line of Che-1(+/-) heterozygous mice. Che-1 homozygous KO mouse is lethal during development, but Che-1(+/-) heterozygous mouse is normal in its general anatomical and physiological characteristics. We analyzed the behavioral characteristic and memory performance of Che-1(+/-) mice in two NF-κB dependent types of memory. We found that Che-1(+/-) mice show similar locomotor activity and thigmotactic behavior than wild type (WT) mice in an open field. In a similar way, no differences were found in anxiety-like behavior between Che-1(+/-) and WT mice in an elevated plus maze as well as in fear response in a contextual fear conditioning (CFC) and object exploration in a novel object recognition (NOR) task. No differences were found between WT and Che-1(+/-) mice performance in CFC training and when tested at 24h or 7days after training. Similar performance was found between groups in NOR task, both in training and 24h testing performance. However, we found that object recognition memory persistence at 7days was impaired in Che-1(+/-) heterozygous mice. This is the first evidence showing that Che-1 is involved in memory processes. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  15. Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms

    PubMed Central

    Marsh, Judith C. W.; Gutierrez-Rodrigues, Fernanda; Cooper, James; Jiang, Jie; Gandhi, Shreyans; Kajigaya, Sachiko; Feng, Xingmin; Ibanez, Maria del Pilar F.; Donaires, Flávia S.; Lopes da Silva, João P.; Li, Zejuan; Das, Soma; Ibanez, Maria; Smith, Alexander E.; Lea, Nicholas; Best, Steven; Ireland, Robin; Kulasekararaj, Austin G.; McLornan, Donal P.; Pagliuca, Anthony; Callebaut, Isabelle; Young, Neal S.; Calado, Rodrigo T.; Townsley, Danielle M.

    2018-01-01

    Biallelic germline mutations in RTEL1 (regulator of telomere elongation helicase 1) result in pathologic telomere erosion and cause dyskeratosis congenita. However, the role of RTEL1 mutations in other bone marrow failure (BMF) syndromes and myeloid neoplasms, and the contribution of monoallelic RTEL1 mutations to disease development are not well defined. We screened 516 patients for germline mutations in telomere-associated genes by next-generation sequencing in 2 independent cohorts; one constituting unselected patients with idiopathic BMF, unexplained cytopenia, or myeloid neoplasms (n = 457) and a second cohort comprising selected patients on the basis of the suspicion of constitutional/familial BMF (n = 59). Twenty-three RTEL1 variants were identified in 27 unrelated patients from both cohorts: 7 variants were likely pathogenic, 13 were of uncertain significance, and 3 were likely benign. Likely pathogenic RTEL1 variants were identified in 9 unrelated patients (7 heterozygous and 2 biallelic). Most patients were suspected to have constitutional BMF, which included aplastic anemia (AA), unexplained cytopenia, hypoplastic myelodysplastic syndrome, and macrocytosis with hypocellular bone marrow. In the other 18 patients, RTEL1 variants were likely benign or of uncertain significance. Telomeres were short in 21 patients (78%), and 3′ telomeric overhangs were significantly eroded in 4. In summary, heterozygous RTEL1 variants were associated with marrow failure, and telomere length measurement alone may not identify patients with telomere dysfunction carrying RTEL1 variants. Pathogenicity assessment of heterozygous RTEL1 variants relied on a combination of clinical, computational, and functional data required to avoid misinterpretation of common variants. PMID:29344583

  16. Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms.

    PubMed

    Marsh, Judith C W; Gutierrez-Rodrigues, Fernanda; Cooper, James; Jiang, Jie; Gandhi, Shreyans; Kajigaya, Sachiko; Feng, Xingmin; Ibanez, Maria Del Pilar F; Donaires, Flávia S; Lopes da Silva, João P; Li, Zejuan; Das, Soma; Ibanez, Maria; Smith, Alexander E; Lea, Nicholas; Best, Steven; Ireland, Robin; Kulasekararaj, Austin G; McLornan, Donal P; Pagliuca, Anthony; Callebaut, Isabelle; Young, Neal S; Calado, Rodrigo T; Townsley, Danielle M; Mufti, Ghulam J

    2018-01-09

    Biallelic germline mutations in RTEL1 (regulator of telomere elongation helicase 1) result in pathologic telomere erosion and cause dyskeratosis congenita. However, the role of RTEL1 mutations in other bone marrow failure (BMF) syndromes and myeloid neoplasms, and the contribution of monoallelic RTEL1 mutations to disease development are not well defined. We screened 516 patients for germline mutations in telomere-associated genes by next-generation sequencing in 2 independent cohorts; one constituting unselected patients with idiopathic BMF, unexplained cytopenia, or myeloid neoplasms (n = 457) and a second cohort comprising selected patients on the basis of the suspicion of constitutional/familial BMF (n = 59). Twenty-three RTEL1 variants were identified in 27 unrelated patients from both cohorts: 7 variants were likely pathogenic, 13 were of uncertain significance, and 3 were likely benign. Likely pathogenic RTEL1 variants were identified in 9 unrelated patients (7 heterozygous and 2 biallelic). Most patients were suspected to have constitutional BMF, which included aplastic anemia (AA), unexplained cytopenia, hypoplastic myelodysplastic syndrome, and macrocytosis with hypocellular bone marrow. In the other 18 patients, RTEL1 variants were likely benign or of uncertain significance. Telomeres were short in 21 patients (78%), and 3' telomeric overhangs were significantly eroded in 4. In summary, heterozygous RTEL1 variants were associated with marrow failure, and telomere length measurement alone may not identify patients with telomere dysfunction carrying RTEL1 variants. Pathogenicity assessment of heterozygous RTEL1 variants relied on a combination of clinical, computational, and functional data required to avoid misinterpretation of common variants.

  17. Breast Calcifications

    MedlinePlus

    ... al. Diagnostic evaluation of women with suspected breast cancer. http://www.uptodate.com/home. Accessed Dec. 9, 2015. Lai KC, et al. Linear breast calcifications. American Journal of Roentgenology. 2012;199:W151. Demetri-Lewis A, ...

  18. Breast Pain

    MedlinePlus

    ... your period and sometimes continuing through your menstrual cycle. The pain may be moderate or severe, and ... Throughout the month, not related to your menstrual cycle. Postmenopausal women sometimes have breast pain, but breast ...

  19. Breast Tomosynthesis

    MedlinePlus

    ... and disease management. top of page How is the procedure performed? Breast tomosynthesis is performed on an outpatient basis. During this exam, a specially qualified radiologic technologist will position your breast in the mammography unit. ...

  20. Breast lift

    MedlinePlus

    ... Planning to have more children Talk with a plastic surgeon if you are considering cosmetic breast surgery. ... before surgery: You may need a mammogram . Your plastic surgeon will do a routine breast exam. You ...

  1. Homozygous and compound heterozygous mutations in the FBN1 gene: unexpected findings in molecular diagnosis of Marfan syndrome.

    PubMed

    Arnaud, Pauline; Hanna, Nadine; Aubart, Mélodie; Leheup, Bruno; Dupuis-Girod, Sophie; Naudion, Sophie; Lacombe, Didier; Milleron, Olivier; Odent, Sylvie; Faivre, Laurence; Bal, Laurence; Edouard, Thomas; Collod-Beroud, Gwenaëlle; Langeois, Maud; Spentchian, Myrtille; Gouya, Laurent; Jondeau, Guillaume; Boileau, Catherine

    2017-02-01

    Marfan syndrome (MFS) is an autosomal-dominant connective tissue disorder usually associated with heterozygous mutations in the gene encoding fibrillin-1 (FBN1). Homozygous and compound heterozygous cases are rare events and have been associated with a clinical severe presentation. Report unexpected findings of homozygosity and compound heterozygosity in the course of molecular diagnosis of heterozygous MFS and compare the findings with published cases. In the context of molecular diagnosis of heterozygous MFS, systematic sequencing of the FBN1 gene was performed in 2500 probands referred nationwide. 1400 probands carried a heterozygous mutation in this gene. Unexpectedly, among them four homozygous cases (0.29%) and five compound heterozygous cases (0.36%) were identified (total: 0.64%). Interestingly, none of these cases carried two premature termination codon mutations in the FBN1 gene. Clinical features for these carriers and their families were gathered and compared. There was a large spectrum of severity of the disease in probands carrying two mutated FBN1 alleles, but none of them presented extremely severe manifestations of MFS in any system compared with carriers of only one mutated FBN1 allele. This observation is not in line with the severe clinical features reported in the literature for four homozygous and three compound heterozygous probands. Homozygotes and compound heterozygotes were unexpectedly identified in the course of molecular diagnosis of MFS. Contrary to previous reports, the presence of two mutated alleles was not associated with severe forms of MFS. Although homozygosity and compound heterozygosity are rarely found in molecular diagnosis, they should not be overlooked, especially among consanguineous families. However, no predictive evaluation of severity should be provided. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  2. The "S.W.A.T." Concept.

    ERIC Educational Resources Information Center

    Williamson, Bob; And Others

    1985-01-01

    Describes Statistical Work Analysis Teams (S.W.A.T.), which marry the two factors necessary for successful statistical analysis with the personal nature of attribute data into a single effort. Discusses S.W.A.T. project guidelines, implementation of the first S.W.A.T. projects, team training, and project completion. (CT)

  3. Breast Cancer

    MedlinePlus

    Breast cancer affects one in eight women during their lives. No one knows why some women get breast cancer, but there are many risk factors. Risks that ... who have family members with breast or ovarian cancer may wish to be tested for the genes. ...

  4. Heterozygous loss of TSC2 alters p53 signaling and human stem cell reprogramming.

    PubMed

    Armstrong, Laura C; Westlake, Grant; Snow, John P; Cawthon, Bryan; Armour, Eric; Bowman, Aaron B; Ess, Kevin C

    2017-12-01

    Tuberous sclerosis complex (TSC) is a pediatric disorder of dysregulated growth and differentiation caused by loss of function mutations in either the TSC1 or TSC2 genes, which regulate mTOR kinase activity. To study aberrations of early development in TSC, we generated induced pluripotent stem cells using dermal fibroblasts obtained from patients with TSC. During validation, we found that stem cells generated from TSC patients had a very high rate of integration of the reprogramming plasmid containing a shRNA against TP53. We also found that loss of one allele of TSC2 in human fibroblasts is sufficient to increase p53 levels and impair stem cell reprogramming. Increased p53 was also observed in TSC2 heterozygous and homozygous mutant human stem cells, suggesting that the interactions between TSC2 and p53 are consistent across cell types and gene dosage. These results support important contributions of TSC2 heterozygous and homozygous mutant cells to the pathogenesis of TSC and the important role of p53 during reprogramming. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  5. PANRETINAL DEGENERATION ASSOCIATED WITH LONG-TERM HYDROXYCHLOROQUINE USE AND HETEROZYGOUS USH2A MUTATION.

    PubMed

    Katsman, Diana; Sanfilippo, Christian; Sarraf, David

    2017-01-01

    To report a case of bilateral panretinal degeneration in a patient with long-term hydroxychloroquine exposure and positive for a heterozygous mutation in the USH2A gene. Retrospective case report. Multimodal imaging including spectral-domain optical coherence tomography, fundus autofluorescence, and fluorescein angiography was performed and the results are presented. Electroretinography findings are also described. The authors report a 39-year-old patient with a history of hydroxychloroquine therapy for 20 years (cumulative dose of 2,774 g). Multimodal retinal imaging demonstrated bilateral paracentral outer retinal atrophy with spectral-domain optical coherence tomography and characteristic of hydroxychloroquine toxicity. Full-field electroretinography showed bilateral panretinal depression of the rod and cone responses. Mutational analysis revealed that the patient was a carrier for an autosomal recessive mutation in the USH2A gene. We report a case of panretinal degeneration but with features characteristic of hydroxychloroquine retinopathy in a patient who was found to be a heterozygous carrier of the USH2A gene, a cause of recessive retinitis pigmentosa without hearing loss. Carrier status for a retinal degenerative mutation may have rendered this patient more susceptible to the retinotoxic effects of long-term hydroxychloroquine therapy.

  6. Idiopathic Short Stature due to Novel Heterozygous Mutation of the Aggrecan Gene

    PubMed Central

    Quintos, Jose Bernardo; Guo, Michael H.; Dauber, Andrew

    2015-01-01

    Background Recently, whole exome sequencing identified heterozygous defects in the Aggrecan gene (ACAN) in three families with short stature and advanced bone age. Objective We report a novel frameshift mutation in ACAN in a family with dominantly inherited short stature, advanced bone age, and premature growth cessation. This is the first case of targeted sequencing of ACAN in this phenotype and confirms that ACAN sequencing is warranted in patients with this rare constellation of findings. Results We present a 5 1/2 year old male with a family history of short stature in 3 generations. The maternal grandfather stands 144.5 cm (Ht SDS -4.7), mother 147.7 cm (Ht SDS -2.6), and index case 99.2 cm (Ht SDS -2.7). Our prepubertal patient has significant bone age advancement (bone age 8 years at chronologic age 5 1/2 years) resulting in a poor predicted adult height of 142 cm (Ht SDS -5.1). DNA sequencing identified a novel heterozygous variant in ACAN, which encodes aggrecan, a proteoglycan in the extracellular matrix of growth plate and other cartilaginous tissues. The mutation (p.Gly1797Glyfs*52) results in premature truncation and presumed loss of protein function. Conclusion Mutations in aggrecan gene should be included in the differential diagnosis of the child with idiopathic short stature or familial short stature and bone age advancement. PMID:25741789

  7. Heterozygous Mutations Causing Partial Prohormone Convertase 1 Deficiency Contribute to Human Obesity

    PubMed Central

    Creemers, John W.M.; Choquet, Hélène; Stijnen, Pieter; Vatin, Vincent; Pigeyre, Marie; Beckers, Sigri; Meulemans, Sandra; Than, Manuel E.; Yengo, Loïc; Tauber, Maithé; Balkau, Beverley; Elliott, Paul; Jarvelin, Marjo-Riitta; Van Hul, Wim; Van Gaal, Luc; Horber, Fritz; Pattou, François; Froguel, Philippe; Meyre, David

    2012-01-01

    Null mutations in the PCSK1 gene, encoding the proprotein convertase 1/3 (PC1/3), cause recessive monogenic early onset obesity. Frequent coding variants that modestly impair PC1/3 function mildly increase the risk for common obesity. The aim of this study was to determine the contribution of rare functional PCSK1 mutations to obesity. PCSK1 exons were sequenced in 845 nonconsanguineous extremely obese Europeans. Eight novel nonsynonymous PCSK1 mutations were identified, all heterozygous. Seven mutations had a deleterious effect on either the maturation or the enzymatic activity of PC1/3 in cell lines. Of interest, five of these novel mutations, one of the previously described frequent variants (N221D), and the mutation found in an obese mouse model (N222D), affect residues at or near the structural calcium binding site Ca-1. The prevalence of the newly identified mutations was assessed in 6,233 obese and 6,274 lean European adults and children, which showed that carriers of any of these mutations causing partial PCSK1 deficiency had an 8.7-fold higher risk to be obese than wild-type carriers. These results provide the first evidence of an increased risk of obesity in heterozygous carriers of mutations in the PCSK1 gene. Furthermore, mutations causing partial PCSK1 deficiency are present in 0.83% of extreme obesity phenotypes. PMID:22210313

  8. Heterozygous mutations causing partial prohormone convertase 1 deficiency contribute to human obesity.

    PubMed

    Creemers, John W M; Choquet, Hélène; Stijnen, Pieter; Vatin, Vincent; Pigeyre, Marie; Beckers, Sigri; Meulemans, Sandra; Than, Manuel E; Yengo, Loïc; Tauber, Maithé; Balkau, Beverley; Elliott, Paul; Jarvelin, Marjo-Riitta; Van Hul, Wim; Van Gaal, Luc; Horber, Fritz; Pattou, François; Froguel, Philippe; Meyre, David

    2012-02-01

    Null mutations in the PCSK1 gene, encoding the proprotein convertase 1/3 (PC1/3), cause recessive monogenic early onset obesity. Frequent coding variants that modestly impair PC1/3 function mildly increase the risk for common obesity. The aim of this study was to determine the contribution of rare functional PCSK1 mutations to obesity. PCSK1 exons were sequenced in 845 nonconsanguineous extremely obese Europeans. Eight novel nonsynonymous PCSK1 mutations were identified, all heterozygous. Seven mutations had a deleterious effect on either the maturation or the enzymatic activity of PC1/3 in cell lines. Of interest, five of these novel mutations, one of the previously described frequent variants (N221D), and the mutation found in an obese mouse model (N222D), affect residues at or near the structural calcium binding site Ca-1. The prevalence of the newly identified mutations was assessed in 6,233 obese and 6,274 lean European adults and children, which showed that carriers of any of these mutations causing partial PCSK1 deficiency had an 8.7-fold higher risk to be obese than wild-type carriers. These results provide the first evidence of an increased risk of obesity in heterozygous carriers of mutations in the PCSK1 gene. Furthermore, mutations causing partial PCSK1 deficiency are present in 0.83% of extreme obesity phenotypes.

  9. G6PD deficiency from lyonization after hematopoietic stem cell transplantation from female heterozygous donors.

    PubMed

    Au, W-Y; Pang, A; Lam, K K Y; Song, Y-Q; Lee, W-M; So, J C C; Kwong, Y-L

    2007-10-01

    To determine whether during hematopoietic stem cell transplantation (HSCT), X-chromosome inactivation (lyonization) of donor HSC might change after engraftment in recipients, the glucose-6-phosphate dehydrogenase (G6PD) gene of 180 female donors was genotyped by PCR/allele-specific primer extension, and MALDI-TOF mass spectrometry/Sequenom MassARRAY analysis. X-inactivation was determined by semiquantitative PCR for the HUMARA gene before/after HpaII digestion. X-inactivation was preserved in most cases post-HSCT, although altered skewing of lyonization might occur to either of the X-chromosomes. Among pre-HSCT clinicopathologic parameters analyzed, only recipient gender significantly affected skewing. Seven donors with normal G6PD biochemically but heterozygous for G6PD mutants were identified. Owing to lyonization changes, some donor-recipient pairs showed significantly different G6PD levels. In one donor-recipient pair, extreme lyonization affecting the wild-type G6PD allele occurred, causing biochemical G6PD deficiency in the recipient. In HSCT from asymptomatic female donors heterozygous for X-linked recessive disorders, altered lyonization might cause clinical diseases in the recipients.

  10. Novel Compound Heterozygous Mutations Expand the Recognized Phenotypes of FARS2-Linked Disease.

    PubMed

    Walker, Melissa A; Mohler, Kyle P; Hopkins, Kyle W; Oakley, Derek H; Sweetser, David A; Ibba, Michael; Frosch, Matthew P; Thibert, Ronald L

    2016-08-01

    Mutations in mitochondrial aminoacyl-tRNA synthetases are an increasingly recognized cause of human diseases, often arising in individuals with compound heterozygous mutations and presenting with system-specific phenotypes, frequently neurologic. FARS2 encodes mitochondrial phenylalanyl transfer ribonucleic acid (RNA) synthetase (mtPheRS), perturbations of which have been reported in 6 cases of an infantile, lethal disease with refractory epilepsy and progressive myoclonus. Here the authors report the case of juvenile onset refractory epilepsy and progressive myoclonus with compound heterozygous FARS2 mutations. The authors describe the clinical course over 6 years of care at their institution and diagnostic studies including electroencephalogram (EEG), brain magnetic resonance imaging (MRI), serum and cerebrospinal fluid analyses, skeletal muscle biopsy histology, and autopsy gross and histologic findings, which include features shared with Alpers-Huttenlocher syndrome, Leigh syndrome, and a previously published case of FARS2 mutation associated infantile onset disease. The authors also present structure-guided analysis of the relevant mutations based on published mitochondrial phenylalanyl transfer RNA synthetase and related protein crystal structures as well as biochemical analysis of the corresponding recombinant mutant proteins. © The Author(s) 2016.

  11. Primaquine-induced haemolysis in females heterozygous for G6PD deficiency.

    PubMed

    Chu, Cindy S; Bancone, Germana; Nosten, François; White, Nicholas J; Luzzatto, Lucio

    2018-03-02

    Oxidative agents can cause acute haemolytic anaemia in persons with G6PD deficiency. Understanding the relationship between G6PD genotype and the phenotypic expression of the enzyme deficiency is necessary so that severe haemolysis can be avoided. The patterns of oxidative haemolysis have been well described in G6PD deficient hemizygous males and homozygous females; and haemolysis in the proportionally more numerous heterozygous females has been documented mainly following consumption of fava beans and more recently dapsone. It has long been known that 8-aminoquinolines, notably primaquine and tafenoquine, cause acute haemolysis in G6PD deficiency. To support wider use of primaquine in Plasmodium vivax elimination, more data are needed on the haemolytic consequences of 8-aminoquinolines in G6PD heterozygous females. Two recent studies (in 2017) have provided precisely such data; and the need has emerged for the development of point of care quantitative testing of G6PD activity. Another priority is exploring alternative 8-aminoquinoline dosing regimens that are practical and improve safety in G6PD deficient individuals.

  12. Permanent Neonatal Diabetes Caused by Dominant, Recessive, or Compound Heterozygous SUR1 Mutations with Opposite Functional Effects

    PubMed Central

    Ellard, Sian ; Flanagan, Sarah E. ; Girard, Christophe A. ; Patch, Ann-Marie ; Harries, Lorna W. ; Parrish, Andrew ; Edghill, Emma L. ; Mackay, Deborah J. G. ; Proks, Peter ; Shimomura, Kenju ; Haberland, Holger ; Carson, Dennis J. ; Shield, Julian P. H. ; Hattersley, Andrew T. ; Ashcroft, Frances M. 

    2007-01-01

    Heterozygous activating mutations in the KCNJ11 gene encoding the pore-forming Kir6.2 subunit of the pancreatic beta cell KATP channel are the most common cause of permanent neonatal diabetes (PNDM). Patients with PNDM due to a heterozygous activating mutation in the ABCC8 gene encoding the SUR1 regulatory subunit of the KATP channel have recently been reported. We studied a cohort of 59 patients with permanent diabetes who received a diagnosis before 6 mo of age and who did not have a KCNJ11 mutation. ABCC8 gene mutations were identified in 16 of 59 patients and included 8 patients with heterozygous de novo mutations. A recessive mode of inheritance was observed in eight patients with homozygous, mosaic, or compound heterozygous mutations. Functional studies of selected mutations showed a reduced response to ATP consistent with an activating mutation that results in reduced insulin secretion. A novel mutational mechanism was observed in which a heterozygous activating mutation resulted in PNDM only when a second, loss-of-function mutation was also present. PMID:17668386

  13. Breast self-exam

    MedlinePlus

    Self-examination of the breast; BSE; Breast cancer - BSE; Breast cancer screening - self exam ... chap 15. US Preventive Services Task Force website. Breast cancer: screening. www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/breast- ...

  14. Breast reconstruction - natural tissue

    MedlinePlus

    ... flap; TUG; Mastectomy - breast reconstruction with natural tissue; Breast cancer - breast reconstruction with natural tissue ... it harder to find a tumor if your breast cancer comes back. The advantage of breast reconstruction with ...

  15. Benign Breast Conditions

    MedlinePlus

    ... common benign breast condition in men is called gynecomastia. This condition causes enlarged breast tissue. Female breasts ... with these less common, benign breast conditions. Male gynecomastia: A man’s breast will feel swollen and tender ...

  16. Breast cancer screening

    MedlinePlus

    Mammogram - breast cancer screening; Breast exam - breast cancer screening; MRI - breast cancer screening ... performed to screen women to detect early breast cancer when it is more likely to be cured. ...

  17. Efficient introduction of specific homozygous and heterozygous mutations using CRISPR/Cas9.

    PubMed

    Paquet, Dominik; Kwart, Dylan; Chen, Antonia; Sproul, Andrew; Jacob, Samson; Teo, Shaun; Olsen, Kimberly Moore; Gregg, Andrew; Noggle, Scott; Tessier-Lavigne, Marc

    2016-05-05

    The bacterial CRISPR/Cas9 system allows sequence-specific gene editing in many organisms and holds promise as a tool to generate models of human diseases, for example, in human pluripotent stem cells. CRISPR/Cas9 introduces targeted double-stranded breaks (DSBs) with high efficiency, which are typically repaired by non-homologous end-joining (NHEJ) resulting in nonspecific insertions, deletions or other mutations (indels). DSBs may also be repaired by homology-directed repair (HDR) using a DNA repair template, such as an introduced single-stranded oligo DNA nucleotide (ssODN), allowing knock-in of specific mutations. Although CRISPR/Cas9 is used extensively to engineer gene knockouts through NHEJ, editing by HDR remains inefficient and can be corrupted by additional indels, preventing its widespread use for modelling genetic disorders through introducing disease-associated mutations. Furthermore, targeted mutational knock-in at single alleles to model diseases caused by heterozygous mutations has not been reported. Here we describe a CRISPR/Cas9-based genome-editing framework that allows selective introduction of mono- and bi-allelic sequence changes with high efficiency and accuracy. We show that HDR accuracy is increased dramatically by incorporating silent CRISPR/Cas-blocking mutations along with pathogenic mutations, and establish a method termed 'CORRECT' for scarless genome editing. By characterizing and exploiting a stereotyped inverse relationship between a mutation's incorporation rate and its distance to the DSB, we achieve predictable control of zygosity. Homozygous introduction requires a guide RNA targeting close to the intended mutation, whereas heterozygous introduction can be accomplished by distance-dependent suboptimal mutation incorporation or by use of mixed repair templates. Using this approach, we generated human induced pluripotent stem cells with heterozygous and homozygous dominant early onset Alzheimer's disease-causing mutations in

  18. A hybrid BAC physical map of potato: a framework for sequencing a heterozygous genome

    PubMed Central

    2011-01-01

    Background Potato is the world's third most important food crop, yet cultivar improvement and genomic research in general remain difficult because of the heterozygous and tetraploid nature of its genome. The development of physical map resources that can facilitate genomic analyses in potato has so far been very limited. Here we present the methods of construction and the general statistics of the first two genome-wide BAC physical maps of potato, which were made from the heterozygous diploid clone RH89-039-16 (RH). Results First, a gel electrophoresis-based physical map was made by AFLP fingerprinting of 64478 BAC clones, which were aligned into 4150 contigs with an estimated total length of 1361 Mb. Screening of BAC pools, followed by the KeyMaps in silico anchoring procedure, identified 1725 AFLP markers in the physical map, and 1252 BAC contigs were anchored the ultradense potato genetic map. A second, sequence-tag-based physical map was constructed from 65919 whole genome profiling (WGP) BAC fingerprints and these were aligned into 3601 BAC contigs spanning 1396 Mb. The 39733 BAC clones that overlap between both physical maps provided anchors to 1127 contigs in the WGP physical map, and reduced the number of contigs to around 2800 in each map separately. Both physical maps were 1.64 times longer than the 850 Mb potato genome. Genome heterozygosity and incomplete merging of BAC contigs are two factors that can explain this map inflation. The contig information of both physical maps was united in a single table that describes hybrid potato physical map. Conclusions The AFLP physical map has already been used by the Potato Genome Sequencing Consortium for sequencing 10% of the heterozygous genome of clone RH on a BAC-by-BAC basis. By layering a new WGP physical map on top of the AFLP physical map, a genetically anchored genome-wide framework of 322434 sequence tags has been created. This reference framework can be used for anchoring and ordering of genomic

  19. The Nance-Horan syndrome: a rare X-linked ocular-dental trait with expression in heterozygous females.

    PubMed

    Bixler, D; Higgins, M; Hartsfield, J

    1984-07-01

    This report describes two families with the Nance-Horan syndrome, an X-linked trait featuring lenticular cataracts and anomalies of tooth shape and number. Previous reports have described blindness in affected males but posterior sutural cataracts with normal vision as the primary ocular expression in heterozygous females. In one of these two families, the affected female is not only blind in one eye but reportedly had supernumerary central incisors (mesiodens) removed. This constitutes the most severe ocular and dental expression of this gene in heterozygous females yet reported.

  20. A novel heterozygous mutation in the Birt-Hogg-Dubé Syndrome.

    PubMed

    Gómez Rivas, Juan; Carrión, Diego M; Alonso Y Gregorio, Sergio; Álvarez-Maestro, Mario; Tabernero Gómez, Ángel; Cisneros Ledo, Jesus

    2017-09-01

    Our aim is to present a novel mutation of the Birt-Hogg-Dubé Syndrome. We present a case report of a 70-year-old male with three solid nodulary lesions of 4, 2.6, and 3 cm each in the right kidney, and two lesions of 1.5 and 1.3 cm in the left kidney. Needle biopsy was performed. The pathological analysis of right kidney lesions revealed a renal tumor suggestive of chromophobe renal cell carcinoma and medullar tumor with zones that suggested oncocytosis. Genetic test results were positive for a novel heterozygous mutation c.1198G>A; p.V400I in exon 11 of the FLCN gene. In patients presenting with bilateral multifocal renal tumors of oncocytic hybrid histology, Birt- Hogg-Dubé syndrome should be the first diagnosis in mind. The mutation found in this patient has not been previously described in the literature in the context of BHD.

  1. Deferasirox pharmacokinetics evaluation in a woman with hereditary haemochromatosis and heterozygous β-thalassaemia.

    PubMed

    Allegra, Sarah; De Francia, Silvia; Longo, Filomena; Massano, Davide; Cusato, Jessica; Arduino, Arianna; Pirro, Elisa; Piga, Antonio; D'Avolio, Antonio

    2016-12-01

    We present the deferasirox pharmacokinetics evaluation of a female patient on iron chelation, for the interesting findings from her genetic background (hereditary haemochromatosis and heterozygous β-thalassaemia) and clinical history (ileostomy; iron overload from transfusions). Drug plasma concentrations were measured by an HPLC-UV validated method, before and after ileum resection. Area under deferasirox concentration curve over 24h (AUC) values were determined by the mixed log-linear rule, using Kinetica software. AUC was low also with high deferasirox dose as well as tolerability. Non invasive tissue iron quantification by magnetic resonance imaging or superconducting quantum interference device were prevented by a metal hip replacement. Good efficacy and normalisation of iron markers was obtained on long term. Therapeutic drug monitoring in patient in critical conditions may help to understand reasons for non response and set individualised treatment. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  2. A Japanese family with nonautoimmune hyperthyroidism caused by a novel heterozygous thyrotropin receptor gene mutation.

    PubMed

    Nakamura, Akie; Morikawa, Shuntaro; Aoyagi, Hayato; Ishizu, Katsura; Tajima, Toshihiro

    2014-06-01

    Hyperthyroidism caused by activating mutations of the thyrotropin receptor gene (TSHR) is rare in the pediatric population. We found a Japanese family with hyperthyroidism without autoantibody. DNA sequence analysis of TSHR was undertaken in this family. The functional consequences for the Gs-adenylyl cyclase and Gq/11-phospholipase C signaling pathways and cell surface expression of receptors were determined in vitro using transiently transfected human embryonic kidney 293 cells. We identified a heterozygous mutation (M453R) in exon 10 of TSHR. In this family, this mutation was found in all individuals who exhibited hyperthyroidism. The results showed that this mutation resulted in constitutive activation of the Gs-adenylyl cyclase system. However, this mutation also caused a reduction in the activation capacity of the Gq/11-phospholipase C pathway, compared with the wild type. We demonstrate that the M453R mutation is the cause of nonautoimmune hyperthyroidism.

  3. Expanded clinical spectrum of spondylocarpotarsal synostosis syndrome and possible manifestation in a heterozygous father.

    PubMed

    Mitter, Diana; Krakow, Deborah; Farrington-Rock, Claire; Meinecke, Peter

    2008-03-15

    We report on a 5-year-old boy with spondylocarpotarsal synostosis (SCT) syndrome who presents with disproportionate short stature, thoracic scoliosis, pes planus, dental enamel hypoplasia, unilateral conductive hearing loss and mild facial dysmorphisms. Radiographs showed abnormal segmentation of the spine with block vertebrae and carpal synostosis. In addition to the typical phenotype of SCT syndrome, he showed pronounced delay of carpal bone age and bilateral epiphyseal dysplasia of the proximal femora. The patient's father has mild short stature and unilateral hip dysplasia. Molecular studies of the filamin B gene (FLNB) revealed a homozygous mutation in the index patient while both parents were heterozygous for the mutation. In this report we expand the phenotype of SCT syndrome in a patient with a causal FLNB mutation. (c) 2008 Wiley-Liss, Inc.

  4. A novel heterozygous SOX2 mutation causing anophthalmia/microphthalmia with genital anomalies.

    PubMed

    Pedace, Lucia; Castori, Marco; Binni, Francesco; Pingi, Alberto; Grammatico, Barbara; Scommegna, Salvatore; Majore, Silvia; Grammatico, Paola

    2009-01-01

    Anophthalmia/microphthalmia is a rare developmental craniofacial defect, which recognizes a wide range of causes, including chromosomal abnormalities, single-gene mutations as well as environmental factors. Heterozygous mutations in the SOX2 gene are the most common monogenic form of anophthalmia/microphthalmia, as they are reported in up to 10-15% cases. Here, we describe a sporadic patient showing bilateral anophthalmia/microphthalmia and micropenis caused by a novel mutation (c.59_60insGG) in the SOX2 gene. Morphological and endocrinological evaluations excluded any anomaly of the hypothalamus-pituitary axis. Our finding supports the hypothesis that SOX2 is particularly prone to slipped-strand mispairing, which results in a high frequency of point deletions/insertions.

  5. Novel heterozygous NOTCH3 pathogenic variant found in two Chinese patients with CADASIL.

    PubMed

    Li, Shufeng; Chen, Yifan; Shan, Haitao; Ma, Fang; Shi, Minke; Xue, Jun

    2017-12-01

    NOTCH3 mutations have been described to cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Here, we report 2 CADASIL patients from a Chinese family. Whole genome sequencing was performed on the two CADASIL patients. The novel variant c.128G>C in exon 2 of NOTCH3 was identified and confirmed through PCR-Sanger sequencing (Human Genome Variation Society nomenclature: HGVS: NOTCH3 c.128G>C; p.Cys43Ser). The heterozygous NOTCH3 variant cause a cysteine to serine substitution at codon 43. According to the variant interpretation guideline of American College of Medical Genetics and Genomics (ACMG), this variant was classified as "pathogenic". Other variants in HTRA1, COL4A1 and COL4A2 were also found, they were classified as "benign". Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Modest increased sensitivity to radiation oncogenesis in ATM heterozygous versus wild-type mammalian cells

    NASA Technical Reports Server (NTRS)

    Smilenov, L. B.; Brenner, D. J.; Hall, E. J.

    2001-01-01

    Subpopulations that are genetically predisposed to radiation-induced cancer could have significant public health consequences. Individuals homozygous for null mutations at the ataxia telangiectasia gene are indeed highly radiosensitive, but their numbers are very small. Ataxia Telangiectasia heterozygotes (1-2% of the population) have been associated with somewhat increased radiosensitivity for some end points, but none directly related to carcinogenesis. Here, intralitter comparisons between wild-type mouse embryo fibroblasts and mouse embryo fibroblasts carrying ataxia telangiectasia mutated (ATM) null mutation indicate that the heterozygous cells are more sensitive to radiation oncogenesis than their normal, litter-matched, counterparts. From these data we suggest that Ataxia Telangiectasia heterozygotes could indeed represent a societally-significant radiosensitive human subpopulation.

  7. Cytomorphologic signs of severe pernicious anemia obscured in a patient with heterozygous hemoglobin Stanleyville II.

    PubMed

    Draube, Andreas; Chemnitz, Jens M; Wickenhauser, Claudia; Staib, Peter; Hallek, Michael; Kreuzer, Karl-Anton

    2007-10-01

    Here, we report a rare coincidence of heterozygous hemoglobinopathy (Hb) Stanleyville II and severe pernicious anemia due to autoimmune gastritis. Hb Stanleyville II is characterized by a single base exchange (AAC-->AAA) resulting in a substitution Asn --> Lys at position 78 of hemoglobin alpha2-chain. Under normal conditions this hemoglobinopathy does not cause any symptoms even if present as homozygous variant. However, in our case diagnosis of pernicious anemia was hampered by the absence of typical erythrocytic macrocytosis and hyperchromasia. In addition, interpretation of bone marrow smears was difficult as characteristic findings for pernicious anemia were little pronounced. All known reasons for the absence of typical cytomorphologic signs in pernicious anemia as underlying iron deficiency and thalassemia could be excluded.

  8. Sector Retinitis Pigmentosa Associated With Novel Compound Heterozygous Mutations of CDH23.

    PubMed

    Branson, Sara V; McClintic, Jedediah I; Stamper, Tara H; Haldeman-Englert, Chad R; John, Vishak J

    2016-02-01

    Usher syndrome is an autosomal recessive condition characterized by retinitis pigmentosa (RP) and congenital hearing loss, with or without vestibular dysfunction. Allelic variants of CDH23 cause both Usher syndrome type 1D (USH1D) and a form of nonsyndromic hearing loss (DFNB12). The authors describe here a 34-year-old patient with congenital hearing loss and a new diagnosis of sector RP who was found to have two novel compound heterozygous mutations in CDH23, including one missense (c.8530C > A; p.Pro2844Thr) and one splice-site (c.5820 + 5G > A) mutation. This is the first report of sector RP associated with these types of mutations in CDH23. Copyright 2016, SLACK Incorporated.

  9. Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction.

    PubMed

    Wesdorp, Mieke; de Koning Gans, Pia A M; Schraders, Margit; Oostrik, Jaap; Huynen, Martijn A; Venselaar, Hanka; Beynon, Andy J; van Gaalen, Judith; Piai, Vitória; Voermans, Nicol; van Rossum, Michelle M; Hartel, Bas P; Lelieveld, Stefan H; Wiel, Laurens; Verbist, Berit; Rotteveel, Liselotte J; van Dooren, Marieke F; Lichtner, Peter; Kunst, Henricus P M; Feenstra, Ilse; Admiraal, Ronald J C; Yntema, Helger G; Hoefsloot, Lies H; Pennings, Ronald J E; Kremer, Hannie

    2018-05-12

    Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein-protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families.

  10. Myocardial layer-specific analysis in patients with heterozygous familial hypercholesterolemia using speckle tracking echocardiography.

    PubMed

    Leng, Zhaoting; Li, Rongjuan; Li, Yijia; Wang, Lvya; Wang, Yueli; Yang, Ya

    2017-03-01

    Familial hypercholesterolemia (FH) is the most common and serious monogenic disorder of lipid metabolism, causing premature coronary heart disease (CHD) due to accelerated atherosclerosis from birth, and the study of left ventricular (LV) function of this disease is seldom. The purpose of this study was to explore the value of layer-specific strain on assessing the early damage of LV function in asymptomatic and left ventricular ejection fraction (LVEF) well-preserved patients with heterozygous FH (HeFH). A total of 49 patients aged 38.7±8.7 diagnosed with heterozygous familial hypercholesterolemia and who had undergone transthoracic echocardiography from 2010 to 2016 were included in this study. A total 32 healthy volunteers aged 35.6±10.3 were included as control group. Longitudinal and circumferential strains of the endocardium, myocardium, and epicardium (LSendo, LSmyo, and LSepi and CSendo, CSmyo, and CSepi) were obtained by a software enabling the analysis of strains in three myocardial layers. In longitudinal strain (LS), the LS of endocardium (LSendo) and the LS of myocardium (LSmyo) are significantly reduced in patients with HeFH (P<.001 in both). In circumferential strain (CS), only the CS of endocardium (CSendo) is significantly reduced (P<.001). The degree of reduction in strain is positively correlated with the TC and LDLC. Layer-specific evaluation of the left ventricle has great value in evaluating early impairment of LV in patients with FH. And this relatively novel technique may made it possible to help us understand the process of LV impairment in patients with FH better, thus preventing further damage. © 2017, Wiley Periodicals, Inc.

  11. Compound heterozygous TYK2 mutations underlie primary immunodeficiency with T-cell lymphopenia.

    PubMed

    Nemoto, Michiko; Hattori, Hiroyoshi; Maeda, Naoko; Akita, Nobuhiro; Muramatsu, Hideki; Moritani, Suzuko; Kawasaki, Tomonori; Maejima, Masami; Ode, Hirotaka; Hachiya, Atsuko; Sugiura, Wataru; Yokomaku, Yoshiyuki; Horibe, Keizo; Iwatani, Yasumasa

    2018-05-03

    Complete tyrosine kinase 2 (TYK2) deficiency has been previously described in patients with primary immunodeficiency diseases. The patients were infected with various pathogens, including mycobacteria and/or viruses, and one of the patients developed hyper-IgE syndrome. A detailed immunological investigation of these patients revealed impaired responses to type I IFN, IL-10, IL-12 and IL-23, which are associated with increased susceptibility to mycobacterial and/or viral infections. Herein, we report a recessive partial TYK2 deficiency in two siblings who presented with T-cell lymphopenia characterized by low naïve CD4 + T-cell counts and who developed Epstein-Barr virus (EBV)-associated B-cell lymphoma. Targeted exome-sequencing of the siblings' genomes demonstrated that both patients carried novel compound heterozygous mutations (c.209_212delGCTT/c.691C > T, p.Cys70Serfs*21/p.Arg231Trp) in the TYK2. The TYK2 protein levels were reduced by 35% in the T cells of the patient. Unlike the response under complete TYK2 deficiency, the patient's T cells responded normally to type I IFN, IL-6, IL-10 and IL-12, whereas the cells displayed an impaired response to IL-23. Furthermore, the level of STAT1 was low in the cells of the patient. These studies reveal a new clinical entity of a primary immunodeficiency with T-cell lymphopenia that is associated with compound heterozygous TYK2 mutations in the patients.

  12. Novel USH2A compound heterozygous mutations cause RP/USH2 in a Chinese family.

    PubMed

    Liu, Xiaowen; Tang, Zhaohui; Li, Chang; Yang, Kangjuan; Gan, Guanqi; Zhang, Zibo; Liu, Jingyu; Jiang, Fagang; Wang, Qing; Liu, Mugen

    2010-03-17

    To identify the disease-causing gene in a four-generation Chinese family affected with retinitis pigmentosa (RP). Linkage analysis was performed with a panel of microsatellite markers flanking the candidate genetic loci of RP. These loci included 38 known RP genes. The complete coding region and exon-intron boundaries of Usher syndrome 2A (USH2A) were sequenced with the proband DNA to screen the disease-causing gene mutation. Restriction fragment length polymorphism (RFLP) analysis and direct DNA sequence analysis were done to demonstrate co-segregation of the USH2A mutations with the family disease. One hundred normal controls were used without the mutations. The disease-causing gene in this Chinese family was linked to the USH2A locus on chromosome 1q41. Direct DNA sequence analysis of USH2A identified two novel mutations in the patients: one missense mutation p.G1734R in exon 26 and a splice site mutation, IVS32+1G>A, which was found in the donor site of intron 32 of USH2A. Neither the p.G1734R nor the IVS32+1G>A mutation was found in the unaffected family members or the 100 normal controls. One patient with a homozygous mutation displayed only RP symptoms until now, while three patients with compound heterozygous mutations in the family of study showed both RP and hearing impairment. This study identified two novel mutations: p.G1734R and IVS32+1G>A of USH2A in a four-generation Chinese RP family. In this study, the heterozygous mutation and the homozygous mutation in USH2A may cause Usher syndrome Type II or RP, respectively. These two mutations expand the mutant spectrum of USH2A.

  13. Short Stature, Accelerated Bone Maturation, and Early Growth Cessation Due to Heterozygous Aggrecan Mutations

    PubMed Central

    Nilsson, Ola; Guo, Michael H.; Dunbar, Nancy; Popovic, Jadranka; Flynn, Daniel; Jacobsen, Christina; Lui, Julian C.; Hirschhorn, Joel N.; Baron, Jeffrey

    2014-01-01

    Context: Many children with idiopathic short stature have a delayed bone age. Idiopathic short stature with advanced bone age is far less common. Objective: The aim was to identify underlying genetic causes of short stature with advanced bone age. Setting and Design: We used whole-exome sequencing to study three families with autosomal-dominant short stature, advanced bone age, and premature growth cessation. Results: Affected individuals presented with short stature [adult heights −2.3 to −4.2 standard deviation scores (SDS)] with histories of early growth cessation or childhood short stature (height SDS −1.9 to −3.5 SDS), advancement of bone age, and normal endocrine evaluations. Whole-exome sequencing identified novel heterozygous variants in ACAN, which encodes aggrecan, a proteoglycan in the extracellular matrix of growth plate and other cartilaginous tissues. The variants were present in all affected, but in no unaffected, family members. In Family 1, a novel frameshift mutation in exon 3 (c.272delA) was identified, which is predicted to cause early truncation of the aggrecan protein. In Family 2, a base-pair substitution was found in a highly conserved location within a splice donor site (c.2026+1G>A), which is also likely to alter the amino acid sequence of a large portion of the protein. In Family 3, a missense variant (c.7064T>C) in exon 14 affects a highly conserved residue (L2355P) and is strongly predicted to perturb protein function. Conclusions: Our study demonstrates that heterozygous mutations in ACAN can cause a mild skeletal dysplasia, which presents clinically as short stature with advanced bone age. The accelerating effect on skeletal maturation has not previously been noted in the few prior reports of human ACAN mutations. Our findings thus expand the spectrum of ACAN defects and provide a new molecular genetic etiology for the unusual child who presents with short stature and accelerated skeletal maturation. PMID:24762113

  14. A High Quality Draft Consensus Sequence of the Genome of a Heterozygous Grapevine Variety

    PubMed Central

    Cartwright, Dustin A.; Cestaro, Alessandro; Pruss, Dmitry; Pindo, Massimo; FitzGerald, Lisa M.; Vezzulli, Silvia; Reid, Julia; Malacarne, Giulia; Iliev, Diana; Coppola, Giuseppina; Wardell, Bryan; Micheletti, Diego; Macalma, Teresita; Facci, Marco; Mitchell, Jeff T.; Perazzolli, Michele; Eldredge, Glenn; Gatto, Pamela; Oyzerski, Rozan; Moretto, Marco; Gutin, Natalia; Stefanini, Marco; Chen, Yang; Segala, Cinzia; Davenport, Christine; Demattè, Lorenzo; Mraz, Amy; Battilana, Juri; Stormo, Keith; Costa, Fabrizio; Tao, Quanzhou; Si-Ammour, Azeddine; Harkins, Tim; Lackey, Angie; Perbost, Clotilde; Taillon, Bruce; Stella, Alessandra; Solovyev, Victor; Fawcett, Jeffrey A.; Sterck, Lieven; Vandepoele, Klaas; Grando, Stella M.; Toppo, Stefano; Moser, Claudio; Lanchbury, Jerry; Bogden, Robert; Skolnick, Mark; Sgaramella, Vittorio; Bhatnagar, Satish K.; Fontana, Paolo; Gutin, Alexander; Van de Peer, Yves; Salamini, Francesco; Viola, Roberto

    2007-01-01

    Background Worldwide, grapes and their derived products have a large market. The cultivated grape species Vitis vinifera has potential to become a model for fruit trees genetics. Like many plant species, it is highly heterozygous, which is an additional challenge to modern whole genome shotgun sequencing. In this paper a high quality draft genome sequence of a cultivated clone of V. vinifera Pinot Noir is presented. Principal Findings We estimate the genome size of V. vinifera to be 504.6 Mb. Genomic sequences corresponding to 477.1 Mb were assembled in 2,093 metacontigs and 435.1 Mb were anchored to the 19 linkage groups (LGs). The number of predicted genes is 29,585, of which 96.1% were assigned to LGs. This assembly of the grape genome provides candidate genes implicated in traits relevant to grapevine cultivation, such as those influencing wine quality, via secondary metabolites, and those connected with the extreme susceptibility of grape to pathogens. Single nucleotide polymorphism (SNP) distribution was consistent with a diffuse haplotype structure across the genome. Of around 2,000,000 SNPs, 1,751,176 were mapped to chromosomes and one or more of them were identified in 86.7% of anchored genes. The relative age of grape duplicated genes was estimated and this made possible to reveal a relatively recent Vitis-specific large scale duplication event concerning at least 10 chromosomes (duplication not reported before). Conclusions Sanger shotgun sequencing and highly efficient sequencing by synthesis (SBS), together with dedicated assembly programs, resolved a complex heterozygous genome. A consensus sequence of the genome and a set of mapped marker loci were generated. Homologous chromosomes of Pinot Noir differ by 11.2% of their DNA (hemizygous DNA plus chromosomal gaps). SNP markers are offered as a tool with the potential of introducing a new era in the molecular breeding of grape. PMID:18094749

  15. Novel compound heterozygous mutations identified by whole exome sequencing in a Japanese patient with geroderma osteodysplastica.

    PubMed

    Takeda, Ryojun; Takagi, Masaki; Shinohara, Hiroyuki; Futagawa, Hiroshi; Narumi, Satoshi; Hasegawa, Tomonobu; Nishimura, Gen; Yoshihashi, Hiroshi

    2017-12-01

    Geroderma osteodysplastica (GO) is a subtype of cutis laxa syndrome characterized by congenital wrinkly skin, a prematurely aged face, extremely short stature, and osteoporosis leading to recurrent fractures. GO exhibits an autosomal recessive inheritance pattern and is caused by loss-of-function mutations in GORAB, which encodes a protein important for Golgi-related transport. Using whole exome sequencing, we identified novel compound heterozygous nonsense mutations in the GORAB in a GO patient. The patient was a 14-year-old Japanese boy. Wrinkled skin and joint laxity were present at birth. At 1 year of age, he was clinically diagnosed with cutis laxa syndrome based on recurrent long bone fractures and clinical features, including wrinkled skin, joint laxity, and a distinctive face. He did not show retarded gross motor and cognitive development. At 11 years of age, he was treated with oral bisphosphonate and vitamin D owing to recurrent multiple spontaneous fractures of the vertebral and extremity bones associated with a low bone mineral density (BMD). Bisphosphonate treatment improved his BMD and fracture rate. Whole exome sequencing revealed two novel compound heterozygous nonsense mutations in the GORAB gene (p.Arg60* and p.Gln124*), and the diagnosis of GO was established. GO is a rare connective tissue disorder. Approximately 60 cases have been described to date, and this is the first report of a patient from Japan. Few studies have reported the effects of bisphosphonate treatment in GO patients with recurrent spontaneous fractures. Based on this case study, we hypothesize that oral bisphosphonate and vitamin D are effective and safe treatment options for the management of recurrent fractures in GO patients. It is important to establish a precise diagnosis of GO to prevent recurrent fractures and optimize treatment plans. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  16. Juvenile Paget’s Disease With Heterozygous Duplication In TNFRSF11A Encoding RANK

    PubMed Central

    Whyte, Michael P.; Tau, Cristina; McAlister, William H.; Zhang, Xiafang; Novack, Deborah V.; Preliasco, Virginia; Santini-Araujo, Eduardo; Mumm, Steven

    2014-01-01

    Mendelian disorders of RANKL/OPG/RANK signaling feature the extremes of aberrant osteoclastogenesis and cause either osteopetrosis or rapid turnover skeletal disease. The patients with autosomal dominant accelerated bone remodeling have familial expansile osteolysis, early-onset Paget’s disease of bone, expansile skeletal hyperphosphatasia, or panostotic expansile bone disease due to heterozygous 18-, 27-, 15-, and 12-bp insertional duplications, respectively, within exon 1 of TNFRSF11A that encodes the signal peptide of RANK. Juvenile Paget’s disease (JPD), an autosomal recessive disorder, manifests extremely fast skeletal remodeling, and is usually caused by loss-of-function mutations within TNFRSF11B that encodes OPG. These disorders are ultra-rare. A 13-year-old Bolivian girl was referred at age 3 years. One femur was congenitally short and curved. Then, both bowed. Deafness at age 2 years involved missing ossicles and eroded cochleas. Teeth often had absorbed roots, broke, and were lost. Radiographs had revealed acquired tubular bone widening, cortical thickening, and coarse trabeculation. Biochemical markers indicated rapid skeletal turnover. Histopathology showed accelerated remodeling with abundant osteoclasts. JPD was diagnosed. Immobilization from a femur fracture caused severe hypercalcemia that responded rapidly to pamidronate treatment followed by bone turnover marker and radiographic improvement. No TNFRSF11B mutation was found. Instead, a unique heterozygous 15-bp insertional tandem duplication (87dup15) within exon 1 of TNFRSF11A predicted the same pentapeptide extension of RANK that causes expansile skeletal hyperphosphatasia (84dup15). Single nucleotide polymorphisms in TNFRSF11A and TNFRSF11B possibly impacted her phenotype. Our findings: i) reveal that JPD can be associated with an activating mutation within TNFRSF11A, ii) expand the range and overlap of phenotypes among the mendelian disorders of RANK activation, and iii) call for mutation

  17. Breast Lumps

    MedlinePlus

    ... 2015. Raftery AT, et al. Breast lumps. In: Churchill's Pocketbook of Differential Diagnosis. 4th ed. Philadelphia, Pa.: Churchill Livingston Elsevier; 2014. http://www.clinicalkey.com. Accessed ...

  18. Project W.A.T.E.R.

    ERIC Educational Resources Information Center

    EnviroTeach, 1992

    1992-01-01

    Introduces networking projects for studying rivers and water quality. Describes two projects in South Africa (Project W.A.T.E.R and SWAP) associated with the international network, Global Rivers Environmental Education Network. Discusses water test kits and educational material developed through Project W.A.T.E.R. (Water Awareness through…

  19. Broad phenotypes in heterozygous NR5A1 46,XY patients with a disorder of sex development: an oligogenic origin?

    PubMed

    Camats, Núria; Fernández-Cancio, Mónica; Audí, Laura; Schaller, André; Flück, Christa E

    2018-06-11

    SF-1/NR5A1 is a transcriptional regulator of adrenal and gonadal development. NR5A1 disease-causing variants cause disorders of sex development (DSD) and adrenal failure, but most affected individuals show a broad DSD/reproductive phenotype only. Most NR5A1 variants show in vitro pathogenic effects, but not when tested in heterozygote state together with wild-type NR5A1 as usually seen in patients. Thus, the genotype-phenotype correlation for NR5A1 variants remains an unsolved question. We analyzed heterozygous 46,XY SF-1/NR5A1 patients by whole exome sequencing and used an algorithm for data analysis based on selected project-specific DSD- and SF-1-related genes. The variants detected were evaluated for their significance in literature, databases and checked in silico using webtools. We identified 19 potentially deleterious variants (one to seven per patient) in 18 genes in four 46,XY DSD subjects carrying heterozygous NR5A1 disease-causing variants. We constructed a scheme of all these hits within the landscape of currently known genes involved in male sex determination and differentiation. Our results suggest that the broad phenotype in these heterozygous NR5A1 46,XY DSD subjects may well be explained by an oligogenic mode of inheritance, in which multiple hits, individually non-deleterious, may contribute to a DSD phenotype unique to each heterozygous SF-1/NR5A1 individual.

  20. Heterozygous mapping strategy (HetMapps)for high resolution genotyping-by-sequencing markers: a case study in grapevine

    USDA-ARS?s Scientific Manuscript database

    Genotyping by sequencing (GBS) provides opportunities to generate high-resolution genetic maps at a low per-sample genotyping cost, but missing data and under-calling of heterozygotes complicate the creation of GBS linkage maps for highly heterozygous species. To overcome these issues, we developed ...

  1. Mipomersen: evidence-based review of its potential in the treatment of homozygous and severe heterozygous familial hypercholesterolemia.

    PubMed

    Parhofer, Klaus G

    2012-01-01

    Familial hypercholesterolemia (FH) is an autosomal-dominant inherited disease with a prevalence of one in 500 (heterozygous) to one in 1,000,000 (homozygous). Mutations of the low-density lipoprotein (LDL) receptor gene, the apolipoprotein B100 gene, or the PCSK9 gene may be responsible for the disease. The resulting LDL hypercholesterolemia results in premature atherosclerosis as early as childhood (homozygous FH) or in adulthood (heterozygous FH). Current treatment modalities include lifestyle modification, combination drug therapy (statin-based), and apheresis. Mipomersen is an antisense oligonucleotide which inhibits apolipoprotein B production independent of LDL receptor function and thus works in homozygous FH, heterozygous FH, and other forms of hypercholesterolemia. Mipomersen is given 200 mg/week subcutaneously. Phase III studies indicate that the LDL cholesterol concentration can be reduced by 25%-47%, lipoprotein(a) levels by 20%-40%, and triglyceride concentrations by approximately 10%. In general, mipomersen has no effect on high-density lipoprotein cholesterol concentrations. Although there is considerable interindividual variability, the observed lipid effects are largely independent of age, gender, concomitant statin therapy, and underlying dyslipoproteinemia. The most common side effects are injection site reactions (70%-100%), flu-like symptoms (29%-46%), and elevated transaminases associated with an increased liver fat content (6%-15%). Mipomersen may be an interesting addon drug in patients with heterozygous or homozygous FH not reaching treatment goals, either because baseline values are very high or because high-dose statins are not tolerated.

  2. Mipomersen: evidence-based review of its potential in the treatment of homozygous and severe heterozygous familial hypercholesterolemia

    PubMed Central

    Parhofer, Klaus G

    2012-01-01

    Familial hypercholesterolemia (FH) is an autosomal-dominant inherited disease with a prevalence of one in 500 (heterozygous) to one in 1,000,000 (homozygous). Mutations of the low-density lipoprotein (LDL) receptor gene, the apolipoprotein B100 gene, or the PCSK9 gene may be responsible for the disease. The resulting LDL hypercholesterolemia results in premature atherosclerosis as early as childhood (homozygous FH) or in adulthood (heterozygous FH). Current treatment modalities include lifestyle modification, combination drug therapy (statin-based), and apheresis. Mipomersen is an antisense oligonucleotide which inhibits apolipoprotein B production independent of LDL receptor function and thus works in homozygous FH, heterozygous FH, and other forms of hypercholesterolemia. Mipomersen is given 200 mg/week subcutaneously. Phase III studies indicate that the LDL cholesterol concentration can be reduced by 25%–47%, lipoprotein(a) levels by 20%–40%, and triglyceride concentrations by approximately 10%. In general, mipomersen has no effect on high-density lipoprotein cholesterol concentrations. Although there is considerable interindividual variability, the observed lipid effects are largely independent of age, gender, concomitant statin therapy, and underlying dyslipoproteinemia. The most common side effects are injection site reactions (70%–100%), flu-like symptoms (29%–46%), and elevated transaminases associated with an increased liver fat content (6%–15%). Mipomersen may be an interesting addon drug in patients with heterozygous or homozygous FH not reaching treatment goals, either because baseline values are very high or because high-dose statins are not tolerated. PMID:22701100

  3. Heterozygous deletion at the SOX10 gene locus in two patients from a Chinese family with Waardenburg syndrome type II.

    PubMed

    Wenzhi, He; Ruijin, Wen; Jieliang, Li; Xiaoyan, Ma; Haibo, Liu; Xiaoman, Wang; Jiajia, Xian; Shaoying, Li; Shuanglin, Li; Qing, Li

    2015-10-01

    Waardenburg syndrome (WS) is a rare disease characterized by sensorineural deafness and pigment disturbance. To date, almost 100 mutations have been reported, but few reports on cases with SOX10 gene deletion. The inheritance pattern of SOX10 gene deletion is still unclear. Our objective was to identify the genetic causes of Waardenburg syndrome type II in a two-generation Chinese family. Clinical evaluations were conducted in both of the patients. Microarray analysis and multiplex ligation-dependent probe amplification (MLPA) were performed to identify disease-related copy number variants (CNVs). DNA sequencing of the SOX10, MITF and SNAI2 genes was performed to identify the pathogenic mutation responsible for WS2. A 280kb heterozygous deletion at the 22q13.1 chromosome region (including SOX10) was detected in both of the patients. No mutation was found in the patients, unaffected family members and 30 unrelated healthy controls. This report is the first to describe SOX10 heterozygous deletions in Chinese WS2 patients. Our result conform the thesis that heterozygous deletions at SOX10 is an important pathogenicity for WS, and present as autosomal dominant inheritance. Nevertheless, heterozygous deletion of the SOX10 gene would be worth investigating to understand their functions and contributions to neurologic phenotypes. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  4. Breast Feeding.

    ERIC Educational Resources Information Center

    International Children's Centre, Paris (France).

    This set of documents consists of English, French, and Spanish translations of four pamphlets on breast-feeding. The pamphlets provide information designed for lay persons, academics and professionals, health personnel and educators, and policy-makers. The contents cover health-related differences between breast and bottle milk; patterns of…

  5. Breast Cancer

    MedlinePlus

    ... the body. Breast cancer is the second most common cancer among women (after skin cancer). The good news is that the rate of death from ... is removed during surgery. Surgery is the most common treatment for breast ... effects on your body. Take good care of yourself. Eat a healthy diet, get ...

  6. Mice heterozygous for the ATM gene are more sensitive to heavy ions exposure than are wildtypes

    NASA Astrophysics Data System (ADS)

    Worgul, B.; Smilenov, L.; Brenner, D.; Vazquez, M.; Hall, E.

    Previous studies have shown that the eyes of atm heterozygous mice exposed to Low LET radiation (X-rays) are more susceptible to the development of cataracts than are those of wildtype mice. The findings, as well as others, run counter to the assumption underpinning current radiation safety guidelines, that individuals are all equally sensitive to the biological effects of radiation. A question, highly relevant to human space activities is whether or not, in similar fashion there may exist a genetic predisposition to High LET radiation damage. Again the lens and, its primary radiopathy, cataract, were used to assay for the effects of ATM deficiency in a late-responding tissue. Together with those of wildtypes, the eyes of AT heterozygous knockout mice were exposed to 325 mGy of 1 GEV/amu 56Fe ions at the AGS facility of Brookhaven National Laboratory. The fluence was equivalent to 1 ion per nuclear area. As was the case in the earlier X-ray studies all irradiations were done on the 28th day after birth. Controls consisted of wildtype irradiated as well as unirradiated wildtype and heterozygotes. Ten mice from each group were examined weekly by conventional slitlamp biomicroscopy for a total of 35 weeks. The time required for prevalence to reach 50% (T50) as an endpoint for each stage indicated that not only cataract onset but also progression were accelerated in the mice haplo-deficient for the atm gene. For example the T50 for definitive cataract onset (stage 1) in the atm heterozygotes was 10 weeks whereas 17 weeks were required for the wildtypes. Similarly at the conclusion of the experiment (35 weeks), 40% of the lenses of allele-deficient mice had progressed to stage 3 (near fully opaque and obviously visually debilitating), while only one lens (5%) from the wildtype irradiated eyes achieved that stage. The data show that heterozygosity for the atm gene predisposes the eye to the cataractogenic influence of heavy ions and suggest that AT heterozygotes in the

  7. Heterozygous inactivation of tsc2 enhances tumorigenesis in p53 mutant zebrafish

    PubMed Central

    Kim, Seok-Hyung; Kowalski, Marie L.; Carson, Robert P.; Bridges, L. Richard; Ess, Kevin C.

    2013-01-01

    SUMMARY Tuberous sclerosis complex (TSC) is a multi-organ disorder caused by mutations of the TSC1 or TSC2 genes. A key function of these genes is to inhibit mTORC1 (mechanistic target of rapamycin complex 1) kinase signaling. Cells deficient for TSC1 or TSC2 have increased mTORC1 signaling and give rise to benign tumors, although, as a rule, true malignancies are rarely seen. In contrast, other disorders with increased mTOR signaling typically have overt malignancies. A better understanding of genetic mechanisms that govern the transformation of benign cells to malignant ones is crucial to understand cancer pathogenesis. We generated a zebrafish model of TSC and cancer progression by placing a heterozygous mutation of the tsc2 gene in a p53 mutant background. Unlike tsc2 heterozygous mutant zebrafish, which never exhibited cancers, compound tsc2;p53 mutants had malignant tumors in multiple organs. Tumorigenesis was enhanced compared with p53 mutant zebrafish. p53 mutants also had increased mTORC1 signaling that was further enhanced in tsc2;p53 compound mutants. We found increased expression of Hif1-α, Hif2-α and Vegf-c in tsc2;p53 compound mutant zebrafish compared with p53 mutant zebrafish. Expression of these proteins probably underlies the increased angiogenesis seen in compound mutant zebrafish compared with p53 mutants and might further drive cancer progression. Treatment of p53 and compound mutant zebrafish with the mTORC1 inhibitor rapamycin caused rapid shrinkage of tumor size and decreased caliber of tumor-associated blood vessels. This is the first report using an animal model to show interactions between tsc2, mTORC1 and p53 during tumorigenesis. These results might explain why individuals with TSC rarely have malignant tumors, but also suggest that cancer arising in individuals without TSC might be influenced by the status of TSC1 and/or TSC2 mutations and be potentially treatable with mTORC1 inhibitors. PMID:23580196

  8. Macrosomia and Hyperinsulinaemic Hypoglycaemia in Patients with Heterozygous Mutations in the HNF4A Gene

    PubMed Central

    Barrett, Timothy; Stals, Karen; Shield, Julian P; Ellard, Sian; Ferrer, Jorge; Hattersley, Andrew T

    2007-01-01

    Background Macrosomia is associated with considerable neonatal and maternal morbidity. Factors that predict macrosomia are poorly understood. The increased rate of macrosomia in the offspring of pregnant women with diabetes and in congenital hyperinsulinaemia is mediated by increased foetal insulin secretion. We assessed the in utero and neonatal role of two key regulators of pancreatic insulin secretion by studying birthweight and the incidence of neonatal hypoglycaemia in patients with heterozygous mutations in the maturity-onset diabetes of the young (MODY) genes HNF4A (encoding HNF-4α) and HNF1A/TCF1 (encoding HNF-1α), and the effect of pancreatic deletion of Hnf4a on foetal and neonatal insulin secretion in mice. Methods and Findings We examined birthweight and hypoglycaemia in 108 patients from families with diabetes due to HNF4A mutations, and 134 patients from families with HNF1A mutations. Birthweight was increased by a median of 790 g in HNF4A-mutation carriers compared to non-mutation family members (p < 0.001); 56% (30/54) of HNF4A-mutation carriers were macrosomic compared with 13% (7/54) of non-mutation family members (p < 0.001). Transient hypoglycaemia was reported in 8/54 infants with heterozygous HNF4A mutations, but was reported in none of 54 non-mutation carriers (p = 0.003). There was documented hyperinsulinaemia in three cases. Birthweight and prevalence of neonatal hypoglycaemia were not increased in HNF1A-mutation carriers. Mice with pancreatic β-cell deletion of Hnf4a had hyperinsulinaemia in utero and hyperinsulinaemic hypoglycaemia at birth. Conclusions HNF4A mutations are associated with a considerable increase in birthweight and macrosomia, and are a novel cause of neonatal hypoglycaemia. This study establishes a key role for HNF4A in determining foetal birthweight, and uncovers an unanticipated feature of the natural history of HNF4A-deficient diabetes, with hyperinsulinaemia at birth evolving to decreased insulin secretion and

  9. Myocardial 123I-metaiodobenzylguanidine scintigraphy in patients with homozygous and heterozygous parkin mutations.

    PubMed

    De Rosa, Anna; Pellegrino, Teresa; Pappatà, Sabina; Pellecchia, Maria Teresa; Peluso, Silvio; Saccà, Francesco; Barone, Paolo; Cuocolo, Alberto; De Michele, Giuseppe

    2017-02-01

    PARK2 is an autosomal recessive parkinsonism caused by parkin gene mutations. Several Parkinson's Disease (PD) cases harbor single parkin mutations, raising a debate about the pathogenic meaning of heterozygous mutations. Here, we evaluate cardiac autonomic innervation in patients with either two or one parkin mutations compared to patients with idiopathic PD (IPD). Myocardial 123 I-metaiodobenzylguanidine (MIBG) scintigraphy was performed in six PD patients with single parkin mutations (HET), four with two mutations (PARK2), and eight with IPD. In comparison to control group, IPD patients showed lower early and late heart-to-mediastinum (H/M) ratios and higher washout rates, whereas HET patients had only lower early H/M ratio, and PARK2 patients were not different for any parameter. At individual level, MIBG findings were abnormal in 7/8 IPD, in 4/6 HET and in 1/4 PARK2 patients. Preserved cardiac 123 I-MIBG uptake confirms that PARK2 pathogenic mechanism, at least partially, differs from that responsible for IPD. HET subjects show intermediate findings, suggesting possible heterogeneity.

  10. Thiamine responsive megaloblastic anemia: a novel SLC19A2 compound heterozygous mutation in two siblings.

    PubMed

    Mozzillo, Enza; Melis, Daniela; Falco, Mariateresa; Fattorusso, Valentina; Taurisano, Roberta; Flanagan, Sarah E; Ellard, Sian; Franzese, Adriana

    2013-08-01

    Thiamine responsive megaloblastic anemia (TRMA) is an autosomal recessive disease caused by loss of function mutations in the SLC19A2 gene. TRMA is characterized by anemia, deafness, and diabetes. In some cases, optic atrophy or more rarely retinitis pigmentosa is noted. We now report two sisters, the eldest of which presented to a different hospital during childhood with sensorineural deafness, which was treated with a hearing prosthesis, insulin requiring diabetes, retinitis pigmentosa, optic atrophy, and macrocytic anemia. These features initially suggested a clinical diagnosis of Wolfram syndrome (WS). Therapy with thiamine was initiated which resulted in the resolution of the anemia. The younger sister, who was affected with sensorineural deafness, was referred to our hospital for non-autoimmune diabetes. She was found to have macrocytosis and ocular abnormalities. Because a diagnosis of TRMA was suspected, therapy with insulin and thiamine was started. Sequencing analysis of the SLC19A2 gene identified a compound heterozygous mutation p.Y81X/p.L457X (c.242insA/c.1370delT) in both sisters. Non-autoimmune diabetes associated with deafness and macrocytosis, without anemia, suggests a diagnosis of TRMA. Patients clinically diagnosed with WS with anemia and/or macrocytosis should be reevaluated for TRMA. © 2012 John Wiley & Sons A/S.

  11. Effects of LSD on grooming behavior in serotonin transporter heterozygous (Sert⁺/⁻) mice.

    PubMed

    Kyzar, Evan J; Stewart, Adam Michael; Kalueff, Allan V

    2016-01-01

    Serotonin (5-HT) plays a crucial role in the brain, modulating mood, cognition and reward. The serotonin transporter (SERT) is responsible for the reuptake of 5-HT from the synaptic cleft and regulates serotonin signaling in the brain. In humans, SERT genetic variance is linked to the pathogenesis of various psychiatric disorders, including anxiety, autism spectrum disorders (ASD) and obsessive-compulsive disorder (OCD). Rodent self-grooming is a complex, evolutionarily conserved patterned behavior relevant to stress, ASD and OCD. Genetic ablation of mouse Sert causes various behavioral deficits, including increased anxiety and grooming behavior. The hallucinogenic drug lysergic acid diethylamide (LSD) is a potent serotonergic agonist known to modulate human and animal behavior. Here, we examined heterozygous Sert(+/-) mouse behavior following acute administration of LSD (0.32 mg/kg). Overall, Sert(+/-) mice displayed a longer duration of self-grooming behavior regardless of LSD treatment. In contrast, LSD increased serotonin-sensitive behaviors, such as head twitching, tremors and backwards gait behaviors in both Sert(+/+) and Sert(+/-) mice. There were no significant interactions between LSD treatment and Sert gene dosage in any of the behavioral domains measured. These results suggest that Sert(+/-) mice may respond to the behavioral effects of LSD in a similar manner to wild-type mice. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Heterozygous Inverdale ewes show increased ovulation rate sensitivity to pre-mating nutrition.

    PubMed

    Demmers, K J; Smaill, B; Davis, G H; Dodds, K G; Juengel, J L

    2011-01-01

    This study aimed to determine whether ewes heterozygous (I+) for the Inverdale mutation of the bone morphogenetic protein-15 (BMP15) gene with high natural ovulation rate (OR) show similar sensitivity to nutritional manipulation as non-carriers (++). Increasing pre-mating nutrition results in OR increases in sheep, but whether this effect occurs in ewes with naturally high OR is unknown. Over 2 years, I+ or ++ ewes were given high (ad libitum) or control (maintenance) pasture allowances for 6 weeks prior to mating at a synchronised oestrus, with OR measured 8 days later. The high group increased in weight compared with controls (+5.84kg; P<0.01), accompanied by increased OR (+19%; P<0.01). As well as having higher OR (+45%; P<0.01), I+ ewes responded to increased feed with a larger proportional increase in OR (+27%; P<0.01) compared with the response in ++ ewes (+11%; P<0.05), suggesting an interaction between BMP15 levels and nutritional signals in the follicle to control OR. Although litter size increases only tended to significance (+12%; P=0.06), extra feed resulted in over 50% of I+ ewes giving birth to more than three lambs, compared with 20-31% of I+ ewes on maintenance rations. This information can guide feed management of prolific Inverdale ewes prior to breeding.

  13. Phenotypic variation among familial hypercholesterolemics heterozygous for either one of two Afrikaner founder LDL receptor mutations.

    PubMed

    Kotze, M J; De Villiers, W J; Steyn, K; Kriek, J A; Marais, A D; Langenhoven, E; Herbert, J S; Graadt Van Roggen, J F; Van der Westhuyzen, D R; Coetzee, G A

    1993-10-01

    Two common founder-related gene mutations that affect the low-density lipoprotein receptor (LDLR) are responsible for approximately 80% of familial hypercholesterolemia (FH) in South African Afrikaners. The FH Afrikaner-1 (FH1) mutation (Asp206-->Glu) in exon 4 results in defective receptors with approximately 20% of normal activity, whereas the FH Afrikaner-2 (FH2) mutation (Val408-->Met) in exon 9 completely abolishes LDLR activity (< 2% normal activity). We analyzed the contribution of these mutations and other factors on the variation of hypercholesterolemia and clinical features in Afrikaner FH heterozygotes. The type of FH mutation, plasma triglyceride levels, and age of patients each contributed significantly to the variation in hypercholesterolemia, whereas smoking status, high-density lipoprotein cholesterol levels, and gender had no influence. Although all FH heterozygotes had frank hypercholesterolemia, patients with the FH1 mutation had significantly lower cholesterol levels than those with the FH2 mutation. FH1 heterozygotes also tended to have milder clinical features. The differences between the two FH groups could not be explained by a difference in the common apolipoprotein E variants. This study demonstrates that mutational heterogeneity in the LDLR gene influences the phenotypic expression of heterozygous FH.

  14. [Infantile hypophosphatasia caused by a novel compound heterozygous mutation: a case report and pedigree analysis].

    PubMed

    Li, Deng-Feng; Lan, Dan; Zhong, Jing-Zi; Dewan, Roma Kajal; Xie, Yan-Shu; Yang, Ying

    2017-05-01

    This article reported the clinical features of one child with infantile hypophosphatasia (HPP) and his pedigree information. The proband was a 5-month-old boy with multiple skeletal dysplasia (koilosternia, bending deformity of both radii, and knock-knee deformity of both knees), feeding difficulty, reduction in body weight, developmental delay, recurrent pneumonia and respiratory failure, and a significant reduction in blood alkaline phosphatase. Among his parents, sister, uncle, and aunt (other family members did not cooperate with us in the examination), his parents and aunt had a slight reduction in alkaline phosphatase and his aunt had scoliosis; there were no other clinical phenotypes or abnormal laboratory testing results. His ALPL gene mutation came from c.228delG mutation in his mother and c.407G>A compound heterozygous mutation in his father. His aunt carried c.228delG mutation. The c.407G>A mutation had been reported as the pathogenic mutation of HPP, and c.228delG mutation was a novel pathogenic mutation. Hypophosphatasia is caused by ALPL gene mutation, and ALPL gene detection is an effective diagnostic method. This study expands the mutation spectrum of ALPL gene and provides a theoretical basis for genetic diagnosis of this disease.

  15. [Novel CHST6 compound heterozygous mutations cause macular corneal dystrophy in a Chinese family].

    PubMed

    Qi, Yan-hua; Dang, Xiu-hong; Su, Hong; Zhou, Nan; Liang, Ting; Wang, Zheng; Huang, Shang-zhi

    2010-02-01

    The aim of this study was to identify mutations of CHST6 gene in a Chinese family with macular corneal dystrophy (MCD) and to investigate the histopathological changes of MCD. Corneal button of the proband was obtained from penetrating keratoplasty for the treatment of severe corneal dystrophy. The sections and ultrathin sections of this specimen were examined under light microscope and transmission electron microscope (TEM). Genomic DNA was extracted from leukocytes in peripheral blood from the family members. The coding region of CHST6 was amplified by polymerase chain reaction (PCR). The PCR products were analyzed by direct sequencing and restriction enzyme digestion. Histochemical study revealed positive results of colloidal iron stain. TEM revealed enlargement of smooth endoplasmic reticulum and the presence of intracytoplasmic vacuoles. Two mutations, Q298X Y358H, were identified in exon 3 of CHST6. Three patients were compound heterozygotes of these two mutations. The C892T transversion occurred at codon 298 turned the codon of glutamine to a stop codon; the T1072C transversion occurred at codon 358 caused a missense mutation, tyrosine to histidine. All six unaffected family members were heterozygotes. These two mutations were not detected in any of the 100 control subjects. The novel compound heterozygous mutation results in loss of CHST6 function and causes the occurrence of MCD. This is the first report of this gene mutation.

  16. Human retinoblastoma susceptibility gene: genomic organization and analysis of heterozygous intragenic deletion mutants.

    PubMed Central

    Bookstein, R; Lee, E Y; To, H; Young, L J; Sery, T W; Hayes, R C; Friedmann, T; Lee, W H

    1988-01-01

    A gene in chromosome region 13q14 has been identified as the human retinoblastoma susceptibility (RB) gene on the basis of altered gene expression found in virtually all retinoblastomas. In order to further characterize the RB gene and its structural alterations, we examined genomic clones of the RB gene isolated from both a normal human genomic library and a library made from DNA of the retinoblastoma cell line Y79. First, a restriction and exon map of the RB gene was constructed by aligning overlapping genomic clones, yielding three contiguous regions ("contigs") of 150 kilobases total length separated by two gaps. At least 20 exons were identified in genomic clones, and these were provisionally numbered. Second, two overlapping genomic clones that demonstrated a DNA deletion of exons 2 through 6 from one RB allele were isolated from the Y79 library. To confirm and extend this result, a unique sequence probe from intron 1 was used to detect similar and possibly identical heterozygous deletions in genomic DNA from three retinoblastoma cell lines, thereby explaining the origins of their shortened RB mRNA transcripts. The same probe detected genomic rearrangements in fibroblasts from two hereditary retinoblastoma patients, indicating that intron 1 includes a frequent site for mutations conferring predisposition to retinoblastoma. Third, this probe also detected a polymorphic site for BamHI with allele frequencies near 0.5/0.5. Identification of commonly mutated regions will contribute significantly to genetic diagnosis in retinoblastoma patients and families. Images PMID:2895471

  17. Nonhomologous Synapsis and Reduced Crossing over in a Heterozygous Paracentric Inversion in Saccharomyces Cerevisiae

    PubMed Central

    Dresser, M. E.; Ewing, D. J.; Harwell, S. N.; Coody, D.; Conrad, M. N.

    1994-01-01

    Homologous chromosome synapsis (``homosynapsis'') and crossing over are well-conserved aspects of meiotic chromosome behavior. The long-standing assumption that these two processes are causally related has been challenged recently by observations in Saccharomyces cerevisiae of significant levels of crossing over (1) between small sequences at nonhomologous locations and (2) in mutants where synapsis is abnormal or absent. In order to avoid problems of local sequence effects and of mutation pleiotropy, we have perturbed synapsis by making a set of isogenic strains that are heterozygous and homozygous for a large chromosomal paracentric inversion covering a well marked genetic interval and then measured recombination. We find that reciprocal recombination in the marked interval in heterozygotes is reduced variably across the interval, on average to ~55% of that in the homozygotes, and that positive interference still modulates crossing over. Cytologically, stable synapsis across the interval is apparently heterologous rather than homologous, consistent with the interpretation that stable homosynapsis is required to initiate or consummate a large fraction of the crossing over observed in wild-type strains. When crossing over does occur in heterozygotes, dicentric and acentric chromosomes are formed and can be visualized and quantitated on blots though not demonstrated in viable spores. We find that there is no loss of dicentric chromosomes during the two meiotic divisions and that the acentric chromosome is recovered at only 1/3 to 1/2 of the expected level. PMID:7851761

  18. Mice heterozygous for cathepsin D deficiency exhibit mania-related behavior and stress-induced depression.

    PubMed

    Zhou, Rui; Lu, Yi; Han, Yong; Li, Xia; Lou, Huifang; Zhu, Liya; Zhen, Xuechu; Duan, Shumin

    2015-12-03

    Mutations in cathepsin D (CTSD), an aspartic protease in the endosomal-lysosomal system, underlie congenital neuronal ceroid-lipofuscinosis (cNCL, also known as CLN10), a devastating neurodegenerative disease. CLN10 patients die within the first few days of life, and in the few patients who live into adulthood psychopathological symptoms have not been reported. Extensive neuropathology and altered neurotransmission have been reported in CTSD-deficient mice; however signs of neuropsychiatric behavior in these mice are not well characterized due to the severe movement disorder and premature death of the animal. In the present study, we show that heterozygous CTSD-deficient (CTSD HET) mice display an overall behavioral profile that is similar to human mania, including hyperlocomotion, d-amphetamine-induced hyperactivity, sleep-disturbance, and reduced anxiety-like behavior. However, under stressful conditions CTSD HET mice manifest depressive-like behavior, including anhedonia, behavioral despair, and enhanced learned helplessness. Chronic administration of lithium chloride or valproic acid, two clinically effective mood stabilizers, reverses the majority of these behavioral abnormalities. In addition, CTSD HET mice display stress-induced hypersecretion of corticosterone. These findings suggest an important role for CTSD in the regulation of mood stabilization. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Recombination and synaptic adjustment in oocytes of mice heterozygous for a large paracentric inversion.

    PubMed

    Torgasheva, Anna A; Rubtsov, Nikolai B; Borodin, Pavel M

    2013-03-01

    Homologous chromosome synapsis in inversion heterozygotes results in the formation of inversion loops. These loops might be transformed into straight, non-homologously paired bivalents via synaptic adjustment. Synaptic adjustment was discovered 30 years ago; however, its relationship with recombination has remained unclear. We analysed this relationship in female mouse embryos heterozygous for large paracentric inversion In(1)1Rk using immunolocalisation of the synaptonemal complex (SYCP3) and mature recombination nodules (MLH1) proteins. The frequency of cells containing bivalents with inversion loops decreased from 69 % to 28 % during pachytene. If an MLH1 focus was present in the non-homologously paired inverted region of the straight bivalent, it was always located in the middle of the inversion. Most of the small, incompletely adjusted loops contained MLH1 foci near the points at which pairing partners were switched. This observation indicates that the degree of synaptic adjustment depended on the crossover position. Complete synaptic adjustment was only possible if a crossover (CO) was located exactly in the middle of the inversion. If a CO was located at any other site, this interrupted synaptic adjustment and resulted in inversion loops of different sizes with an MLH1 focus at or near the edge of the remaining loop.

  20. vGLUT2 heterozygous mice show more susceptibility to clonic seizures induced by pentylenetetrazol.

    PubMed

    Schallier, Anneleen; Massie, Ann; Loyens, Ellen; Moechars, Diederik; Drinkenburg, Wilhelmus; Michotte, Yvette; Smolders, Ilse

    2009-01-01

    Glutamate, the most abundant excitatory neurotransmitter in the central nervous system, is well known to be implicated in epileptic seizures. Therefore, impairments in glutamate transport could have an involvement in the mechanism of epileptogenesis. The uptake of glutamate into synaptic vesicles is mediated by vesicular glutamate transporters (vGLUTs). There are three known vGLUT isoforms, vGLUT1-3. In this study, we are particularly interested in the vGLUT2 isoform. We investigated the possible role of vGLUT2 in pentylenetetrazol (PTZ)-induced seizure generation. Seizure threshold of PTZ was compared in vGLUT2 heterozygous knock out (HET) and wild type (WT) mice. In comparison with their WT littermates a lower dose of PTZ was needed in the vGLUT2 HET mice until the onset of the first myoclonic jerk. The threshold for PTZ-induced clonic seizure activity was also lower in the vGLUT2 HET mice. These results indicate, for the first time, that vGLUT2 is likely involved in the epileptogenesis of generalized seizures.

  1. Nature vs. nurture: can enrichment rescue the behavioural phenotype of BDNF heterozygous mice?

    PubMed

    Chourbaji, Sabine; Brandwein, Christiane; Vogt, Miriam A; Dormann, Christof; Hellweg, Rainer; Gass, Peter

    2008-10-10

    In earlier experiments we have demonstrated that group-housing in a rather impoverished "standard" environment can be a crucial stress factor in male C57Bl/6 mice. The present study aimed at investigating the effect of combining a probable genetic vulnerability--postulated by the "Neurotrophin Hypothesis of Depression"--with the potentially modulating influence of a stressful environment such as "impoverished" standard housing conditions. For that purpose mice with a partial deletion of brain-derived neurotrophic factor (BDNF) were group-housed under standard and enriched housing conditions and analysed in a well-established test battery for emotional behaviours. Standard group-housing affected emotional behaviour in male and female BDNF heterozygous mice, causing an increase in anxiety, changes in exploration as well as nociception. Providing the animals' cages with supplementary enrichment, however, led to a rescue of emotional alterations, which emphasises the significance of external factors and their relevance for a valid investigation of genetic aspects in these mutants as well as others, which may be examined in terms of stress-responsiveness or emotionality.

  2. Breast lump removal

    MedlinePlus

    ... is removed, it is often called an excisional breast biopsy, instead of a lumpectomy. Description Sometimes, the health ... Mastectomy - discharge Surgical wound care - open Images Female breast Needle biopsy of the breast Open biopsy of the breast ...

  3. Breast augmentation surgery

    MedlinePlus

    ... the shape of your breasts. Talk with a plastic surgeon if you are considering breast augmentation. Discuss ... mammograms or breast x-rays before surgery. The plastic surgeon will do a routine breast exam. Several ...

  4. Long-term behavioral and NMDA receptor effects of young-adult corticosterone treatment in BDNF heterozygous mice.

    PubMed

    Klug, Maren; Hill, Rachel A; Choy, Kwok Ho Christopher; Kyrios, Michael; Hannan, Anthony J; van den Buuse, Maarten

    2012-06-01

    Psychiatric illnesses, such as schizophrenia, are most likely caused by an interaction between genetic predisposition and environmental factors, including stress during development. The neurotrophin, brain-derived neurotrophic factor (BDNF) has been implicated in this illness as BDNF levels are decreased in the brain of patients with schizophrenia. The aim of the present study was to assess the combined effect of reduced BDNF levels and postnatal stress, simulated by chronic young-adult treatment with the stress hormone, corticosterone. From 6 weeks of age, female and male BDNF heterozygous mice and their wild-type controls were chronically treated with corticosterone in their drinking water for 3 weeks. At 11 weeks of age, male, but not female BDNF heterozygous mice treated with corticosterone exhibited a profound memory deficit in the Y-maze. There were no differences between the groups in baseline prepulse inhibition (PPI), a measure of sensorimotor gating, or its disruption by treatment with MK-801. However, an increase in startle caused by MK-801 treatment was absent in male, but not female BDNF heterozygous mice, irrespective of corticosterone treatment. Analysis of protein levels of the NMDA receptor subunits NR1, NR2A, NR2B and NR2C, showed a marked increase of NR2B levels in the dorsal hippocampus of male BDNF heterozygous mice treated with corticosterone. In the ventral hippocampus, significantly reduced levels of NR2A, NR2B and NR2C were observed in male BDNF heterozygous mice. The NMDA receptor effects in hippocampal sub-regions could be related to the spatial memory deficits and the loss of the effect of MK-801 on startle in these mice, respectively. No significant changes in NMDA receptor subunit levels were observed in any of the female groups. Similarly, no significant changes in levels of BDNF or its receptor, TrkB, were found other than the expected reduced levels of BDNF in heterozygous mice. In conclusion, the data show differential interactive

  5. Radiation induces genomic instability and mammary ductal dysplasia in Atm heterozygous mice

    NASA Technical Reports Server (NTRS)

    Weil, M. M.; Kittrell, F. S.; Yu, Y.; McCarthy, M.; Zabriskie, R. C.; Ullrich, R. L.

    2001-01-01

    Ataxia-telangiectasia (AT) is a genetic syndrome resulting from the inheritance of two defective copies of the ATM gene that includes among its stigmata radiosensitivity and cancer susceptibility. Epidemiological studies have demonstrated that although women with a single defective copy of ATM (AT heterozygotes) appear clinically normal, they may never the less have an increased relative risk of developing breast cancer. Whether they are at increased risk for radiation-induced breast cancer from medical exposures to ionizing radiation is unknown. We have used a murine model of AT to investigate the effect of a single defective Atm allele, the murine homologue of ATM, on the susceptibility of mammary epithelial cells to radiation-induced transformation. Here we report that mammary epithelial cells from irradiated mice with one copy of Atm truncated in the PI-3 kinase domain were susceptible to radiation-induced genomic instability and generated a 10% incidence of dysplastic mammary ducts when transplanted into syngenic recipients, whereas cells from Atm(+/+) mice were stable and formed only normal ducts. Since radiation-induced ductal dysplasia is a precursor to mammary cancer, the results indicate that AT heterozygosity increases susceptibility to radiogenic breast cancer in this murine model system.

  6. Breast cancer

    MedlinePlus

    ... chance of being cured. Tamoxifen is approved for breast cancer prevention in women age 35 and older who are ... chance of getting cancer. This includes: Eating healthy foods Maintaining a healthy weight Limiting alcohol consumption to 1 drink per day

  7. Breast infection

    MedlinePlus

    Breast infections are usually caused by common bacteria ( Staphylococcus aureus ) found on normal skin. The bacteria enter through ... 2017:chap 8. Que Y-A, Moreillon P. Staphylococcus aureus (including staphylococcal toxic shock syndrome). In: Bennett JE, ...

  8. Screening for large genomic rearrangements in the FANCA gene reveals extensive deletion in a Finnish breast cancer family.

    PubMed

    Solyom, Szilvia; Winqvist, Robert; Nikkilä, Jenni; Rapakko, Katrin; Hirvikoski, Pasi; Kokkonen, Hannaleena; Pylkäs, Katri

    2011-03-28

    A portion of familial breast cancer cases are caused by mutations in the same genes that are inactivated in the downstream part of Fanconi anemia (FA) signaling pathway. Here we have assessed the FANCA gene for breast cancer susceptibility by examining blood DNA for aberrations from 100 Northern Finnish breast cancer families using the MLPA method. We identified a novel heterozygous deletion, removing the promoter and 12 exons of the gene in one family. This allele was absent from 124 controls. We conclude that FANCA deletions might contribute to breast cancer susceptibility, potentially in combination with other germline mutations. To our knowledge, this is the first study reporting a large deletion in an upstream FA gene in familial breast cancer. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  9. Loss of MSH2 and MSH6 due to heterozygous germline defects in MSH3 and MSH6.

    PubMed

    Morak, Monika; Käsbauer, Sarah; Kerscher, Martina; Laner, Andreas; Nissen, Anke M; Benet-Pagès, Anna; Schackert, Hans K; Keller, Gisela; Massdorf, Trisari; Holinski-Feder, Elke

    2017-10-01

    Lynch Syndrome (LS) is the most common dominantly inherited colorectal cancer (CRC) predisposition and is caused by a heterozygous germline defect in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2. High microsatellite instability (MSI-H) and loss of MMR protein expression in tumours reflecting a defective MMR are indicators for LS, as well as a positive family history of early onset CRC. MSH2 and MSH6 form a major functional heterodimer, and MSH3 is an alternative binding partner for MSH2. So far, the role of germline MSH3 variants remains unclear, as to our knowledge heterozygous truncating variants are not regarded causative for LS, but were detected in patients with CRC, and recently biallelic MSH3 defects have been identified in two patients with adenomatous polyposis. By gene screening we investigated the role of MSH3 in 11 LS patients with truncating MSH6 germline variants and an unexplained MSH2 protein loss in their corresponding MSI-H tumours. We report the first two LS patients harbouring heterozygous germline variants c.1035del and c.2732T>G in MSH3 coincidentally with truncating variants in MSH6. In the patient with truncating germline variants in MSH3 and MSH6, two additional somatic second hits in both genes abrogate all binding partners for the MSH2 protein which might subsequently be degraded. The clinical relevance of MSH3 germline variants is currently under re-evaluation, and heterozygous MSH3 defects alone do not seem to induce a LS phenotype, but might aggravate the MSH6 phenotype in affected family members.

  10. Novel compound heterozygous mutations in MYO7A gene associated with autosomal recessive sensorineural hearing loss in a Chinese family.

    PubMed

    Ma, Yalin; Xiao, Yun; Zhang, Fengguo; Han, Yuechen; Li, Jianfeng; Xu, Lei; Bai, Xiaohui; Wang, Haibo

    2016-04-01

    Mutations in MYO7A gene have been reported to be associated with Usher Syndrome type 1B (USH1B) and nonsyndromic hearing loss (DFNB2, DFNA11). Most mutations in MYO7A gene caused USH1B, whereas only a few reported mutations led to DFNB2 and DFNA11. The current study was designed to investigate the mutations among a Chinese family with autosomal recessive hearing loss. In this study, we present the clinical, genetic and molecular characteristics of a Chinese family. Targeted capture of 127 known deafness genes and next-generation sequencing were employed to study the genetic causes of two siblings in the Chinese family. Sanger sequencing was employed to examine those variant mutations in the members of this family and other ethnicity-matched controls. We identified the novel compound heterozygous mutant alleles of MYO7A gene: a novel missense mutation c.3671C>A (p.A1224D) and a reported insert mutation c.390_391insC (p.P131PfsX9). Variants were further confirmed by Sanger sequencing. These two compound heterozygous variants were co-segregated with autosomal recessive hearing loss phenotype. The gene mutation analysis and protein sequence alignment further supported that the novel compound heterozygous mutations were pathogenic. The novel compound heterozygous mutations (c.3671C>A and c.390_391insC) in MYO7A gene identified in this study were responsible for the autosomal recessive sensorineural hearing loss of this Chinese family. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. Production of heterozygous alpha 1,3-galactosyltransferase (GGTA1) knock-out transgenic miniature pigs expressing human CD39.

    PubMed

    Choi, Kimyung; Shim, Joohyun; Ko, Nayoung; Eom, Heejong; Kim, Jiho; Lee, Jeong-Woong; Jin, Dong-Il; Kim, Hyunil

    2017-04-01

    Production of transgenic pigs for use as xenotransplant donors is a solution to the severe shortage of human organs for transplantation. The first barrier to successful xenotransplantation is hyperacute rejection, a rapid, massive humoral immune response directed against the pig carbohydrate GGTA1 epitope. Platelet activation, adherence, and clumping, all major features of thrombotic microangiopathy, are inevitable results of immune-mediated transplant rejection. Human CD39 rapidly hydrolyzes ATP and ADP to AMP; AMP is hydrolyzed by ecto-5'-nucleotidase (CD73) to adenosine, an anti-thrombotic and cardiovascular protective mediator. In this study, we developed a vector-based strategy for ablation of GGTA1 function and concurrent expression of human CD39 (hCD39). An hCD39 expression cassette was constructed to target exon 4 of GGTA1. We established heterozygous GGTA1 knock-out cell lines expressing hCD39 from pig ear fibroblasts for somatic cell nuclear transfer (SCNT). We also described production of heterozygous GGTA1 knock-out piglets expressing hCD39 and analyzed expression and function of the transgene. Human CD39 was expressed in heart, kidney and aorta. Human CD39 knock-in heterozygous ear fibroblast from transgenic cloned pigs, but not in non-transgenic pig's cells. Expression of GGTA1 gene was lower in the knock-in heterozygous ear fibroblast from transgenic pigs compared to the non-transgenic pig's cell. The peripheral blood mononuclear cells (PBMC) from the transgenic pigs were more resistant to lysis by pooled complement-preserved normal human serum than that from wild type (WT) pig. Accordingly, GGTA1 mutated piglets expressing hCD39 will provide a new organ source for xenotransplantation research.

  12. Myosin-binding Protein C Compound Heterozygous Variant Effect on the Phenotypic Expression of Hypertrophic Cardiomyopathy.

    PubMed

    Rafael, Julianny Freitas; Cruz, Fernando Eugênio Dos Santos; Carvalho, Antônio Carlos Campos de; Gottlieb, Ilan; Cazelli, José Guilherme; Siciliano, Ana Paula; Dias, Glauber Monteiro

    2017-04-01

    Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disease caused by mutations in genes encoding sarcomere proteins. It is the major cause of sudden cardiac death in young high-level athletes. Studies have demonstrated a poorer prognosis when associated with specific mutations. The association between HCM genotype and phenotype has been the subject of several studies since the discovery of the genetic nature of the disease. This study shows the effect of a MYBPC3 compound variant on the phenotypic HCM expression. A family in which a young man had a clinical diagnosis of HCM underwent clinical and genetic investigations. The coding regions of the MYH7, MYBPC3 and TNNT2 genes were sequenced and analyzed. The proband present a malignant manifestation of the disease, and is the only one to express HCM in his family. The genetic analysis through direct sequencing of the three main genes related to this disease identified a compound heterozygous variant (p.E542Q and p.D610H) in MYBPC3. A family analysis indicated that the p.E542Q and p.D610H alleles have paternal and maternal origin, respectively. No family member carrier of one of the variant alleles manifested clinical signs of HCM. We suggest that the MYBPC3-biallelic heterozygous expression of p.E542Q and p.D610H may cause the severe disease phenotype seen in the proband. Resumo A cardiomiopatia hipertrófica (CMH) é uma doença autossômica dominante causada por mutações em genes que codificam as proteínas dos sarcômeros. É a principal causa de morte súbita cardíaca em atletas jovens de alto nível. Estudos têm demonstrado um pior prognóstico associado a mutações específicas. A associação entre genótipo e fenótipo em CMH tem sido objeto de diversos estudos desde a descoberta da origem genética dessa doença. Este trabalho apresenta o efeito de uma mutação composta em MYBPC3 na expressão fenotípica da CMH. Uma família na qual um jovem tem o diagnóstico clínico de CMH foi

  13. Breast fibromatosis associated with breast implants.

    PubMed

    Seo, Yoon Nae; Park, Young Mi; Yoon, Hye Kyoung; Lee, Sun Joo; Choo, Hye Jung; Ryu, Ji Hwa

    2015-09-01

    Fibromatosis refers to an extra-abdominal desmoid tumor or aggressive fibromatosis. Breast fibromatosis can develop in association with the capsule around a breast implant, although reports of cases of fibromatosis associated with breast implants are rare. As the demand for breast augmentation has increased, it is important to understand the diseases associated with breast implants. In the present report, we describe a case of breast fibromatosis that developed adjacent to a breast implant and demonstrated a relatively well-defined border even though it invaded the surrounding structures. We also explore the specific imaging features for diagnosing breast fibromatosis in association with implants by reviewing previous literature.

  14. Chronic Toxoplasma gondii in Nurr1-Null Heterozygous Mice Exacerbates Elevated Open Field Activity

    PubMed Central

    Eells, Jeffrey B.; Varela-Stokes, Andrea; Guo-Ross, Shirley X.; Kummari, Evangel; Smith, Holly M.; Cox, Erin; Lindsay, David S.

    2015-01-01

    Latent infection with Toxoplasma gondii is common in humans (approximately 30% of the global population) and is a significant risk factor for schizophrenia. Since prevalence of T. gondii infection is far greater than prevalence of schizophrenia (0.5-1%), genetic risk factors are likely also necessary to contribute to schizophrenia. To test this concept in an animal model, Nurr1-null heterozygous (+/-) mice and wild-type (+/+) mice were evaluate using an emergence test, activity in an open field and with a novel object, response to bobcat urine and prepulse inhibition of the acoustic startle response (PPI) prior to and 6 weeks after infection with T. gondii. In the emergence test, T. gondii infection significantly decreased the amount of time spent in the cylinder. Toxoplasma gondii infection significantly elevated open field activity in both +/+ and +/- mice but this increase was significantly exacerbated in +/- mice. T. gondii infection reduced PPI in male +/- mice but this was not statistically significant. Aversion to bobcat urine was abolished by T. gondii infection in +/+ mice. In female +/- mice, aversion to bobcat urine remained after T. gondii infection while the male +/- mice showed no aversion to bobcat urine. Antibody titers of infected mice were a critical variable associated with changes in open field activity, such that an inverted U shaped relationship existed between antibody titers and the percent change in open field activity with a significant increase in activity at low and medium antibody titers but no effect at high antibody titers. These data demonstrate that the Nurr1 +/- genotype predisposes mice to T. gondii-induced alterations in behaviors that involve dopamine neurotransmission and are associated with symptoms of schizophrenia. We propose that these alterations in murine behavior were due to further exacerbation of the altered dopamine neurotransmission in Nurr1 +/- mice. PMID:25855987

  15. Chronic Toxoplasma gondii in Nurr1-null heterozygous mice exacerbates elevated open field activity.

    PubMed

    Eells, Jeffrey B; Varela-Stokes, Andrea; Guo-Ross, Shirley X; Kummari, Evangel; Smith, Holly M; Cox, Erin; Lindsay, David S

    2015-01-01

    Latent infection with Toxoplasma gondii is common in humans (approximately 30% of the global population) and is a significant risk factor for schizophrenia. Since prevalence of T. gondii infection is far greater than prevalence of schizophrenia (0.5-1%), genetic risk factors are likely also necessary to contribute to schizophrenia. To test this concept in an animal model, Nurr1-null heterozygous (+/-) mice and wild-type (+/+) mice were evaluate using an emergence test, activity in an open field and with a novel object, response to bobcat urine and prepulse inhibition of the acoustic startle response (PPI) prior to and 6 weeks after infection with T. gondii. In the emergence test, T. gondii infection significantly decreased the amount of time spent in the cylinder. Toxoplasma gondii infection significantly elevated open field activity in both +/+ and +/- mice but this increase was significantly exacerbated in +/- mice. T. gondii infection reduced PPI in male +/- mice but this was not statistically significant. Aversion to bobcat urine was abolished by T. gondii infection in +/+ mice. In female +/- mice, aversion to bobcat urine remained after T. gondii infection while the male +/- mice showed no aversion to bobcat urine. Antibody titers of infected mice were a critical variable associated with changes in open field activity, such that an inverted U shaped relationship existed between antibody titers and the percent change in open field activity with a significant increase in activity at low and medium antibody titers but no effect at high antibody titers. These data demonstrate that the Nurr1 +/- genotype predisposes mice to T. gondii-induced alterations in behaviors that involve dopamine neurotransmission and are associated with symptoms of schizophrenia. We propose that these alterations in murine behavior were due to further exacerbation of the altered dopamine neurotransmission in Nurr1 +/- mice.

  16. A 3-year study of atorvastatin in children and adolescents with heterozygous familial hypercholesterolemia.

    PubMed

    Langslet, Gisle; Breazna, Andrei; Drogari, Euridiki

    2016-01-01

    The efficacy and safety of atorvastatin in children/adolescents aged 10-17 years with heterozygous familial hypercholesterolemia (HeFH) have been demonstrated in trials of up to 1 year in duration. However, the efficacy/safety of >1 year use of atorvastatin in children/adolescents with HeFH, including children from 6 years of age, has not been assessed. To characterize the efficacy and safety of atorvastatin over 3 years and to assess the impact on growth and development in children aged 6-15 years with HeFH. A total of 272 subjects aged 6-15 years with HeFH and low-density lipoprotein cholesterol (LDL-C) ≥4.0 mmol/L (154 mg/dL) were enrolled in a 3-year study (NCT00827606). Subjects were initiated on atorvastatin (5 mg or 10 mg) with doses increased to up to 80 mg based on LDL-C levels. Mean percentage reductions from baseline in LDL-C at 36 months/early termination were 43.8% for subjects at Tanner stage (TS) 1 and 39.9% for TS ≥2. There was no evidence of variations in the lipid-lowering efficacy of atorvastatin between the TS groups analyzed (1 vs ≥2) or in subjects aged <10 vs ≥10 years, and the treatment had no adverse effect on growth or maturation. Atorvastatin had a favorable safety and tolerability profile, and only 6 (2.2%) subjects discontinued because of adverse events. Atorvastatin over 3 years was efficacious, had no impact on growth/maturation, and was well tolerated in children and adolescents with HeFH aged 6-15 years. Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.

  17. Estimating the prevalence of heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis

    PubMed Central

    Akioyamen, Leo E; Genest, Jacques; Shan, Shubham D; Reel, Rachel L; Albaum, Jordan M; Chu, Anna; Tu, Jack V

    2017-01-01

    Objectives Heterozygous familial hypercholesterolaemia (FH) confers a significant risk for premature cardiovascular disease (CVD). However, the estimated prevalence of FH varies substantially among studies. We aimed to provide a summary estimate of FH prevalence in the general population and assess variations in frequency across different sociodemographic characteristics. Setting, participants and outcome measures We searched MEDLINE, EMBASE, Global Health, the Cochrane Library, PsycINFO and PubMed for peer-reviewed literature using validated strategies. Results were limited to studies published in English between January 1990 and January 2017. Studies were eligible if they determined FH prevalence using clinical criteria or DNA-based analyses. We determined a pooled point prevalence of FH in adults and children and assessed the variation of the pooled frequency by age, sex, geographical location, diagnostic method, study quality and year of publication. Estimates were pooled using random-effects meta-analysis. Differences by study-level characteristics were investigated through subgroups, meta-regression and sensitivity analyses. Results The pooled prevalence of FH from 19 studies including 2 458 456 unique individuals was 0.40% (95% CI 0.29% to 0.52%) which corresponds to a frequency of 1 in 250 individuals. FH prevalence was found to vary by age and geographical location but not by any other covariates. Results were consistent in sensitivity analyses. Conclusions Our systematic review suggests that FH is a common disorder, affecting 1 in 250 individuals. These findings underscore the need for early detection and management to decrease CVD risk. PMID:28864697

  18. [Hereditary heterozygous factor VII deficiency in patients undergoing surgery : Clinical relevance].

    PubMed

    Woehrle, D; Martinez, M; Bolliger, D

    2016-10-01

    A hereditary deficiency in coagulation factor VII (FVII) may affect the international normalized ratio (INR) value. However, FVII deficiency is occasionally associated with a tendency to bleed spontaneously. We hypothesized that perioperative substitution with coagulation factor concentrates might not be indicated in most patients. In this retrospective data analysis, we included all patients with hereditary heterozygous FVII deficiency who underwent surgical procedures at the University Hospital Basel between December 2010 and November 2015. In addition, by searching the literature, we identified publications reporting patients with FVII deficiency undergoing surgical procedures without perioperative substitution. We identified 22 patients undergoing 46 surgical procedures, resulting in a prevalence of 1:1500-2000. Coagulation factor concentrates were administered during the perioperative period in 15 procedures (33 %), whereas in the other 31 procedures (66 %), FVII deficiency was not substituted. No postoperative bleeding or thromboembolic events were reported. In addition, we found no differences in pre- and postoperative hemoglobin and coagulation parameters, with the exception of an improved postoperative INR value in the substituted group. In the literature review, we identified five publications, including 125 patients with FVII deficiency, undergoing 213 surgical procedures with no perioperative substitution. Preoperative substitution using coagulation factor concentrates does not seem to be mandatory in patients with an FVII level ≥15 %. For decision-making on preoperative substitution, patient history of an increased tendency to bleed may be more important than the FVII level or increased INR value.

  19. Value of the Definition of Severe Familial Hypercholesterolemia for Stratification of Heterozygous Patients.

    PubMed

    Pérez-Calahorra, Sofia; Sánchez-Hernández, Rosa María; Plana, Núria; Marco-Benedi, Victoria; Pedro-Botet, Juan; Almagro, Fátima; Brea, Angel; Ascaso, Juan Francisco; Lahoz, Carlos; Civeira, Fernando

    2017-03-01

    Familial hypercholesterolemia (FH) is characterized by high low-density lipoprotein (LDL) cholesterol with co-dominant transmission and high risk of cardiovascular disease (CVD), although with high variability among subjects. Currently, CVD stratification tools for heterozygous FH (HeFH) are not available. A definition of severe HeFH has been recently proposed by the International Atherosclerosis Society (IAS), but it has not been validated. Our study aims to see clinical characteristics and prevalence of CVD in subjects defined as severe HeFH by IAS criteria. Probable or definite HeFH introduced in the Dyslipidemia Registry of Spanish Arteriosclerosis Society were analyzed by the IAS criteria. Univariate and multivariate analysis was used to assess the association of CVD with the IAS criteria. About 1,732 HeFH cases were analyzed. Severe HeFH had higher prevalence of familial history of CVD, personal history of tendon xanthomas, LDL cholesterol, and CVD than nonsevere HeFH. A total of 656 (77.1%) and 441 (50.1%) of men and women, respectively, fulfilled the IAS criteria of severe HeFH. In the univariate analysis, subjects defined as severe HeFH showed odds ratio 3.016 (95% CI 3.136 to 4.257, p <0.001) for CVD. However, when traditional risk factors were included in the multivariate analysis, only the presence of cholesterol >400 mg/dl had a statistically significant association with CVD odds ratio 8.76 (95% CI 3.90 to 19.69, p <0.001). In conclusion, the IAS definition of severe HeFH is not significantly associated with CVD when adjusted for classic risk factors. Risk stratification in HeFH is an important issue, but the proposed criteria do not seem to solve this problem. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. CREG1 heterozygous mice are susceptible to high fat diet-induced obesity and insulin resistance.

    PubMed

    Tian, Xiaoxiang; Yan, Chenghui; Liu, Meili; Zhang, Quanyu; Liu, Dan; Liu, Yanxia; Li, Shaohua; Han, Yaling

    2017-01-01

    Cellular repressor of E1A-stimulated genes 1 (CREG1) is a small glycoprotein whose physiological function is unknown. In cell culture studies, CREG1 promotes cellular differentiation and maturation. To elucidate its physiological functions, we deleted the Creg1 gene in mice and found that loss of CREG1 leads to early embryonic death, suggesting that it is essential for early development. In the analysis of Creg1 heterozygous mice, we unexpectedly observed that they developed obesity as they get older. In this study, we further studied this phenotype by feeding wild type (WT) and Creg1 heterozygote (Creg1+/-) mice a high fat diet (HFD) for 16 weeks. Our data showed that Creg1+/- mice exhibited a more prominent obesity phenotype with no change in food intake compared with WT controls when challenged with HFD. Creg1 haploinsufficiency also exacerbated HFD-induced liver steatosis, dyslipidemia and insulin resistance. In addition, HFD markedly increased pro-inflammatory cytokines in plasma and epididymal adipose tissue in Creg1+/- mice as compared with WT controls. The activation level of NF-κB, a major regulator of inflammatory response, in epididymal adipose tissue was also elevated in parallel with the cytokines in Creg1+/- mice. These pro-inflammatory responses elicited by CREG1 reduction were confirmed in 3T3-L1-derived adipocytes with CREG1 depletion by siRNA transfection. Given that adipose tissue inflammation has been shown to play a key role in obesity-induced insulin resistance and metabolic syndrome, our results suggest that Creg1 haploinsufficiency confers increased susceptibility of adipose tissue to inflammation, leading to aggravated obesity and insulin resistance when challenged with HFD. This study uncovered a novel function of CREG1 in metabolic disorders.

  1. Cysteamine treatment ameliorates alterations in GAD67 expression and spatial memory in heterozygous reeler mice

    PubMed Central

    Kutiyanawalla, Ammar; Promsote, Wanwisa; Terry, Alvin; Pillai, Anilkumar

    2011-01-01

    Brain derived neurotrophic factor (BDNF) signaling through its receptor, TrkB is known to regulate GABAergic function and glutamic acid decarboxylase (GAD) 67 expression in neurons. Alterations in BDNF signaling have been implicated in the pathophysiology of schizophrenia and as a result, they are a potential therapeutic target. Interestingly, heterozygous reeler mice (HRM) have decreased GAD67 expression in the frontal cortex and hippocampus and they exhibit many behavioral and neurochemical abnormalities similar to schizophrenia. In the present study, we evaluated the potential of cysteamine, a neuroprotective compound to improve the deficits in GAD67 expression and cognitive function in HRM. We found that cysteamine administration (150 mg/kg/day, through drinking water) for 30 days significantly ameliorated the decreases in GAD67, mature BDNF and full-length TrkB protein levels found in frontal cortex and hippocampus of HRM. A significant attenuation of the increased levels of truncated BDNF in frontal cortex and hippocampus, as well as truncated TrkB in frontal cortex of HRM was also observed following cysteamine treatment. In behavioral studies, HRM were impaired in a Y-maze spatial recognition memory task, but not in a spontaneous alternation task or a sensorimotor, prepulse inhibition (PPI) procedure. Cysteamine improved Y-maze spatial recognition in HRM to the level of wide-type controls and it improved PPI in both wild-type and HRM. Finally, mice deficient in TrkB, showed a reduced response to cysteamine in GAD67 expression suggesting that TrkB signaling plays an important role in GAD67 regulation by cysteamine. PMID:21777509

  2. De novo Uroplakin IIIa heterozygous mutations cause human renal adysplasia leading to severe kidney failure.

    PubMed

    Jenkins, Dagan; Bitner-Glindzicz, Maria; Malcolm, Sue; Hu, Chih-Chi A; Allison, Jennifer; Winyard, Paul J D; Gullett, Ambrose M; Thomas, David F M; Belk, Rachel A; Feather, Sally A; Sun, Tung-Tien; Woolf, Adrian S

    2005-07-01

    Human renal adysplasia usually occurs sporadically, and bilateral disease is the most common cause of childhood end-stage renal failure, a condition that is lethal without intervention using dialysis or transplantation. De novo heterozygous mutations in Uroplakin IIIa (UPIIIa) are reported in four of 17 children with kidney failure caused by renal adysplasia in the absence of an overt urinary tract obstruction. One girl and one boy in unrelated kindreds had a missense mutation at a CpG dinucleotide in the cytoplasmic domain of UPIIIa (Pro273Leu), both of whom had severe vesicoureteric reflux, and the girl had persistent cloaca; two other patients had de novo mutations in the 3' UTR (963 T-->G; 1003 T-->C), and they had renal adysplasia in the absence of any other anomaly. The mutations were absent in all sets of parents and in siblings, none of whom had radiologic evidence of renal adysplasia, and mutations were absent in two panels of 192 ethnically matched control chromosomes. UPIIIa was expressed in nascent urothelia in ureter and renal pelvis of human embryos, and it is suggested that perturbed urothelial differentiation may generate human kidney malformations, perhaps by altering differentiation of adjacent smooth muscle cells such that the metanephros is exposed to a functional obstruction of urine flow. With advances in renal replacement therapy, children with renal failure, who would otherwise have died, are surviving to adulthood. Therefore, although the mechanisms of action of the UPIIIa mutations have yet to be determined, these findings have important implications regarding genetic counseling of affected individuals who reach reproductive age.

  3. [A clinical and hereditary analysis of novel complex heterozygous KCNJ1 mutation in a Bartter syndrome type Ⅱ patient].

    PubMed

    Li, X Y; Jiang, Y; Xu, L J; Duan, L; Peng, X Y; Chen, L M; Xia, W B; Xing, X P

    2017-10-01

    Bartter syndrome (BS) is a hereditary condition transmitted as an autosomal recessive (Bartter type 1 to 4) or dominant trait (Bartter type 5). The disease associates hypokalemic alkalosis with varying degrees of hypercalciuria. Here we presented a case (BS type Ⅱ) of a 17 years old female presented with polyhydramnios, polyuria, nephrocalcinosis and hypokalemia, which was alleviated after treatment with celecoxib and vitamin D(3). DNA sequencing identified compound heterozygous KCNJ 1 gene mutations, c. 931C >T (p.R311W) and c. 445-446insCCTGAACAC (p.V149Afs, 150X), with the latter a novel mutation. Her father and mother were heterozygous carriers of c. 931C >T (p.R311W) and c. 445-446insCCTGAACAC (p.V149Afs, 150X), respectively. In conclusion, this case of BS type Ⅱ is caused by a novel compound heterozygous KCNJ 1 mutation. Further studies are needed to verify the effect of celecoxib in BS patients.

  4. [A novel compound heterozygous mutation in ABCA3 gene in a child with diffuse parenchymal lung disease].

    PubMed

    Bao, Y M; Liu, X L; Liu, X L; Chen, J H; Zheng, Y J

    2017-11-02

    Objective: To summarize the clinical characteristics of the diffuse parenchymal lung diseases in a child caused by a novel compound heterozygous ABCA3 mutation and explore the association between the phenotype and ABCA3 mutation. Method: The clinical material of a patient diagnosed with diffuse parenchymal lung disease with ABCA3 mutation in December 2016 in Shenzhen Children's Hospital was analyzed. The information about ABCA3 gene mutation updated before April, 2017 was searched and collected from the gene databases (including 1000Genomes, HGMD, EXAC) and the literatures (including Wanfang Chinese database and Pubmed). Result: The girl was one year and nine months old. She presented with chronic cough, tachypnea, cyanosis and failure to thrive since she was one year and three months old. Her condition gradually deteriorated after she was empirically treated. Physical examination showed malnutrition, tachypnea and clubbed-fingers. Her high resolution computed tomography (HRCT) revealed diffused ground-glass opacities, thickened interlobular septum, and multiple subpleural small air-filled lung cysts. The second generation sequencing study identified a novel compound heterozygous mutation (c.1755delC+c.2890G>A) in her ABCA3 gene, which derived respectively from her parents and has not been reported in the database and the literatures mentioned above. Conclusion: c.1755delC+c.2890G>A is a new kind of compound heterozygous mutation in ABCA3, which can cause children's diffuse parenchymal lung disease. Its phenotype is related to its genotype.

  5. Phenotypic comparison of individuals with homozygous or heterozygous mutation of NOTCH3 in a large CADASIL family.

    PubMed

    Abou Al-Shaar, Hussam; Qadi, Najeeb; Al-Hamed, Mohamed H; Meyer, Brian F; Bohlega, Saeed

    2016-08-15

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary microangiopathy caused by mutations in NOTCH3, very rarely homoallelic. To describe the clinical, radiological, and neuropsychological features in an extended CADASIL family including members with either a homozygous or heterozygous NOTCH3 R1231C mutation. The pedigree included 3 generations of a family with 13 affected individuals. The patients were examined clinically and radiologically. Neuropsychological testing was performed on the proband. Sequencing of the entire coding DNA sequence (CDS) and flanking regions of NOTCH3 was undertaken using PCR amplification and direct Sanger sequencing. Homozygous C3769T mutation, predicting R1231C in exon 22 of NOTCH3 was found in 7 family members. Six other family members harbored the same in the heterozygous state. Homozygous individuals showed a slightly more severe clinical and radiological phenotype of earlier onset compared to their heterozygous counterparts. This study reports the largest number of patients with homozygous NOTCH3 mutation. The phenotype and imaging features of homozygous individuals is within the spectrum of CADASIL, although slightly at the severe end when compared to heterozygotes carrying the same mutation. Both genetic modifiers and environmental factors may play an essential role in modification and alteration of the clinical phenotype and white matter changes among CADASIL patients. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Assay for identification of heterozygous single-nucleotide polymorphism (Ala67Thr) in human poliovirus receptor gene.

    PubMed

    Nandi, Shyam Sundar; Sharma, Deepa Kailash; Deshpande, Jagadish M

    2016-07-01

    It is important to understand the role of cell surface receptors in susceptibility to infectious diseases. CD155 a member of the immunoglobulin super family, serves as the poliovirus receptor (PVR). Heterozygous (Ala67Thr) polymorphism in CD155 has been suggested as a risk factor for paralytic outcome of poliovirus infection. The present study pertains to the development of a screening test to detect the single nucleotide (SNP) polymorphism in the CD155 gene. New primers were designed for PCR, sequencing and SNP analysis of Exon2 of CD155 gene. DNAs extracted from either whole blood (n=75) or cells from oral cavity (n=75) were used for standardization and validation of the SNP assay. DNA sequencing was used as the gold standard method. A new SNP assay for detection of heterozygous Ala67Thr genotype was developed and validated by testing 150 DNA samples. Heterozygous CD155 was detected in 27.33 per cent (41/150) of DNA samples tested by both SNP detection assay and sequencing. The SNP detection assay was successfully developed for identification of Ala67Thr polymorphism in human PVR/CD155 gene. The SNP assay will be useful for large scale screening of DNA samples.

  7. CHEK2*1100delC homozygosity in the Netherlands—prevalence and risk of breast and lung cancer

    PubMed Central

    Huijts, Petra EA; Hollestelle, Antoinette; Balliu, Brunilda; Houwing-Duistermaat, Jeanine J; Meijers, Caro M; Blom, Jannet C; Ozturk, Bahar; Krol-Warmerdam, Elly MM; Wijnen, Juul; Berns, Els MJJ; Martens, John WM; Seynaeve, Caroline; Kiemeney, Lambertus A; van der Heijden, Henricus F; Tollenaar, Rob AEM; Devilee, Peter; van Asperen, Christi J

    2014-01-01

    The 1100delC mutation in the CHEK2 gene has a carrier frequency of up to 1.5% in individuals from North-West Europe. Women heterozygous for 1100delC have an increased breast cancer risk (odds ratio 2.7). To explore the prevalence and clinical consequences of 1100delC homozygosity in the Netherlands, we genotyped a sporadic breast cancer hospital-based cohort, a group of non-BRCA1/2 breast cancer families, and breast tumors from a tumor tissue bank. Three 1100delC homozygous patients were found in the cohort of 1434 sporadic breast cancer patients, suggesting an increased breast cancer risk for 1100delC homozygotes (odds ratio 3.4, 95% confidence interval 0.4–32.6, P=0.3). Another 1100delC homozygote was found in 592 individuals from 108 non-BRCA1/2 breast cancer families, and two more were found after testing 1706 breast tumors and confirming homozygosity on their wild-type DNA. Follow-up data was available for five homozygous patients, and remarkably, three of them had developed contralateral breast cancer. A possible relationship between 1100delC and lung cancer risk was investigated in 457 unrelated lung cancer patients but could not be confirmed. Due to the small number of 1100delC homozygotes identified, the breast cancer risk estimate associated with this genotype had limited accuracy but is probably higher than the risk in heterozygous females. Screening for CHEK2 1100delC could be beneficial in countries with a relatively high allele frequency. PMID:23652375

  8. Ataxia-telangiectasia gene (ATM) mutation heterozygosity in breast cancer: a narrative review.

    PubMed

    Jerzak, K J; Mancuso, T; Eisen, A

    2018-04-01

    Despite the fact that heterozygosity for a pathogenic ATM variant is present in 1%-2% of the adult population, clinical guidelines to inform physicians and genetic counsellors about optimal management in that population are lacking. In this narrative review, we describe the challenges and controversies in the management of women who are heterozygous for a pathogenic ATM variant with respect to screening for breast and other malignancies, to choices for systemic therapy, and to decisions about radiation therapy. Given that the lifetime risk for breast cancer in women who are heterozygous for a pathogenic ATM variant is likely greater than 25%, those women should undergo annual mammographic screening starting at least by 40 years of age. For women in this group who have a strong family history of breast cancer, earlier screening with both magnetic resonance imaging and mammography should be considered. High-quality data to inform the management of established breast cancer in carriers of pathogenic ATM variants are lacking. Although deficiency in the ATM gene product might confer sensitivity to dna-damaging pharmaceuticals such as inhibitors of poly (adp-ribose) polymerase or platinum agents, prospective clinical trials have not been conducted in the relevant patient population. Furthermore, the evidence with respect to radiation therapy is mixed; some data suggest increased toxicity, and other data suggest improved clinical benefit from radiation in women who are carriers of a pathogenic ATM variant. As in the 2017 U.S. National Comprehensive Cancer Network guidelines, we recommend high-risk imaging for women in Ontario who are heterozygous for a pathogenic ATM variant. Currently, ATM carrier status should not influence decisions about systemic or radiation therapy in the setting of an established breast cancer diagnosis.

  9. Prospective study on the potential of RAAS blockade to halt renal disease in Alport syndrome patients with heterozygous mutations.

    PubMed

    Stock, Johanna; Kuenanz, Johannes; Glonke, Niklas; Sonntag, Joseph; Frese, Jenny; Tönshoff, Burkhard; Höcker, Britta; Hoppe, Bernd; Feldkötter, Markus; Pape, Lars; Lerch, Christian; Wygoda, Simone; Weber, Manfred; Müller, Gerhard-Anton; Gross, Oliver

    2017-01-01

    Patients with autosomal or X-linked Alport syndrome (AS) with heterozygous mutations in type IV collagen genes have a 1-20 % risk of progressing to end-stage renal disease during their lifetime. We evaluated the long-term renal outcome of patients at risk of progressive disease (chronic kidney disease stages 1-4) with/without nephroprotective therapy. This was a prospective, non-interventional, observational study which included data from a 4-year follow-up of AS patients with heterozygous mutations whose datasets had been included in an analysis of the 2010 database of the European Alport Registry. Using Kaplan-Meier estimates and logrank tests, we prospectively analyzed the updated datasets of 52 of these patients and 13 new datasets (patients added to the Registry after 2011). The effects of therapy, extrarenal symptoms and inheritance pattern on renal outcome were analyzed. The mean prospective follow-up was 46 ± 10 months, and the mean time on therapy was 8.4 ± 4.4 (median 7; range 2-18) years. The time from the appearance of the first symptom to diagnosis was 8.1 ± 14.2 (range 0-52) years. At the time of starting therapy, 5.4 % of patients had an estimated glomerular filtration rate of <60 ml/min, 67.6 % had proteinuria and 27.0 % had microalbuminuria. Therapeutic strategies included angiotensin-converting enzymer inhibitors (97.1 %), angiotensin receptor antagonists (1 patient), dual therapy (11.8 %) and statins (8.8 %). Among patients included in the prospective dataset, prevented the need for dialysis. Among new patients, no patient at risk for renal failure progressed to the next disease stage after 4 years follow-up; three patients even regressed to a lower stage during therapy. Treatment with blockers of the renin-angiotensin-aldosterone system prevents progressive renal failure in AS patients with heterozygous mutations in the genes causing AS. Considerable numbers of aging AS patients on dialysis may have heterozygous mutations in these

  10. Comparison of three assembly strategies for a heterozygous seedless grapevine genome assembly.

    PubMed

    Patel, Sagar; Lu, Zhixiu; Jin, Xiaozhu; Swaminathan, Padmapriya; Zeng, Erliang; Fennell, Anne Y

    2018-01-17

    De novo heterozygous assembly is an ongoing challenge requiring improved assembly approaches. In this study, three strategies were used to develop de novo Vitis vinifera 'Sultanina' genome assemblies for comparison with the inbred V. vinifera (PN40024 12X.v2) reference genome and a published Sultanina ALLPATHS-LG assembly (AP). The strategies were: 1) a default PLATANUS assembly (PLAT_d) for direct comparison with AP assembly, 2) an iterative merging strategy using METASSEMBLER to combine PLAT_d and AP assemblies (MERGE) and 3) PLATANUS parameter modifications plus GapCloser (PLAT*_GC). The three new assemblies were greater in size than the AP assembly. PLAT*_GC had the greatest number of scaffolds aligning with a minimum of 95% identity and ≥1000 bp alignment length to V. vinifera (PN40024 12X.v2) reference genome. SNP analysis also identified additional high quality SNPs. A greater number of sequence reads mapped back with zero-mismatch to the PLAT_d, MERGE, and PLAT*_GC (>94%) than was found in the AP assembly (87%) indicating a greater fidelity to the original sequence data in the new assemblies than in AP assembly. A de novo gene prediction conducted using seedless RNA-seq data predicted > 30,000 coding sequences for the three new de novo assemblies, with the greatest number (30,544) in PLAT*_GC and only 26,515 for the AP assembly. Transcription factor analysis indicated good family coverage, but some genes found in the VCOST.v3 annotation were not identified in any of the de novo assemblies, particularly some from  the MYB and ERF families. The PLAT_d and PLAT*_GC had a greater number of synteny blocks with the V. vinifera (PN40024 12X.v2) reference genome than AP or MERGE. PLAT*_GC provided the most contiguous assembly with only 1.2% scaffold N, in contrast to AP (10.7% N), PLAT_d (6.6% N) and Merge (6.4% N). A PLAT*_GC pseudo-chromosome assembly with chromosome alignment to the reference genome V. vinifera, (PN40024 12X.v2) provides new information

  11. An Insertional Translocation in Neurospora That Generates Duplications Heterozygous for Mating Type

    PubMed Central

    Perkins, David D.

    1972-01-01

    In strain T(I→II)39311 a long interstitial segment is transposed from IL to IIR, where it is inserted in reversed order with respect to the centromere. In crosses of T x T essentially all asci have eight viable, black spores, and all progeny are phenotypically normal. When T(I→II)39311 is crossed by Normal sequence (N), the expected duplication class is viable while the corresponding deficiency is lethal; 44% of the asci have 8 Black (viable) spores and 0 White (inviable) spores, 41% have 4 Black: 4 White, and 10% have 6 Black: 2 White. These are the ascus types expected from normal centromere disjunction without crossing over (8B:0W and 4B:4W equally probable), and with crossing over between centromere and break point (6B:2W). On germination, 8B:0W asci give rise to only parental types—4 T and 4 N; 4B:4W asci usually give four duplication (Dup) progeny; and 6B:2W asci usually give 2 T, 2 N, 2 Dup. Thus one third of all viable, black ascospores contain duplications.—Recessive markers in the donor chromosome which contributes the translocated segment can be mapped by duplication coverage. Ratios of 2 Dominant: 1 Recessive vs. 1 Dominant: 2 Recessive distinguish location in or outside the transposed segment. Eleven loci including mating type have been shown to lie within the segment, and markers at four loci have been transferred into the segment by meiotic recombination. The frequency of marker transfer indicates that the inserted segment usually pairs with its homologue. Ascus types that would result from single exchanges within the insertion are infrequent, as expected if asci containing dicentric bridges usually do not survive.—Duplication ascospores germinate to produce distinctive inhibited colonies. Later these "escape" to grow like wild type, and genes that were initially heterozygous in the duplication segregate when escape occurs. As with duplications from pericentric inversion In(IL→IR)H4250 (Newmeyer and Taylor 1967), the initial inhibition is

  12. Double PALB2 and BRCA1/BRCA2 mutation carriers are rare in breast cancer and breast-ovarian cancer syndrome families from the French Canadian founder population.

    PubMed

    Ancot, Frédéric; Arcand, Suzanna L; Mes-Masson, Anne-Marie; Provencher, Diane M; Tonin, Patricia N

    2015-06-01

    French Canadian families with breast cancer and breast-ovarian cancer syndrome harbor specific BRCA1, BRCA2 and PALB2 germline mutations, which have been attributed to common founders. Mutations in these genes confer an increased risk to breast and ovarian cancers, and have been identified to play a role in and directly interact with the common homologous recombination DNA repair pathways. Our previous study described the case of a female diagnosed with breast cancer at 45 years old, who harbored the PALB2:c.2323C>T [p.Q775X] and BRCA2:c.9004G>A [p.E3002K] germline mutations, which have been found to recur in the French Canadian cancer families. As the frequency of double heterozygous carriers of breast-ovarian cancer susceptibility alleles is unknown, and due to the possibility that there may be implications for genetic counseling and management for these carriers, the present study investigated the co-occurrence of BRCA1/BRCA2 and PALB2 mutations in the French Canadian cancer families. The PALB2:c.2323C>T [p.Q775X] mutation, which is the only PALB2 mutation to have been identified in French Canadian cancer families, was screened in 214 breast cancer cases and 22 breast-ovarian cancer cases from 114 BRCA1/BRCA2 mutation-positive French Canadian breast cancer (n=61) and breast-ovarian cancer (n=53) families using a tailored polymerase chain reaction-based TaqMan® SNP Genotyping Assay. No additional PALB2:c.2323C>T [p.Q775X] mutation carriers were identified among the BRCA1/BRCA2 mutation carriers. The results suggest that carriers of the PALB2:c.2323C>T [p.Q775X] mutation rarely co-occur in French Canadian breast cancer and breast-ovarian cancer families harboring BRCA1 or BRCA2 mutations.

  13. A post-transcriptional compensatory pathway in heterozygous ventricular myosin light chain 2-deficient mice results in lack of gene dosage effect during normal cardiac growth or hypertrophy.

    PubMed

    Minamisawa, S; Gu, Y; Ross, J; Chien, K R; Chen, J

    1999-04-09

    Our previous study of homozygous mutants of the ventricular specific isoform of myosin light chain 2 (mlc-2v) demonstrated that mlc-2v plays an essential role in murine heart development (Chen, J., Kubalak, S. W., Minamisawa, S., Price, R. L., Becker, K. D., Hickey, R., Ross, J., Jr., and Chien, K. R. (1998) J. Biol. Chem. 273, 1252-1256). As gene dosage of some myofibrillar proteins can affect muscle function, we have analyzed heterozygous mutants in depth. Ventricles of heterozygous mutants displayed a 50% reduction in mlc-2v mRNA, yet expressed normal levels of protein both under basal conditions and following induction of cardiac hypertrophy by aortic constriction. Heterozygous mutants exhibited cardiac function comparable to that of wild-type littermate controls both prior to and following aortic constriction. There were no significant differences in contractility and responses to calcium between wild-type and heterozygous unloaded cardiomyocytes. We conclude that heterozygous mutants show neither a molecular nor a physiological cardiac phenotype either at base line or following hypertrophic stimuli. These results suggest that post-transcriptional compensatory mechanisms play a major role in maintaining the level of MLC-2v protein in murine hearts. In addition, as our mlc-2v knockout mutants were created by a knock-in of Cre recombinase into the endogenous mlc-2v locus, this study demonstrates that heterozygous mlc-2v cre knock-in mice are appropriate for ventricular specific gene targeting.

  14. Breast Cancer in Men

    MedlinePlus

    FACTS FOR LIFE Breast Cancer in Men Do men get breast cancer? Since men have breast tissue, they can get breast cancer, but it’s rare. About 1 percent of ... breast cancer cases in the U.S. occur in men. It may sound like a small number, but ...

  15. Breast Cancer Surgery

    MedlinePlus

    FACTS FOR LIFE Breast Cancer Surgery The goal of breast cancer surgery is to remove the whole tumor from the breast. Some lymph nodes ... might still be in the body. Types of breast cancer surgery There are two types of breast cancer ...

  16. Risks of Breast Cancer Screening

    MedlinePlus

    ... of Breast & Gynecologic Cancers Breast Cancer Screening Research Breast Cancer Screening (PDQ®)–Patient Version What is screening? Go ... cancer screening: Cancer Screening Overview General Information About Breast Cancer Key Points Breast cancer is a disease in ...

  17. Benign Breast Problems and Conditions

    MedlinePlus

    ... a benign breast condition? • What is breast self-awareness? • Glossary What is a benign breast condition? A ... risks, and test results. What is breast self-awareness? Being aware of how your breasts normally look ...

  18. Putative Digenic Inheritance of Heterozygous RP1L1 and C2orf71 Null Mutations in Syndromic Retinal Dystrophy

    PubMed Central

    Liu, Yangfan P.; Bosch, Daniëlle G.M.; Siemiatkowska, Anna M.; Rendtorff, Nanna Dahl; Boonstra, F. Nienke; Möller, Claes; Tranebjærg, Lisbeth; Katsanis, Nicholas; Cremers, Frans P.M.

    2018-01-01

    Background Retinitis pigmentosa (RP) is the most common cause of inherited retinal degeneration and can occur in non-syndromic and syndromic forms. Syndromic RP is accompanied by other symptoms such as intellectual disability, hearing loss, or congenital abnormalities. Both forms are known to exhibit complex genetic interactions that can modulate the penetrance and expressivity of the phenotype. Materials and methods In an individual with atypical RP, hearing loss, ataxia and cerebellar atrophy whole exome sequencing was performed. The candidate pathogenic variants were tested by developing an in vivo zebrafish model and assaying for retinal and cerebellar integrity. Results Exome sequencing revealed a complex heterozygous protein-truncating mutation in RP1L1, p.[(Lys111Glnfs*27; Q2373*)], and a heterozygous nonsense mutation in C2orf71, p.(Ser512*). Mutations in both genes have previously been implicated in autosomal recessive non-syndromic RP, raising the possibility of a digenic model in this family. Functional testing in a zebrafish model for two key phenotypes of the affected person showed that the combinatorial suppression of rp1l1 and c2orf71l induced discrete pathology in terms of reduction of eye size with concomitant loss of rhodopsin in the photoreceptors, and disorganization of the cerebellum. Conclusions We propose that the combination of heterozygous loss-of-function mutations in these genes drives syndromic retinal dystrophy, likely through the genetic interaction of at least two loci. Haploinsufficiency at each of these loci is insufficient to induce overt pathology. PMID:27029556

  19. Mosaic synaptopathy and functional defects in Cav1.4 heterozygous mice and human carriers of CSNB2

    PubMed Central

    Michalakis, Stylianos; Shaltiel, Lior; Sothilingam, Vithiyanjali; Koch, Susanne; Schludi, Verena; Krause, Stefanie; Zeitz, Christina; Audo, Isabelle; Lancelot, Marie-Elise; Hamel, Christian; Meunier, Isabelle; Preising, Markus N.; Friedburg, Christoph; Lorenz, Birgit; Zabouri, Nawal; Haverkamp, Silke; Garrido, Marina Garcia; Tanimoto, Naoyuki; Seeliger, Mathias W.; Biel, Martin; Wahl-Schott, Christian A.

    2014-01-01

    Mutations in CACNA1F encoding the α1-subunit of the retinal Cav1.4 L-type calcium channel have been linked to Cav1.4 channelopathies including incomplete congenital stationary night blindness type 2A (CSNB2), Åland Island eye disease (AIED) and cone-rod dystrophy type 3 (CORDX3). Since CACNA1F is located on the X chromosome, Cav1.4 channelopathies are typically affecting male patients via X-chromosomal recessive inheritance. Occasionally, clinical symptoms have been observed in female carriers, too. It is currently unknown how these mutations lead to symptoms in carriers and how the retinal network in these females is affected. To investigate these clinically important issues, we compared retinal phenotypes in Cav1.4-deficient and Cav1.4 heterozygous mice and in human female carrier patients. Heterozygous Cacna1f carrier mice have a retinal mosaic consistent with differential X-chromosomal inactivation, characterized by adjacent vertical columns of affected and non-affected wild-type-like retinal network. Vertical columns in heterozygous mice are well comparable to either the wild-type retinal network of normal mice or to the retina of homozygous mice. Affected retinal columns display pronounced rod and cone photoreceptor synaptopathy and cone degeneration. These changes lead to vastly impaired vision-guided navigation under dark and normal light conditions and reduced retinal electroretinography (ERG) responses in Cacna1f carrier mice. Similar abnormal ERG responses were found in five human CACNA1F carriers, four of which had novel mutations. In conclusion, our data on Cav1.4 deficient mice and human female carriers of mutations in CACNA1F are consistent with a phenotype of mosaic CSNB2. PMID:24163243

  20. Confirmation and refinement of the heterozygous deletion of the small leucine-rich proteoglycans associated with posterior amorphous corneal dystrophy.

    PubMed

    Cervantes, Aleck E; Gee, Katherine M; Whiting, Martha F; Frausto, Ricardo F; Aldave, Anthony J

    2018-04-19

    To present the clinical and cytogenetic features of a previously unreported family with posterior amorphous corneal dystrophy (PACD) associated with a heterozygous deletion of the small leucine-rich proteoglycan (SRLP) genes on chromosome 12. Clinical characterization was performed using slit lamp biomicroscopic and optical coherence tomography (OCT) imaging. Genomic DNA was collected from affected and unaffected family members, and a cytogenomic array was used to identify copy number variations (CNV) present in the PACD locus. Three members of a Guatemalan family presented with clinical characteristics consistent with PACD: bilateral posterior stromal lamellar opacification, decreased corneal curvature, and iridocorneal adhesions. OCT imaging demonstrated decreased corneal thickness and hyperreflectivity of the posterior third of the corneal stroma. CNV analysis confirmed the presumed clinical diagnosis of PACD by revealing a 0.304 Mb heterozygous deletion in the PACD locus on chromosome 12 that included the four SLRP genes (KERA, LUM, DCN, and EPYC) deleted in each of the PACD families in which CNV analysis has been reported. This is the first report of the OCT appearance of PACD and the second confirmation of a heterozygous deletion of chromosome 12q21.33 as the cause of PACD, highlighting the utility of array-based cytogenomics to confirm the suspected clinical diagnosis of PACD. As the smallest previously reported pathogenic deletion was 0.701 Mb, the 0.304-Mb deletion we report is the smallest identified to date and reduces the size of the PACD locus to 0.275 Mb.

  1. Determination of optimal cutoff value to accurately identify glucose-6-phosphate dehydrogenase-deficient heterozygous female neonates.

    PubMed

    Miao, Jing-Kun; Chen, Qi-Xiong; Bao, Li-Ming; Huang, Yi; Zhang, Juan; Wan, Ke-Xing; Yi, Jing; Wang, Shi-Yi; Zou, Lin; Li, Ting-Yu

    2013-09-23

    Conventional screening tests to assess G6PD deficiency use a low cutoff value of 2.10 U/gHb which may not be adequate for detecting females with heterozygous deficiency. The aim of present study was to determine an appropriate cutoff value with increased sensitivity in identifying G6PD-deficient heterozygous females. G6PD activity analysis was performed on 51,747 neonates using semi-quantitative fluorescent spot test. Neonates suspected with G6PD deficiency were further analyzed using quantitatively enzymatic assay and for common G6PD mutations. The cutoff values of G6PD activity were estimated using the receiver operating characteristic curve. Our results demonstrated that using 2.10 U/g Hb as a cutoff, the sensitivity of the assay to detect female neonates with G6PD heterozygous deficiency was 83.3%, as compared with 97.6% using 2.55 U/g Hb as a cutoff. The high cutoff identified 21% (8/38) of the female neonates with partial G6PD deficiency which were not detected with 2.10 U/g Hb. Our study found that high cutoffs, 2.35 and 2.55 U/g Hb, would increase assay's sensitivity to identify male and female G6PD deficiency neonates, respectively. We established a reliable cutoff value of G6PD activity with increased sensitivity in identifying female newborns with partial G6PD deficiency. Copyright © 2013 Elsevier B.V. All rights reserved.

  2. Breast Implants

    MedlinePlus

    ... sale in the United States: saline-filled and silicone gel-filled. Both types have a silicone outer shell. They vary in size, shell thickness, ... implant them. Provide information on saline-filled and silicone gel-filled breast implants, including data supporting a ...

  3. Interleukin 2 production in a family with systemic lupus erythematosus and a C4Q0 heterozygous inheritance.

    PubMed Central

    Gutierrez, C; Cabrero, E; Vicario, J L; Martín Villa, M; Rengel, M A; Gomez Campdera, F J; Yebra, M; Fernández-Cruz, E; Arnaiz Villena, A

    1991-01-01

    Interleukin 2 production was studied in a family with systemic lupus erythematosus (SLE) and a C4Q0 heterozygous inheritance. Autoimmune manifestations seemed to be associated with the HLA haplotype containing the C4Q0 allele, which was shared by all four ill family members. Concentrations of interleukin 2, however, did not associate either with the haplotype or with the clinical or serological manifestations, as diminished concentrations of interleukin 2 were found in only two subjects with SLE. Thus the defect in this family seemed to be acquired rather than genetically conditioned. PMID:1888202

  4. Cost-effectiveness of PCSK9 Inhibitor Therapy in Patients With Heterozygous Familial Hypercholesterolemia or Atherosclerotic Cardiovascular Disease.

    PubMed

    Kazi, Dhruv S; Moran, Andrew E; Coxson, Pamela G; Penko, Joanne; Ollendorf, Daniel A; Pearson, Steven D; Tice, Jeffrey A; Guzman, David; Bibbins-Domingo, Kirsten

    2016-08-16

    Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were recently approved for lowering low-density lipoprotein cholesterol in heterozygous familial hypercholesterolemia (FH) or atherosclerotic cardiovascular disease (ASCVD) and have potential for broad ASCVD prevention. Their long-term cost-effectiveness and effect on total health care spending are uncertain. To estimate the cost-effectiveness of PCSK9 inhibitors and their potential effect on US health care spending. The Cardiovascular Disease Policy Model, a simulation model of US adults aged 35 to 94 years, was used to evaluate cost-effectiveness of PCSK9 inhibitors or ezetimibe in heterozygous FH or ASCVD. The model incorporated 2015 annual PCSK9 inhibitor costs of $14,350 (based on mean wholesale acquisition costs of evolocumab and alirocumab); adopted a health-system perspective, lifetime horizon; and included probabilistic sensitivity analyses to explore uncertainty. Statin therapy compared with addition of ezetimibe or PCSK9 inhibitors. Lifetime major adverse cardiovascular events (MACE: cardiovascular death, nonfatal myocardial infarction, or stroke), incremental cost per quality-adjusted life-year (QALY), and total effect on US health care spending over 5 years. Adding PCSK9 inhibitors to statins in heterozygous FH was estimated to prevent 316,300 MACE at a cost of $503,000 per QALY gained compared with adding ezetimibe to statins (80% uncertainty interval [UI], $493,000-$1,737,000). In ASCVD, adding PCSK9 inhibitors to statins was estimated to prevent 4.3 million MACE compared with adding ezetimibe at $414,000 per QALY (80% UI, $277,000-$1,539,000). Reducing annual drug costs to $4536 per patient or less would be needed for PCSK9 inhibitors to be cost-effective at less than $100,000 per QALY. At 2015 prices, PCSK9 inhibitor use in all eligible patients was estimated to reduce cardiovascular care costs by $29 billion over 5 years, but drug costs increased by an estimated $592 billion (a 38

  5. X-linked G6PD deficiency protects hemizygous males but not heterozygous females against severe malaria.

    PubMed

    Guindo, Aldiouma; Fairhurst, Rick M; Doumbo, Ogobara K; Wellems, Thomas E; Diallo, Dapa A

    2007-03-01

    Glucose-6-phosphate dehydrogenase (G6PD) is important in the control of oxidant stress in erythrocytes, the host cells for Plasmodium falciparum. Mutations in this enzyme produce X-linked deficiency states associated with protection against malaria, notably in Africa where the A- form of G6PD deficiency is widespread. Some reports have proposed that heterozygous females with mosaic populations of normal and deficient erythrocytes (due to random X chromosome inactivation) have malaria resistance similar to or greater than hemizygous males with populations of uniformly deficient erythrocytes. These proposals are paradoxical, and they are not consistent with currently hypothesized mechanisms of protection. We conducted large case-control studies of the A- form of G6PD deficiency in cases of severe or uncomplicated malaria among two ethnic populations of rural Mali, West Africa, where malaria is hyperendemic. Our results indicate that the uniform state of G6PD deficiency in hemizygous male children conferred significant protection against severe, life-threatening malaria, and that it may have likewise protected homozygous female children. No such protection was evident from the mosaic state of G6PD deficiency in heterozygous females. We also found no significant differences in the parasite densities of males and females with differences in G6PD status. Pooled odds ratios from meta-analysis of our data and data from a previous study confirmed highly significant protection against severe malaria in hemizygous males but not in heterozygous females. Among the different forms of severe malaria, protection was principally evident against cerebral malaria, the most frequent form of life-threatening malaria in these studies. The A- form of G6PD deficiency in Africa is under strong natural selection from the preferential protection it provides to hemizygous males against life-threatening malaria. Little or no such protection is present among heterozygous females. Although these

  6. Lower metabolic rate in individuals heterozygous for either a frameshift or a functional missense MC4R variant.

    PubMed

    Krakoff, Jonathan; Ma, Lijun; Kobes, Sayuko; Knowler, William C; Hanson, Robert L; Bogardus, Clifton; Baier, Leslie J

    2008-12-01

    Humans with functional variants in the melanocortin 4 receptor (MC4R) are obese, hyperphagic, and hyperinsulinemic but have been reported to have no difference in energy expenditure. We investigated the association of two MC4R variants, Arg165Gln (R165Q) and A insertion at nucleotide 100 (NT100), with adiposity in 3,074 full-heritage Pima Indians, a subset of whom had metabolic measures including 24-h energy expenditure (n = 252) and resting metabolic rate (RMR) (n = 364). Among the 3,074 subjects, 43 were heterozygous for R165Q and 14 for NT100 (frequency = 0.007 and 0.002). Mean (+/- SD) BMI was higher among subjects with R165Q (39.3 +/- 8.6 kg/m(2)) or NT100 (41.2 +/- 7.8) than subjects without either variant (37.1 +/- 8.4) (P = 0.04 and 0.02, adjusted for age, sex, and birth year and accounting for family membership). The 24-h energy expenditure (four with NT100; three with R165Q) or RMR (six with NT100; two with R165Q) was lower in heterozygous subjects but only met statistical significance when heterozygous subjects were combined and compared with subjects without either variant: least-squares means, 2,163 kcal/24 h (95% CI 2,035-2,291) vs. 2,307 kcal/24 h (2,285-2,328), P = 0.03 for 24-h energy expenditure, and 1,617 kcal/24 h (1,499-1,734) vs. 1,754 kcal/24 h (1,736-1,772), P = 0.02 for RMR; adjusted for age, sex, fat-free mass, and fat mass). For RMR, this difference persisted, even after accounting for family membership. Pima Indians heterozygous for R165Q or NT100 in MC4R have higher BMIs and lower energy expenditure (by approximately 140 kcal/day), indicating that lower energy expenditure was a component of the increased adiposity.

  7. X-Linked G6PD Deficiency Protects Hemizygous Males but Not Heterozygous Females against Severe Malaria

    PubMed Central

    Doumbo, Ogobara K; Wellems, Thomas E; Diallo, Dapa A

    2007-01-01

    Background Glucose-6-phosphate dehydrogenase (G6PD) is important in the control of oxidant stress in erythrocytes, the host cells for Plasmodium falciparum. Mutations in this enzyme produce X-linked deficiency states associated with protection against malaria, notably in Africa where the A− form of G6PD deficiency is widespread. Some reports have proposed that heterozygous females with mosaic populations of normal and deficient erythrocytes (due to random X chromosome inactivation) have malaria resistance similar to or greater than hemizygous males with populations of uniformly deficient erythrocytes. These proposals are paradoxical, and they are not consistent with currently hypothesized mechanisms of protection. Methods and Findings We conducted large case-control studies of the A− form of G6PD deficiency in cases of severe or uncomplicated malaria among two ethnic populations of rural Mali, West Africa, where malaria is hyperendemic. Our results indicate that the uniform state of G6PD deficiency in hemizygous male children conferred significant protection against severe, life-threatening malaria, and that it may have likewise protected homozygous female children. No such protection was evident from the mosaic state of G6PD deficiency in heterozygous females. We also found no significant differences in the parasite densities of males and females with differences in G6PD status. Pooled odds ratios from meta-analysis of our data and data from a previous study confirmed highly significant protection against severe malaria in hemizygous males but not in heterozygous females. Among the different forms of severe malaria, protection was principally evident against cerebral malaria, the most frequent form of life-threatening malaria in these studies. Conclusions The A− form of G6PD deficiency in Africa is under strong natural selection from the preferential protection it provides to hemizygous males against life-threatening malaria. Little or no such protection is

  8. Low-density lipoprotein receptor-negative compound heterozygous familial hypercholesterolemia: Two lifetime journeys of lipid-lowering therapy.

    PubMed

    Yahya, Reyhana; Mulder, Monique T; Sijbrands, Eric J G; Williams, Monique; Roeters van Lennep, Jeanine E

    We present the case history of 2 patients with low-density lipoprotein receptor-negative compound heterozygous familial hypercholesterolemia who did not receive lipoprotein apheresis. We describe the subsequent effect of all lipid-lowering medications during their life course including resins, statins, ezetimibe, nicotinic acid/laropiprant, mipomersen, and lomitapide. These cases tell the story of siblings affected with this rare disease, who are free of symptoms but still are at a very high cardiovascular disease risk, and their treatment from childhood. Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.

  9. Parieto-occipital lobe epilepsy caused by a POLG1 compound heterozygous A467T/W748S genotype.

    PubMed

    Roshal, David; Glosser, David; Zangaladze, Andro

    2011-06-01

    We describe a 16-year-old woman with a rare POLG1 A467T/W748S genotype, with a wide range of neurological manifestations, including focal parieto-occipital lobe seizures, migraine headaches, cerebellar ataxia, sensory-motor axonal neuropathy, and impairment of visual perception and cognitive function. Treatment of epilepsy in patients with a POLG1 compound heterozygous A467T/W748S genotype is very challenging; the epilepsy may preferentially respond to sodium channel blockers. The POLG1-related syndrome has a variable clinical course, and disease morbidity and mortality may be correlated with the genotype. Copyright © 2011 Elsevier Inc. All rights reserved.

  10. Breast Changes and Conditions

    Cancer.gov

    Breast changes include benign conditions and those that increase the risk of breast cancer. Symptoms and treatment of breast conditions such as ADH, ALH, cysts, DCIS, and LCIS are explained to women who may have received an abnormal mammogram finding.

  11. Male Breast Cancer

    MedlinePlus

    Although breast cancer is much more common in women, men can get it too. It happens most often to men between ... 60 and 70. Breast lumps usually aren't cancer. However, most men with breast cancer have lumps. ...

  12. Male Breast Cancer

    MedlinePlus

    ... or to other parts of the body. Where breast cancer begins in men Everyone is born with a ... and inflammatory breast cancer. Inherited genes that increase breast cancer risk Some men inherit abnormal (mutated) genes from ...

  13. Pseudomonal breast infection

    PubMed Central

    Rastall, S; Catchpole, C; Bright-Thomas, R; Thrush, S

    2010-01-01

    Breast infection and breast sepsis secondary to Pseudomonas aeruginosa is uncommon. We report two cases of pseudomonal breast infection leading to septic shock and abscess formation in women with non-responding breast infection. The management of breast infection is broad-spectrum antibiotics and ultrasound with aspiration of any collection. To treat breast infection effectively, the causative organism must be isolated to enable appropriate antibiotic therapy. PMID:20412664

  14. Breast Reduction Surgery

    MedlinePlus

    ... considering breast reduction surgery, consult a board-certified plastic surgeon. It's important to understand what breast reduction surgery entails — including possible risks and complications — as ...

  15. Novel Compound Heterozygous Spatacsin Mutations in a Greek Kindred with Hereditary Spastic Paraplegia SPG11 and Dementia.

    PubMed

    Fraidakis, Matthew J; Brunetti, Maura; Blackstone, Craig; Filippi, Massimo; Chiò, Adriano

    2016-01-01

    SPG11 belongs to the autosomal recessive hereditary spastic paraplegias (HSP) and presents during childhood or puberty with a complex clinical phenotype encompassing learning difficulties, ataxia, peripheral neuropathy, amyotrophy, and mental retardation. We hereby present the case of a 30-year-old female patient with complex autosomal recessive HSP with thinning of the corpus callosum (TCC) and dementia that was compound heterozygous with two novel mutations in the SPG11 gene. Sequence analysis of the SPG11 gene revealed two novel mutations in a compound heterozygous state in the index patient (c.2431C>T/p.Gln811Ter and c.6755_6756insT/p.Glu2252Aspfs*88). MRI showed abnormal TCC, white matter (WM) hyperintensities periventricularly, and the 'ears of the lynx' sign. Diffusion tensor imaging showed a mild-to-moderate decrease in fractional anisotropy and an increase in mean diffusivity in WM compared to age-matched controls, while magnetic resonance spectroscopy showed abnormal findings in affected WM with a decrease in N-acetyl-aspartate in WM regions of interest. This is the first SPG11 kindred from the Greek population to be reported in the medical literature. © 2016 S. Karger AG, Basel.

  16. Novel compound heterozygous mutations in CNGA1in a Chinese family affected with autosomal recessive retinitis pigmentosa by targeted sequencing.

    PubMed

    Wang, Min; Gan, Dekang; Huang, Xin; Xu, Gezhi

    2016-07-08

    About 37 genes have been reported to be involved in autosomal recessive retinitis pigmentosa, a hereditary retinal disease. However, causative genes remain unclear in a lot of cases. Two sibs of a Chinese family with ocular disease were diagnosed in Eye and ENT Hospital of Fudan University. Targeted sequencing performed on proband to screen pathogenic mutations. PCR combined Sanger sequencing then performed on eight family members including two affected and six unaffected individuals to determine whether mutations cosegregate with disease. Two affected members exhibited clinical features that fit the criteria of autosomal recessive retinitis pigmentosa. Two heterozygous mutations (NM000087, p.Y82X and p.L89fs) in CNGA1 were revealed on proband. Affected members were compound heterozygotes for the two mutations whereas unaffected members either had no mutation or were heterozygote carriers for only one of the two mutations. That is, these mutations cosegregate with autosomal recessive retinitis pigmentosa. Compound heterozygous mutations (NM000087, p.Y82X and p.L89fs) in exon 6 of CNGA1are pathogenic mutations in this Chinese family. Of which, p.Y82X is firstly reported in patient with autosomal recessive retinitis pigmentosa.

  17. Novel compound heterozygous mutations in MYO7A Associated with Usher syndrome 1 in a Chinese family.

    PubMed

    Gao, Xue; Wang, Guo-Jian; Yuan, Yong-Yi; Xin, Feng; Han, Ming-Yu; Lu, Jing-Qiao; Zhao, Hui; Yu, Fei; Xu, Jin-Cao; Zhang, Mei-Guang; Dong, Jiang; Lin, Xi; Dai, Pu

    2014-01-01

    Usher syndrome is an autosomal recessive disease characterized by sensorineural hearing loss, age-dependent retinitis pigmentosa (RP), and occasionally vestibular dysfunction. The most severe form is Usher syndrome type 1 (USH1). Mutations in the MYO7A gene are responsible for USH1 and account for 29-55% of USH1 cases. Here, we characterized a Chinese family (no. 7162) with USH1. Combining the targeted capture of 131 known deafness genes, next-generation sequencing, and bioinformatic analysis, we identified two deleterious compound heterozygous mutations in the MYO7A gene: a reported missense mutation c.73G>A (p.G25R) and a novel nonsense mutation c.462C>A (p.C154X). The two compound variants are absent in 219 ethnicity-matched controls, co-segregates with the USH clinical phenotypes, including hearing loss, vestibular dysfunction, and age-dependent penetrance of progressive RP, in family 7162. Therefore, we concluded that the USH1 in this family was caused by compound heterozygous mutations in MYO7A.

  18. Disruption of hippocampus-regulated behavioural and cognitive processes by heterozygous constitutive deletion of SynGAP.

    PubMed

    Muhia, Mary; Yee, Benjamin K; Feldon, Joram; Markopoulos, Foivos; Knuesel, Irene

    2010-02-01

    The brain-specific Ras/Rap-GTPase activating protein (SynGAP) is a prime candidate linking N-methyl-d-aspartate receptors to the regulation of the ERK/MAP kinase signalling cascade, suggested to be essential for experience-dependent synaptic plasticity. Here, we evaluated the behavioural phenotype of SynGAP heterozygous knockout mice (SG(+/-)), expressing roughly half the normal levels of SynGAP. In the cognitive domain, SG(+/-) mice demonstrated severe working and reference memory deficits in the radial arm maze task, a mild impairment early in the transfer test of the water maze task, and a deficiency in spontaneous alternation in an elevated T-maze. In the non-cognitive domain, SG(+/-) mice were hyperactive in the open field and appeared less anxious in the elevated plus maze test. In contrast, object recognition memory performance was not impaired in SG(+/-) mice. The reduction in SynGAP thus resulted in multiple behavioural traits suggestive of aberrant cognitive and non-cognitive processes normally mediated by the hippocampus. Immunohistochemical evaluation further revealed a significant reduction in calbindin-positive interneurons in the hippocampus and doublecortin-positive neurons in the dentate gyrus of adult SG(+/-) mice. Heterozygous constitutive deletion of SynGAP is therefore associated with notable behavioural as well as morphological phenotypes indicative of hippocampal dysfunction. Any suggestion of a possible causal link between them however remains a matter for further investigation.

  19. Combined pituitary hormone deficiency with unique pituitary dysplasia and morning glory syndrome related to a heterozygous PROKR2 mutation

    PubMed Central

    Asakura, Yumi; Muroya, Koji; Hanakawa, Junko; Sato, Takeshi; Aida, Noriko; Narumi, Satoshi; Hasegawa, Tomonobu; Adachi, Masanori

    2015-01-01

    Abstract Recent reports have indicated the role of the prokineticin receptor 2 gene (PROKR2) in the etiology of congenital hypopituitarism, including septo-optic dysplasia and Kallmann syndrome. In the present study, using next-generation targeted sequencing, we identified a novel heterozygous PROKR2 variant (c.742C>T; p.R248W) in a female patient who had combined pituitary hormone deficiency (CPHD), morning glory syndrome and a severely malformed pituitary gland. No other mutation was present in 27 genes related to hypogonadotropic hypogonadism, pituitary hormone deficiency and optic nerve malformation. The substituted amino acid was located on the third intracellular loop of the PROKR2 protein, which is a G protein-coupled receptor. Computational analyses with two programs (SIFT and PolyPhen-2) showed that the substitution was deleterious to PROKR2 function. The p.R248W mutation was transmitted from the patient’s mother, who had a slightly delayed menarche. Collectively, we provide further genetic evidence linking heterozygous PROKR2 mutations and the development of CPHD. PMID:25678757

  20. Combined pituitary hormone deficiency with unique pituitary dysplasia and morning glory syndrome related to a heterozygous PROKR2 mutation.

    PubMed

    Asakura, Yumi; Muroya, Koji; Hanakawa, Junko; Sato, Takeshi; Aida, Noriko; Narumi, Satoshi; Hasegawa, Tomonobu; Adachi, Masanori

    2015-01-01

    Recent reports have indicated the role of the prokineticin receptor 2 gene (PROKR2) in the etiology of congenital hypopituitarism, including septo-optic dysplasia and Kallmann syndrome. In the present study, using next-generation targeted sequencing, we identified a novel heterozygous PROKR2 variant (c.742C>T; p.R248W) in a female patient who had combined pituitary hormone deficiency (CPHD), morning glory syndrome and a severely malformed pituitary gland. No other mutation was present in 27 genes related to hypogonadotropic hypogonadism, pituitary hormone deficiency and optic nerve malformation. The substituted amino acid was located on the third intracellular loop of the PROKR2 protein, which is a G protein-coupled receptor. Computational analyses with two programs (SIFT and PolyPhen-2) showed that the substitution was deleterious to PROKR2 function. The p.R248W mutation was transmitted from the patient's mother, who had a slightly delayed menarche. Collectively, we provide further genetic evidence linking heterozygous PROKR2 mutations and the development of CPHD.

  1. [Acute abdominal pain due to splenic infarction in a patient with heterozygous sickle cell disease exposed to high altitude].

    PubMed

    Ruiz Semba, Edgar; Garavito Rentería, Jorge; Jiménez Bustamante, Jorge; Arteaga Caro, Ronal; García Del Aguila, José Luis; Chávez Gil, Vannya

    2006-01-01

    Hemoglobinopathy S, Depranocytosis or Sickle Cell Disease is the most common hemoglobinopathy in the world. In its heterozygous form (Sickle Cell Trait), it affects 8% of the black population in the U.S. and 25% of the black population in Africa, and is found less frequently in the Mediterranean area, India, Middle East and Latin America. The basic alteration is a substitution of glutamic acid by valin in the sixth position of the beta globin chain, which causes polymerization at low oxygen tension thereby distorting the structure of erythrocytes and increasing blood viscosity, which, in turn, generates obstructions of the capillary arterial blood flow to different areas of the body thus causing microinfarctions. Although Splenic Infarction is rare, it is recognized as a serious complication of Heterozygous Sickle Cell Disease (Sickle Cell Trait). We present the case of a 21 year-old mestizo male patient who came in with an acute case of abdominal pain after arriving to work in the Casapalca mining city (located in the Peruvian Andes at 4200 m.a.s.l.) and was referred to our Hospital in Lima for exams. We present the case because it is an unusual cause of acute abdominal pain, and because this condition is rare in Peru and there are few publications about it.

  2. Lifetime exercise intolerance with lactic acidosis as key manifestation of novel compound heterozygous ACAD9 mutations causing complex I deficiency.

    PubMed

    Schrank, Bertold; Schoser, Benedikt; Klopstock, Thomas; Schneiderat, Peter; Horvath, Rita; Abicht, Angela; Holinski-Feder, Elke; Augustis, Sarunas

    2017-05-01

    We report a 36-year-old female having lifetime exercise intolerance and lactic acidosis with nausea associated with novel compound heterozygous Acyl-CoA dehydrogenase 9 gene (ACAD9) mutations (p.Ala390Thr and p.Arg518Cys). ACAD9 is an assembly factor for the mitochondrial respiratory chain complex I. ACAD9 mutations are recognized as frequent causes of complex I deficiency. Our patient presented with exercise intolerance, rapid fatigue, and nausea since early childhood. Mild physical workload provoked the occurrence of nausea and vomiting repeatedly. Her neurological examination, laboratory findings and muscle biopsy demonstrated no abnormalities. A bicycle spiroergometry provoked significant lactic acidosis during and following exercise pointing towards a mitochondrial disorder. Subsequently, the analysis of respiratory chain enzyme activities in muscle revealed severe isolated complex I deficiency. Candidate gene sequencing revealed two novel heterozygous ACAD9 mutations. This patient report expands the mutational and phenotypic spectrum of diseases associated with mutations in ACAD9. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Glucose-6-phosphate dehydrogenase deficiency and malaria: cytochemical detection of heterozygous G6PD deficiency in women.

    PubMed

    Peters, Anna L; Van Noorden, Cornelis J F

    2009-11-01

    Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a X-chromosomally transmitted disorder of the erythrocyte that affects 400 million people worldwide. Diagnosis of heterozygously-deficient women is complicated: as a result of lyonization, these women have a normal and a G6PD-deficient population of erythrocytes. The cytochemical assay is the only reliable assay to discriminate between heterozygously-deficient women and non-deficient women or homozygously-deficient women. G6PD deficiency is mainly found in areas where malaria is or has been endemic. In these areas, malaria is treated with drugs that can cause (severe) hemolysis in G6PD-deficient individuals. A cheap and reliable test is necessary for diagnosing the deficiency to prevent hemolytic disorders when treating malaria. In this review, it is concluded that the use of two different tests for diagnosing men and women is the ideal approach to detect G6PD deficiency. The fluorescent spot test is inexpensive and easy to perform but only reliable for discriminating hemizygous G6PD-deficient men from non-deficient men. For women, the cytochemical assay is recommended. However, this assay is more expensive and difficult to perform and should be simplified into a kit for use in developing countries.

  4. Comprehensive behavioral analysis of RNG105 (Caprin1) heterozygous mice: Reduced social interaction and attenuated response to novelty

    PubMed Central

    Ohashi, Rie; Takao, Keizo; Miyakawa, Tsuyoshi; Shiina, Nobuyuki

    2016-01-01

    RNG105 (also known as Caprin1) is a major RNA-binding protein in neuronal RNA granules, and is responsible for mRNA transport to dendrites and neuronal network formation. A recent study reported that a heterozygous mutation in the Rng105 gene was found in an autism spectrum disorder (ASD) patient, but it remains unclear whether there is a causal relation between RNG105 deficiency and ASD. Here, we subjected Rng105+/− mice to a comprehensive behavioral test battery, and revealed the influence of RNG105 deficiency on mouse behavior. Rng105+/− mice exhibited a reduced sociality in a home cage and a weak preference for social novelty. Consistently, the Rng105+/− mice also showed a weak preference for novel objects and novel place patterns. Furthermore, although the Rng105+/− mice exhibited normal memory acquisition, they tended to have relative difficulty in reversal learning in the spatial reference tasks. These findings suggest that the RNG105 heterozygous knockout leads to a reduction in sociality, response to novelty and flexibility in learning, which are implicated in ASD-like behavior. PMID:26865403

  5. Double heterozygous mutations of MITF and PAX3 result in Waardenburg syndrome with increased penetrance in pigmentary defects.

    PubMed

    Yang, T; Li, X; Huang, Q; Li, L; Chai, Y; Sun, L; Wang, X; Zhu, Y; Wang, Z; Huang, Z; Li, Y; Wu, H

    2013-01-01

    Waardenburg syndrome (WS) is characterized by sensorineural hearing loss and pigmentary defects of the hair, skin, and iris. Heterozygous mutations of MITF and its transactivator gene PAX3 are associated with Waardenburg syndrome type II (WS2) and type I (WS1), respectively. Most patients with MITF or PAX3 mutations, however, show variable penetrance of WS-associated phenotypes even within families segregating the same mutation, possibly mediated by genetic background or specific modifiers. In this study, we reported a rare Waardenburg syndrome simplex family in which a pair of WS parents gave birth to a child with double heterozygous mutations of MITF and PAX3. Compared to his parents who carried a single mutation in either MITF or PAX3, this child showed increased penetrance of pigmentary defects including white forelock, white eyebrows and eyelashes, and patchy facial depigmentation. This observation suggested that the expression level of MITF is closely correlated to the penetrance of WS, and variants in transcription regulator genes of MITF may modify the relevant clinical phenotypes. © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

  6. Early-Onset X-Linked Retinitis Pigmentosa in a Heterozygous Female Harboring an Intronic Donor Splice Site Mutation in the Retinitis Pigmentosa GTPase Regulator Gene.

    PubMed

    Shifera, Amde Selassie; Kay, Christine Nichols

    2015-01-01

    To report a heterozygous female presenting with an early-onset and severe form of X-linked retinitis pigmentosa (XLRP). This is a case series presenting the clinical findings in a heterozygous female with XLRP and two of her family members. Fundus photography, fundus autofluorescence, ocular coherence tomography, and visual perimetry are presented. The proband reported here is a heterozygous female who presented at the age of 8 years with an early onset and aggressive form of XLRP. The patient belongs to a four-generation family with a total of three affected females and four affected males. The patient was initially diagnosed with retinitis pigmentosa (RP) at the age of 4 years. Genetic testing identified a heterozygous donor splice site mutation in intron 1 (IVS1 + 1G > A) of the retinitis pigmentosa GTPase regulator gene. The father of the proband was diagnosed with RP when he was a young child. The sister of the proband, evaluated at the age of 6 years, showed macular pigmentary changes. Although carriers of XLRP are usually asymptomatic or have a mild disease of late onset, the proband presented here exhibited an early-onset, aggressive form of the disease. It is not clear why some carrier females manifest a severe phenotype. A better understanding of the genetic processes involved in the penetrance and expressivity of XLRP in heterozygous females could assist in providing the appropriate counseling to affected families.

  7. Recombinant Peptides as Biomarkers for Metastatic Breast Cancer Response

    DTIC Science & Technology

    2007-10-01

    could be specific to breast cancer tumor models has just been concluded. In vivo biopanning wsa conducted with a T7 phage -based random peptide library...peptides selected from phage -displayed libraries. 15. SUBJECT TERMS Breast cancer, phage display, molecular imaging, personalized medicine 16...recombinant peptides from phage -displayed peptide libraries can be selected that bind to receptors activated in response to therapy. These peptides in turn

  8. Breast Cancer Overview

    MedlinePlus

    ... are here Home > Types of Cancer > Breast Cancer Breast Cancer This is Cancer.Net’s Guide to Breast Cancer. Use the menu below to choose the Overview/ ... social workers, and patient advocates. Cancer.Net Guide Breast Cancer Introduction Statistics Medical Illustrations Risk Factors and Prevention ...

  9. Breast Cancer -- Male

    MedlinePlus

    ... Home > Types of Cancer > Breast Cancer in Men Breast Cancer in Men This is Cancer.Net’s Guide to Breast Cancer in Men. Use the menu below to choose ... social workers, and patient advocates. Cancer.Net Guide Breast Cancer in Men Introduction Statistics Risk Factors and Prevention ...

  10. Breast cancer in men

    MedlinePlus

    ... in situ - male; Intraductal carcinoma - male; Inflammatory breast cancer - male; Paget disease of the nipple - male; Breast cancer - male ... The cause of breast cancer in men is not clear. But there are risk factors that make breast cancer more likely in men: Exposure to ...

  11. Changes to Your Breasts

    MedlinePlus

    ... to your breasts ... that they’ll never grow. Remember that your breasts don’t need to look like your friend’s breasts or a magazine model’s breasts. The world would be boring if everyone looked the same! ...

  12. A heterozygous putative null mutation in ROM1 without a mutation in peripherin/RDS in a family with retinitis pigmentosa

    SciTech Connect

    Sakuma, Hitoshi; Inana, G.; Murakami, Akira

    1995-05-20

    ROM1 is a 351-amino-acid, 37-kDa outer segment membrane protein of rod photoreceptors. ROM1 is related to peripherin/RDS, another outer segment membrane protein found in both rods and cones. The precise function of ROM1 or peripherin/RDS is not known, but they have been suggested to play important roles in the function and/or structure of the rod photoreceptor outer segment disks. A recent report implicated ROM1 in disease by suggesting that RP can be caused by a heterozygous null mutation in ROM1 but only in combination with another heterozygous mutation in peripherin/RDS. Screening of the ROM1 gene using polymerase chain reaction amplification,more » denaturing gradient gel electrophoresis, and direct DNA sequencing identified the same heterozygous putative null mutation in a family with RP.« less

  13. A case of gastric cancer metastasis to the breast in a female with BRCA2 germline mutation and literature review.

    PubMed

    Dulskas, Audrius; Al Bandar, Mahdi; Choi, Yoon Young; Shin, Su-Jin; Beom, Seung-Hoon; Son, Taeil; Kim, Hyung-Il; Cheong, Jae-Ho; Hyung, Woo Jin; Noh, Sung Hoon

    2017-12-05

    Gastric cancer is a deadly disease. Common sites of distant metastasis of gastric cancer are the peritoneum, liver, lymph nodes, and lung. The breast is a rare site of metastasis in gastric cancer which occurs in males dominantly. Here, we report the first case of metastatic gastric cancer to the breast in a patient with the breast cancer 2 (BRCA2) germline mutation. A 34-year-old female was admitted to the hospital with dyspepsia and a palpable mass in the left breast. Gastric cancer was confirmed to be signet ring cell adenocarcinoma. The breast mass exhibited histological properties consistent with gastric cancer. Immunohistochemistry results showed the breast tumor was CDX-2 and CK20-positive, but ER-, CK7-, and GATA3-negative. The BRCA1 gene had a wild-type sequence, but a heterozygous variant was discovered in BRCA2 in exon 10 (c.1744A > C, p.T582P); the significance of this variant is unknown. The patient received palliative XELOX (capecitabine + oxaliplatin) with radiation therapy to the stomach. The breast tumor resolved completely, but the overall response was partial. Gastric cancer metastasis to the breast is rare, but should be considered in young female patients with signet ring cell type gastric cancer.

  14. Aneuploidy in the embryonic progeny of females heterozygous for the Robertsonian chromosome (9.12) in genetically wild Peru-Coppock mice (Mus musculus).

    PubMed

    Harris, M J; Wallace, M E; Evans, E P

    1986-01-01

    The spontaneous appearance of a Robertsonian translocation in a laboratory colony of genetically wild Peru-Coppock mice gave the opportunity to study potential meiotic nondisjunction soon after the formation of the new chromosome and also in a hitherto untested combination of genotype and environment Metaphase II scores from the progenitor male had indicated a nondisjunction rate of approximately 10%, a figure that was confirmed by the finding of an estimated 12-16% total trisomic and probable monosomic zygotes in chromosomal studies of Day 9 embryos from heterozygous females. The chromosome studies also showed the presence of a significant excess of normal embryos that were heterozygous for the Robertsonian chromosome.

  15. Explosive mutation accumulation triggered by heterozygous human Pol ε proofreading-deficiency is driven by suppression of mismatch repair.

    PubMed

    Hodel, Karl P; de Borja, Richard; Henninger, Erin E; Campbell, Brittany B; Ungerleider, Nathan; Light, Nicholas; Wu, Tong; LeCompte, Kimberly G; Goksenin, A Yasemin; Bunnell, Bruce A; Tabori, Uri; Shlien, Adam; Pursell, Zachary F

    2018-02-28

    Tumors defective for DNA polymerase (Pol) ε proofreading have the highest tumor mutation burden identified. A major unanswered question is whether loss of Pol ε proofreading by itself is sufficient to drive this mutagenesis, or whether additional factors are necessary. To address this, we used a combination of next generation sequencing and in vitro biochemistry on human cell lines engineered to have defects in Pol ε proofreading and mismatch repair. Absent mismatch repair, monoallelic Pol ε proofreading deficiency caused a rapid increase in a unique mutation signature, similar to that observed in tumors from patients with biallelic mismatch repair deficiency and heterozygous Pol ε mutations. Restoring mismatch repair was sufficient to suppress the explosive mutation accumulation. These results strongly suggest that concomitant suppression of mismatch repair, a hallmark of colorectal and other aggressive cancers, is a critical force for driving the explosive mutagenesis seen in tumors expressing exonuclease-deficient Pol ε. © 2018, Hodel et al.

  16. De-Novo Assembly and Analysis of the Heterozygous Triploid Genome of the Wine Spoilage Yeast Dekkera bruxellensis AWRI1499

    PubMed Central

    Chambers, Paul J.; Pretorius, Isak S.

    2012-01-01

    Despite its industrial importance, the yeast species Dekkera (Brettanomyces) bruxellensis has remained poorly understood at the genetic level. In this study we describe whole genome sequencing and analysis for a prevalent wine spoilage strain, AWRI1499. The 12.7 Mb assembly, consisting of 324 contigs in 99 scaffolds (super-contigs) at 26-fold coverage, exhibits a relatively high density of single nucleotide polymorphisms (SNPs). Haplotype sampling for 1.2% of open reading frames suggested that the D. bruxellensis AWRI1499 genome is comprised of a moderately heterozygous diploid genome, in combination with a divergent haploid genome. Gene content analysis revealed enrichment in membrane proteins, particularly transporters, along with oxidoreductase enzymes. Availability of this assembly and annotation provides a resource for further investigation of genomic organization in this species, and functional characterization of genes that may confer important phenotypic traits. PMID:22470482

  17. Autosomal-dominant Leber Congenital Amaurosis Caused by a Heterozygous CRX Mutation in a Father and Son.

    PubMed

    Arcot Sadagopan, Karthikeyan; Battista, Robert; Keep, Rosanne B; Capasso, Jenina E; Levin, Alex V

    2015-06-01

    Leber congenital amaurosis (LCA) is most often an autosomal recessive disorder. We report a father and son with autosomal dominant LCA due to a mutation in the CRX gene. DNA screening using an allele specific assay of 90 of the most common LCA-causing variations in the coding sequences of AIPL1, CEP290, CRB1, CRX, GUCY2D, RDH12 and RPE65 was performed on the father. Automated DNA sequencing of his son examining exon 3 of the CRX gene was subsequently performed. Both father and son have a heterozygous single base pair deletion of an adenine at codon 153 in the coding sequence of the CRX gene resulting in a frameshift mutation. Mutations involving the CRX gene may demonstrate an autosomal dominant inheritance pattern for LCA.

  18. Explosive mutation accumulation triggered by heterozygous human Pol ε proofreading-deficiency is driven by suppression of mismatch repair

    PubMed Central

    Campbell, Brittany B; Ungerleider, Nathan; Light, Nicholas; Wu, Tong; LeCompte, Kimberly G; Goksenin, A Yasemin; Bunnell, Bruce A; Tabori, Uri; Shlien, Adam

    2018-01-01

    Tumors defective for DNA polymerase (Pol) ε proofreading have the highest tumor mutation burden identified. A major unanswered question is whether loss of Pol ε proofreading by itself is sufficient to drive this mutagenesis, or whether additional factors are necessary. To address this, we used a combination of next generation sequencing and in vitro biochemistry on human cell lines engineered to have defects in Pol ε proofreading and mismatch repair. Absent mismatch repair, monoallelic Pol ε proofreading deficiency caused a rapid increase in a unique mutation signature, similar to that observed in tumors from patients with biallelic mismatch repair deficiency and heterozygous Pol ε mutations. Restoring mismatch repair was sufficient to suppress the explosive mutation accumulation. These results strongly suggest that concomitant suppression of mismatch repair, a hallmark of colorectal and other aggressive cancers, is a critical force for driving the explosive mutagenesis seen in tumors expressing exonuclease-deficient Pol ε. PMID:29488881

  19. Altered hippocampal replay is associated with memory impairment in mice heterozygous for the Scn2a gene.

    PubMed

    Middleton, Steven J; Kneller, Emily M; Chen, Shuo; Ogiwara, Ikuo; Montal, Mauricio; Yamakawa, Kazuhiro; McHugh, Thomas J

    2018-06-04

    An accumulating body of experimental evidence has implicated hippocampal replay occurring within sharp wave ripples (SPW-Rs) as crucial for learning and memory in healthy subjects. This raises speculation that neurological disorders impairing memory disrupt either SPW-Rs or their underlying neuronal activity. We report that mice heterozygous for the gene Scn2a, a site of frequent de novo mutations in humans with intellectual disability, displayed impaired spatial memory. While we observed no changes during encoding, to either single place cells or cell assemblies, we identified abnormalities restricted to SPW-R episodes that manifest as decreased cell assembly reactivation strengths and truncated hippocampal replay sequences. Our results suggest that alterations to hippocampal replay content may underlie disease-associated memory deficits.

  20. Thyroid function in mice with compound heterozygous and homozygous disruptions of SRC-1 and TIF-2 coactivators: evidence for haploinsufficiency.

    PubMed

    Weiss, Roy E; Gehin, Martine; Xu, Jianming; Sadow, Peter M; O'Malley, Bert W; Chambon, Pierre; Refetoff, Samuel

    2002-04-01

    Steroid receptor coactivator (SRC)-1 and transcriptional intermediary factor (TIF)-2 are homologous nuclear receptor coactivators. We have investigated their possible redundancy as thyroid hormone (TH) coactivators by measuring thyroid function in compound SRC-1 and TIF-2 knock out (KO) mice. Whereas SRC-1 KO (SRC-1(-/-)) mice are resistant to TH and SRC-1(+/-) are not, we now demonstrate that TIF-2 KO (TIF-2(-/-)) mice have normal thyroid function. Yet double heterozygous, SRC-1(+/-)/TIF-2(+/-) mice manifested resistance to TH of a similar degree as that in mice completely deficient in SRC-1. KO of both SRC-1 and TIF-2 resulted in marked increases of serum TH and thyrotropin concentrations. This work demonstrates gene dosage effect in nuclear coactivators manifesting as haploinsufficiency and functional redundancy of SRC-1 and TIF-2.

  1. Compound heterozygous HAX1 mutations in a Swedish patient with severe congenital neutropenia and no neurodevelopmental abnormalities.

    PubMed

    Carlsson, Göran; Elinder, Göran; Malmgren, Helena; Trebinska, Alicja; Grzybowska, Ewa; Dahl, Niklas; Nordenskjöld, Magnus; Fadeel, Bengt

    2009-12-01

    Kostmann disease or severe congenital neutropenia (SCN) is an autosomal recessive disorder of neutrophil production. Homozygous HAX1 mutations were recently identified in SCN patients belonging to the original family in northern Sweden described by Kostmann. Moreover, recent studies have suggested an association between neurological dysfunction and HAX1 deficiency. Here we describe a patient with a compound heterozygous HAX1 mutation consisting of a nonsense mutation (c.568C > T, p.Glu190X) and a frame-shift mutation (c.91delG, p.Glu31LysfsX54) resulting in a premature stop codon. The patient has a history of neutropenia and a propensity for infections, but has shown no signs of neurodevelopmental abnormalities.

  2. Heterozygous M1V variant of ELA-2 gene mutation associated with G-CSF refractory severe congenital neutropenia.

    PubMed

    Setty, Bhuvana A; Yeager, Nicholas D; Bajwa, Rajinder P

    2011-09-01

    Severe congenital neutropenia is an autosomal recessive disorder characterized by maturation arrest at the promyelocyte/myelocyte phase in the bone marrow, absolute neutrophil count <0.5 × 10(9) /L and recurrent bacterial infections. Homozygous mutations of either HAX-1 or ELA-2 have been described. We report the case of a premature male infant with congenital neutropenia, associated with multiple infections, refractory to treatment with granulocyte colony stimulating factor who subsequently underwent matched sibling donor stem-cell transplant. He was found to be heterozygous for the M1V variant of the ELA-2 gene that we postulate to be causative for his severe neutropenia Copyright © 2011 Wiley-Liss, Inc.

  3. A compound heterozygous mutation in SLC34A3 causes hereditary hypophosphatemic rickets with hypercalciuria in a Chinese patient.

    PubMed

    Chi, Yue; Zhao, Zhen; He, Xiaodong; Sun, Yue; Jiang, Yan; Li, Mei; Wang, Ou; Xing, Xiaoping; Sun, Andrew Y; Zhou, Xueying; Meng, Xunwu; Xia, Weibo

    2014-02-01

    Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare metabolic disorder inherited in an autosomal recessive fashion and characterized by hypophosphatemia, short stature, rickets and/or osteomalacia, and secondary absorptive hypercalciuria. HHRH was recently mapped to chromosome 9q34, which contains the gene SLC34A3 which encodes the renal proximal tubular sodium-phosphate cotransporter NaPi-IIc. Here we describe a 29-year-old man with a history of childhood rickets who presented with increased renal phosphate clearance leading to hypophosphatemia, hypercalciuria, low serum parathyroid hormone (PTH), elevated serum 1,25-dihydroxyvitamin D (1,25(OH)2D) and recurrent nephrolithiasis. We performed a mutation analysis of SLC34A3 (exons and adjacent introns) of the proband and his parents to determine if there was a genetic contribution. The proband proved to be compound heterozygous for two missense mutations in SLC34A3: one novel mutation in exon 7 c.571G>C (p.G191R) and one previously identified mutation in exon 13 c.1402C>T (p.R468W). His parents were both asymptomatic heterozygous carriers of one of these two mutations. We also performed an oral phosphate loading test and compared serum phosphate, intact PTH, and intact fibroblast growth factor 23 (iFGF23) in this patient versus patients with other forms of hypophosphatemic rickets, the results of which further revealed that the mechanism of hypophosphatemia in HHRH is independent of FGF23. This is the first report of HHRH in the Chinese population. Our findings of the novel mutation in exon 7 add to the list of more than 20 reported mutations of SLC34A3. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. Clinical Features and Long-Term Outcome of Nephrotic Syndrome Associated with Heterozygous NPHS1 and NPHS2 Mutations

    PubMed Central

    Caridi, Gianluca; Gigante, Maddalena; Ravani, Pietro; Trivelli, Antonella; Barbano, Giancarlo; Scolari, Francesco; Dagnino, Monica; Murer, Luisa; Murtas, Corrado; Edefonti, Alberto; Allegri, Landino; Amore, Alessandro; Coppo, Rosanna; Emma, Francesco; De Palo, Tommaso; Penza, Rosa; Gesualdo, Loreto; Ghiggeri, Gian Marco

    2009-01-01

    Background and objectives: Mutations in nephrin (NPHS1) and podocin (NPHS2) genes represent a major cause of idiopathic nephrotic syndrome (NS) in children. It is not yet clear whether the presence of a single mutation acts as a modifier of the clinical course of NS. Design, setting, participants, & measurements: We reviewed the clinical features of 40 patients with NS associated with heterozygous mutations or variants in NPHS1 (n = 7) or NPHS2 (n = 33). Long-term renal survival probabilities were compared with those of a concurrent cohort with idiopathic NS. Results: Patients with a single mutation in NPHS1 received a diagnosis before those with potentially nongenetic NS and had a good response to therapies. Renal function was normal in all cases. For NPHS2, six patients had single heterozygous mutations, six had a p.P20L variant, and 21 had a p.R229Q variant. Age at diagnosis and the response to drugs were comparable in all NS subgroups. Overall, they had similar renal survival probabilities as non-NPHS1/NPHS2 cases (log-rank χ2 0.84, P = 0.656) that decreased in presence of resistance to therapy (P < 0.001) and in cases with renal lesions of glomerulosclerosis and IgM deposition (P < 0.001). Cox regression confirmed that the only significant predictor of dialysis was resistance to therapy. Conclusions: Our data indicate that single mutation or variant in NPHS1 and NPHS2 does not modify the outcome of primary NS. These patients should be treated following consolidated schemes and have good chances for a good long-term outcome. PMID:19406966

  5. Draft Sequencing of the Heterozygous Diploid Genome of Satsuma (Citrus unshiu Marc.) Using a Hybrid Assembly Approach

    PubMed Central

    Shimizu, Tokurou; Tanizawa, Yasuhiro; Mochizuki, Takako; Nagasaki, Hideki; Yoshioka, Terutaka; Toyoda, Atsushi; Fujiyama, Asao; Kaminuma, Eli; Nakamura, Yasukazu

    2017-01-01

    Satsuma (Citrus unshiu Marc.) is one of the most abundantly produced mandarin varieties of citrus, known for its seedless fruit production and as a breeding parent of citrus. De novo assembly of the heterozygous diploid genome of Satsuma (“Miyagawa Wase”) was conducted by a hybrid assembly approach using short-read sequences, three mate-pair libraries, and a long-read sequence of PacBio by the PLATANUS assembler. The assembled sequence, with a total size of 359.7 Mb at the N50 length of 386,404 bp, consisted of 20,876 scaffolds. Pseudomolecules of Satsuma constructed by aligning the scaffolds to three genetic maps showed genome-wide synteny to the genomes of Clementine, pummelo, and sweet orange. Gene prediction by modeling with MAKER-P proposed 29,024 genes and 37,970 mRNA; additionally, gene prediction analysis found candidates for novel genes in several biosynthesis pathways for gibberellin and violaxanthin catabolism. BUSCO scores for the assembled scaffold and predicted transcripts, and another analysis by BAC end sequence mapping indicated the assembled genome consistency was close to those of the haploid Clementine, pummel, and sweet orange genomes. The number of repeat elements and long terminal repeat retrotransposon were comparable to those of the seven citrus genomes; this suggested no significant failure in the assembly at the repeat region. A resequencing application using the assembled sequence confirmed that both kunenbo-A and Satsuma are offsprings of Kishu, and Satsuma is a back-crossed offspring of Kishu. These results illustrated the performance of the hybrid assembly approach and its ability to construct an accurate heterozygous diploid genome. PMID:29259619

  6. DNA hypermethylation and X chromosome inactivation are major determinants of phenotypic variation in women heterozygous for G6PD mutations.

    PubMed

    Wang, Jin; Xiao, Qi-Zhi; Chen, You-Ming; Yi, Sheng; Liu, Dun; Liu, Yan-Hui; Zhang, Cui-Mei; Wei, Xiao-Feng; Zhou, Yu-Qiu; Zhong, Xing-Ming; Zhao, Cun-You; Xiong, Fu; Wei, Xiang-Cai; Xu, Xiang-Min

    2014-12-01

    Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked incompletely dominant enzyme deficiency that results from G6PD gene mutations. Women heterozygous for G6PD mutations exhibit variation in the loss of enzyme activity but the cause of this phenotypic variation is unclear. We determined DNA methylation and X-inactivation patterns in 71 G6PD-deficient female heterozygotes and 68 G6PD non-deficient controls with the same missense mutations (G6PD Canton c.1376G>T or Kaiping c.1388G>A) to correlate determinants with variable phenotypes. Specific CpG methylations within the G6PD promoter were significantly higher in G6PD-deficient heterozygotes than in controls. Preferential X-inactivation of the G6PD wild-type allele was determined in heterozygotes. The incidence of preferential X-inactivation was 86.2% in the deficient heterozygote group and 31.7% in the non-deficient heterozygote group. A significant negative correlation was observed between X-inactivation ratios of the wild-type allele and G6PD/6-phosphogluconate dehydrogenase (6PGD) ratios in heterozygous G6PD Canton (r=-0.657, p<0.001) or Kaiping (r=-0.668, p<0.001). Multivariate logistic regression indicated that heterozygotes with hypermethylation of specific CpG sites in the G6PD promoter and preferential X-inactivation of the wild-type allele were at risk of enzyme deficiency. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Heterozygous Monocarboxylate Transporter 1 (MCT1, SLC16A1) Deficiency as a Cause of Recurrent Ketoacidosis.

    PubMed

    Balasubramaniam, Shanti; Lewis, Barry; Greed, Lawrence; Meili, David; Flier, Annegret; Yamamoto, Raina; Bilić, Karmen; Till, Claudia; Sass, Jörn Oliver

    2016-01-01

    We describe two half-siblings with monocarboxylate transporter 1 (MCT1, SLC16A1) deficiency, a defect on ketone body utilization, that has only recently been identified (van Hasselt et al., N Engl J Med, 371:1900-1907, 2014) as a cause for recurrent ketoacidoses. Our index patient is a boy with non-consanguineous parents who had presented acutely with impaired consciousness and severe metabolic ketoacidosis following a 3-day history of gastroenteritis at age 5 years. A 12.5-year-old half-brother who shared the proband's mother also had a previous history of recurrent ketoacidoses. Results of mutation and enzyme activity analyses in proband samples advocated against methylacetoacetyl-coenzyme A thiolase ("beta-ketothiolase") and succinyl-coenzyme A: 3-oxoacyl coenzyme A transferase (SCOT) deficiencies. A single heterozygous c.982C>T transition in the SLC16A1 gene resulting in a stop mutation (p.Arg328Ter) was detected in both boys. It was shared by their healthy mother and by the proband's half-sister, but was absent in the proband's father. MCT1 deficiency may be more prevalent than is apparent, as clinical manifestations can occur both in individuals with bi- and monoallelic mutations. It may be an important differential diagnosis in recurrent ketoacidosis with or without hypoglycemia, particularly in the absence of any specific metabolic profiles in blood and urine. Early diagnosis may enable improved disease management. Careful identification of potential triggers of metabolic decompensations in individuals even with single heterozygous mutations in the SLC16A1 gene is indicated.

  8. A novel heterozygous germline deletion in MSH2 gene in a five generation Chinese family with Lynch syndrome

    PubMed Central

    Liang, Shengran; Ling, Chao; You, Yan; Xu, Lai; Zhong, Min-Er; Xiao, Yi; Qiu, Hui-Zhong; Lu, Jun-Yang; Banerjee, Santasree

    2017-01-01

    Lynch syndrome (LS) is one of the most common familial forms of colorectal cancer predisposing syndrome with an autosomal dominant mode of inheritance. LS is caused by the germline mutations in DNA mismatch repair (MMR) genes including MSH2, MLH1, MSH6 and PMS2. Clinically, LS is characterized by high incidence of early-onset colorectal cancer as well as endometrial, small intestinal and urinary tract cancers, usually occur in the third to fourth decade of the life. Here we describe a five generation Chinese family with LS clinically diagnosed according to the Amsterdam II criteria. Immuno-histochemical staining of MSH2 and MSH6 shows only foci nuclear positive on the surface of the tumor with strong expression of MLH1 and PMS2 with diffuse immunoreactivity. In order to dig into the molecular basis of this LS pedigree, we collected the proband's blood sample, extracted the genomic DNA and applied the genetic screening. As a result, we identified a novel heterozygous deletion in MSH2 gene by targeted next generation sequencing, which is also proved to be co-segregated among other affected family members by following validation. To our knowledge, this novel heterozygous deletion (c.1676_1679 delTAAA) in MSH2 gene causes frameshift mutation (p.Asn560Lysfs*29) and leads to the formation of a truncated MSH2 protein which is confirmed to be a deleterious mutation according to the variant interpretation guidelines of American College of Medical Genetics and Genomics (ACMG). Identification of novel DNA mismatch repair (MMR) gene mutations can definitely benefit to the clinical diagnosis and management. PMID:28903413

  9. Impaired bidirectional NMDA receptor dependent synaptic plasticity in the dentate gyrus of adult female Fmr1 heterozygous knockout mice.

    PubMed

    Yau, S Y; Bostrom, C A; Chiu, J; Fontaine, C J; Sawchuk, S; Meconi, A; Wortman, R C; Truesdell, E; Truesdell, A; Chiu, C; Hryciw, B N; Eadie, B D; Ghilan, M; Christie, B R

    2016-12-01

    Fragile-X syndrome (FXS) is caused by the transcriptional repression of the Fmr1 gene resulting in loss of the Fragile-X mental retardation protein (FMRP). This leads to cognitive impairment in both male and female patients, however few studies have focused on the impact of FXS in females. Significant cognitive impairment has been reported in approximately 35% of women who exhibit a heterozygous Fmr1 gene mutation, however to date there is a paucity of information regarding the mechanistic underpinnings of these deficits. We, and others, have recently reported that there is significant impairment in N-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) and long-term depression (LTD) in the hippocampal dentate gyrus (DG) of male Fmr1 knock out mice. Here we examined if female mice displaying a heterozygous loss of the Fmr1 gene (Fmr1 +/- ) would exhibit similar impairments in DG-dependent spatial memory processing and NMDAR hypofunction. We found that Female Fmr1 +/- mice did not show impaired metabotropic glutamate receptor (mGluR)-LTD in the CA1 region, and could perform well on a temporal ordering task that is thought to involve this brain region. In contrast, female Fmr1 +/- mice showed impairments in a pattern separation task thought to involve the DG, and also displayed a significant impairment in both NMDAR-dependent LTD and LTP in this region. The LTP impairment could be rescued by administering the NMDAR co-agonist, glycine. Our data suggests that NMDAR hypofunction in the DG may partly contribute to learning and memory impairment in female Fmr1 +/- mice. Targeting NMDAR-dependent mechanisms may offer hope as a new therapeutic approach for treating female FXS patients with learning and memory impairments. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Draft Sequencing of the Heterozygous Diploid Genome of Satsuma (Citrus unshiu Marc.) Using a Hybrid Assembly Approach.

    PubMed

    Shimizu, Tokurou; Tanizawa, Yasuhiro; Mochizuki, Takako; Nagasaki, Hideki; Yoshioka, Terutaka; Toyoda, Atsushi; Fujiyama, Asao; Kaminuma, Eli; Nakamura, Yasukazu

    2017-01-01

    Satsuma ( Citrus unshiu Marc.) is one of the most abundantly produced mandarin varieties of citrus, known for its seedless fruit production and as a breeding parent of citrus. De novo assembly of the heterozygous diploid genome of Satsuma ("Miyagawa Wase") was conducted by a hybrid assembly approach using short-read sequences, three mate-pair libraries, and a long-read sequence of PacBio by the PLATANUS assembler. The assembled sequence, with a total size of 359.7 Mb at the N 50 length of 386,404 bp, consisted of 20,876 scaffolds. Pseudomolecules of Satsuma constructed by aligning the scaffolds to three genetic maps showed genome-wide synteny to the genomes of Clementine, pummelo, and sweet orange. Gene prediction by modeling with MAKER-P proposed 29,024 genes and 37,970 mRNA; additionally, gene prediction analysis found candidates for novel genes in several biosynthesis pathways for gibberellin and violaxanthin catabolism. BUSCO scores for the assembled scaffold and predicted transcripts, and another analysis by BAC end sequence mapping indicated the assembled genome consistency was close to those of the haploid Clementine, pummel, and sweet orange genomes. The number of repeat elements and long terminal repeat retrotransposon were comparable to those of the seven citrus genomes; this suggested no significant failure in the assembly at the repeat region. A resequencing application using the assembled sequence confirmed that both kunenbo-A and Satsuma are offsprings of Kishu, and Satsuma is a back-crossed offspring of Kishu. These results illustrated the performance of the hybrid assembly approach and its ability to construct an accurate heterozygous diploid genome.

  11. Compound heterozygous NEK1 variants in two siblings with oral-facial-digital syndrome type II (Mohr syndrome)

    PubMed Central

    Monroe, Glen R; Kappen, Isabelle FPM; Stokman, Marijn F; Terhal, Paulien A; van den Boogaard, Marie-José H; Savelberg, Sanne MC; van der Veken, Lars T; van Es, Robert JJ; Lens, Susanne M; Hengeveld, Rutger C; Creton, Marijn A; Janssen, Nard G; Mink van der Molen, Aebele B; Ebbeling, Michelle B; Giles, Rachel H; Knoers, Nine V; van Haaften, Gijs

    2016-01-01

    The oral-facial-digital (OFD) syndromes comprise a group of related disorders with a combination of oral, facial and digital anomalies. Variants in several ciliary genes have been associated with subtypes of OFD syndrome, yet in most OFD patients the underlying cause remains unknown. We investigated the molecular basis of disease in two brothers with OFD type II, Mohr syndrome, by performing single-nucleotide polymorphism (SNP)-array analysis on the brothers and their healthy parents to identify homozygous regions and candidate genes. Subsequently, we performed whole-exome sequencing (WES) on the family. Using WES, we identified compound heterozygous variants c.[464G>C][1226G>A] in NIMA (Never in Mitosis Gene A)-Related Kinase 1 (NEK1). The novel variant c.464G>C disturbs normal splicing in an essential region of the kinase domain. The nonsense variant c.1226G>A, p.(Trp409*), results in nonsense-associated alternative splicing, removing the first coiled-coil domain of NEK1. Candidate variants were confirmed with Sanger sequencing and alternative splicing assessed with cDNA analysis. Immunocytochemistry was used to assess cilia number and length. Patient-derived fibroblasts showed severely reduced ciliation compared with control fibroblasts (18.0 vs 48.9%, P<0.0001), but showed no significant difference in cilia length. In conclusion, we identified compound heterozygous deleterious variants in NEK1 in two brothers with Mohr syndrome. Ciliation in patient fibroblasts is drastically reduced, consistent with a ciliary defect pathogenesis. Our results establish NEK1 variants involved in the etiology of a subset of patients with OFD syndrome type II and support the consideration of including (routine) NEK1 analysis in patients suspected of OFD. PMID:27530628

  12. Compound heterozygous NEK1 variants in two siblings with oral-facial-digital syndrome type II (Mohr syndrome).

    PubMed

    Monroe, Glen R; Kappen, Isabelle Fpm; Stokman, Marijn F; Terhal, Paulien A; van den Boogaard, Marie-José H; Savelberg, Sanne Mc; van der Veken, Lars T; van Es, Robert Jj; Lens, Susanne M; Hengeveld, Rutger C; Creton, Marijn A; Janssen, Nard G; Mink van der Molen, Aebele B; Ebbeling, Michelle B; Giles, Rachel H; Knoers, Nine V; van Haaften, Gijs

    2016-12-01

    The oral-facial-digital (OFD) syndromes comprise a group of related disorders with a combination of oral, facial and digital anomalies. Variants in several ciliary genes have been associated with subtypes of OFD syndrome, yet in most OFD patients the underlying cause remains unknown. We investigated the molecular basis of disease in two brothers with OFD type II, Mohr syndrome, by performing single-nucleotide polymorphism (SNP)-array analysis on the brothers and their healthy parents to identify homozygous regions and candidate genes. Subsequently, we performed whole-exome sequencing (WES) on the family. Using WES, we identified compound heterozygous variants c.[464G>C];[1226G>A] in NIMA (Never in Mitosis Gene A)-Related Kinase 1 (NEK1). The novel variant c.464G>C disturbs normal splicing in an essential region of the kinase domain. The nonsense variant c.1226G>A, p.(Trp409*), results in nonsense-associated alternative splicing, removing the first coiled-coil domain of NEK1. Candidate variants were confirmed with Sanger sequencing and alternative splicing assessed with cDNA analysis. Immunocytochemistry was used to assess cilia number and length. Patient-derived fibroblasts showed severely reduced ciliation compared with control fibroblasts (18.0 vs 48.9%, P<0.0001), but showed no significant difference in cilia length. In conclusion, we identified compound heterozygous deleterious variants in NEK1 in two brothers with Mohr syndrome. Ciliation in patient fibroblasts is drastically reduced, consistent with a ciliary defect pathogenesis. Our results establish NEK1 variants involved in the etiology of a subset of patients with OFD syndrome type II and support the consideration of including (routine) NEK1 analysis in patients suspected of OFD.

  13. Olaparib In Metastatic Breast Cancer

    ClinicalTrials.gov

    2018-03-27

    Metastatic Breast Cancer; Invasive Breast Cancer; Somatic Mutation Breast Cancer (BRCA1); Somatic Mutation Breast Cancer (BRCA2); CHEK2 Gene Mutation; ATM Gene Mutation; PALB2 Gene Mutation; RAD51 Gene Mutation; BRIP1 Gene Mutation; NBN Gene Mutation

  14. Whole-exome sequencing and digital PCR identified a novel compound heterozygous mutation in the NPHP1 gene in a case of Joubert syndrome and related disorders.

    PubMed

    Koyama, Shingo; Sato, Hidenori; Wada, Manabu; Kawanami, Toru; Emi, Mitsuru; Kato, Takeo

    2017-03-27

    Joubert syndrome and related disorders (JSRD) is a clinically and genetically heterogeneous condition with autosomal recessive or X-linked inheritance, which share a distinctive neuroradiological hallmark, the so-called molar tooth sign. JSRD is classified into six clinical subtypes based on associated variable multiorgan involvement. To date, 21 causative genes have been identified in JSRD, which makes genetic diagnosis difficult. We report here a case of a 28-year-old Japanese woman diagnosed with JS with oculorenal defects with a novel compound heterozygous mutation (p.Ser219*/deletion) in the NPHP1 gene. Whole-exome sequencing (WES) of the patient identified the novel nonsense mutation in an apparently homozygous state. However, it was absent in her mother and heterozygous in her father. A read depth-based copy number variation (CNV) detection algorithm using WES data of the family predicted a large heterozygous deletion mutation in the patient and her mother, which was validated by digital polymerase chain reaction, indicating that the patient was compound heterozygous for the paternal nonsense mutation and the maternal deletion mutation spanning the site of the single nucleotide change. It should be noted that analytical pipelines that focus purely on sequence information cannot distinguish homozygosity from hemizygosity because of its inability to detect large deletions. The ability to detect CNVs in addition to single nucleotide variants and small insertion/deletions makes WES an attractive diagnostic tool for genetically heterogeneous disorders.

  15. The relationship between the enzyme activity, lipid peroxidation and red blood cells deformability in hemizygous and heterozygous glucose-6-phosphate dehydrogenase deficient individuals.

    PubMed

    Gurbuz, N; Yalcin, O; Aksu, T A; Baskurt, O K

    2004-01-01

    Glucose-6-phosphate dehydrogenase (G6PD) activity, red blood cell (RBC) lipid peroxidation and deformability were investigated in hemizygous and heterozygous G6PD deficient subjects and compared with normal individuals. None of the subjects were in acute hemolytic crises. G6PD activity was assessed based on the spectrophotometric determination of generated NADPH. Lipid peroxidation was measured as thiobarbutiric acid reactive substances (TBARS). RBC deformability was analyzed by ektacytometry. RBC lipid peroxidation was found to be significantly higher in hemizygous subjects compared to control and heterozygous subjects, while RBC deformability was found to be significantly impaired. However, although lipid peroxidation was higher than control, RBC deformability was not significantly different from control in heterozygous individuals, characterized by significantly lower RBC G6PD activity. There were no significant correlations between these three parameters when the three groups were analyzed separately, but a significant negative correlation was found to exist between G6PD activity and TBARS when the pooled data from the three groups were used for the analysis. This was also true for the relationship between RBC deformability and G6PD activity. It has been concluded that G6PD activity is not a good predictor of oxidative damage resulting in mechanical impairment in heterozygous individuals.

  16. Comparative analyses of lung transcriptomes in patients with alveolar capillary dysplasia with misalignment of pulmonary veins and in foxf1 heterozygous knockout mice

    USDA-ARS?s Scientific Manuscript database

    Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV) is a developmental disorder of the lungs, primarily affecting their vasculature. FOXF1 haploinsufficiency due to heterozygous genomic deletions and point mutations have been reported in most patients with ACDMPV. The majority...

  17. Screening for Breast Cancer.

    PubMed

    Niell, Bethany L; Freer, Phoebe E; Weinfurtner, Robert Jared; Arleo, Elizabeth Kagan; Drukteinis, Jennifer S

    2017-11-01

    The goal of screening is to detect breast cancers when still curable to decrease breast cancer-specific mortality. Breast cancer screening in the United States is routinely performed with mammography, supplemental digital breast tomosynthesis, ultrasound, and/or MR imaging. This article aims to review the most commonly used breast imaging modalities for screening, discuss how often and when to begin screening with specific imaging modalities, and examine the pros and cons of screening. By the article's end, the reader will be better equipped to have informed discussions with patients and medical professionals regarding the benefits and disadvantages of breast cancer screening. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. CHEK2*1100delC homozygosity is associated with a high breast cancer risk in women.

    PubMed

    Adank, Muriel A; Jonker, Marianne A; Kluijt, Irma; van Mil, Saskia E; Oldenburg, Rogier A; Mooi, Wolter J; Hogervorst, Frans B L; van den Ouweland, Ans M W; Gille, Johan J P; Schmidt, Marjanka K; van der Vaart, Aad W; Meijers-Heijboer, Hanne; Waisfisz, Quinten

    2011-12-01

    Mutations in the CHEK2 gene confer a moderately increased breast cancer risk. The risk for female carriers of the CHEK2*1100delC mutation is twofold increased. Breast cancer risk for carrier women is higher in a familial breast cancer setting which is due to coinheritance of additional genetic risk factors. This study investigated the occurrence of homozygosity for the CHEK2*1100delC allele among familial breast cancer cases and the associated breast cancer risk. Homozygosity for the CHEK2*1100delC allele was identified in 8/2554 Dutch independent familial non-BRCA1/2 breast cancer cases. The genotype relative risk for breast cancer of homozygous and heterozygous familial breast cancer cases was 101.34 (95% CI 4.47 to 121 000) and 4.04 (95% CI 0.88 to 21.0), respectively. Female homozygotes appeared to have a greater than twofold increased breast cancer risk compared to familial CHEK2*1100delC heterozygotes (p=0.044). These results and the occurrence of multiple primary tumours in 7/10 homozygotes indicate a high cancer risk in homozygous women from non-BRCA1/2 families. Intensive breast surveillance is therefore justified in these homozygous women. It is concluded that diagnostic testing for biallelic mutations in CHEK2 is indicated in non-BRCA1/2 breast cancer families, especially in populations with a relatively high prevalence of deleterious mutations in CHEK2.

  19. Effects of endoplasmic reticulum stressors on maturation and signaling of hemizygous and heterozygous wild-type and mutant forms of KIT.

    PubMed

    Brahimi-Adouane, Sabrina; Bachet, Jean-Baptiste; Tabone-Eglinger, Séverine; Subra, Frédéric; Capron, Claude; Blay, Jean-Yves; Emile, Jean-François

    2013-06-01

    Gain of function mutations of KIT are frequent in some human tumors, and are sensible to tyrosine kinase inhibitors. In most tumors, oncogenic mutations are heterozygous, however most in vitro data of KIT activation have been obtained with hemizygous mutation. This study aimed to investigate the maturation and activation of wild-type (WT) and mutant (M) forms of KIT in hemizygous and heterozygous conditions. WT and two types of exon 11 deletions M forms of human KIT were expressed in NIH3T3 cell lines. Membrane expression of KIT was quantified by flow cytometry. Quantification of glycosylated forms of KIT and phosphorylated forms of AKT and ERK were performed by western blot. Simultaneous activation of WT KIT and treatment with endoplasmic reticulum (ER) inhibitors, tunicamycin or brefeldin A induced a complete inhibition of membrane expression of the 145 kDa form of KIT. By contrast activation or ER inhibitors alone, only partly inhibited this form. ER inhibitors also inhibited KIT activation-dependent phosphorylation of AKT and ERK1/2. Brefeldin A induced a complete down regulation of the 145 kDa form in hemizygous M, and induced an intra-cellular accumulation of the 125 kDa form in WT but not in hemizygous M. Heterozygous cells had glycosylation and response to ER inhibitors patterns more similar to WT than to hemizygous M. Phosphorylated AKT was reduced in hemizygous cells in comparison to WT KIT cells and heterozygous cells, and in the presence of brefeldin A in all cell lines. Effects of ER inhibitors are significantly different in hemizygous and heterozygous mutants. Differences in intra-cellular trafficking of KIT forms result in differences in downstream signaling pathways, and activation of PI3K/AKT pathway appears to be tied to the presence of the mature 145 kDa form of KIT at the membrane surface. Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  20. The heterozygous N291S mutation in the lipoprotein lipase gene impairs whole-body insulin sensitivity and affects a distinct set of plasma metabolites in humans.

    PubMed

    Berg, Sofia Mikkelsen; Havelund, Jesper; Hasler-Sheetal, Harald; Kruse, Vibeke; Pedersen, Andreas James Thestrup; Hansen, Aleksander Bill; Nybo, Mads; Beck-Nielsen, Henning; Højlund, Kurt; Færgeman, Nils Joakim

    Mutations in the lipoprotein lipase gene causing decreased lipoprotein lipase activity are associated with surrogate markers of insulin resistance and the metabolic syndrome in humans. We investigated the hypothesis that a heterozygous lipoprotein lipase mutation (N291S) induces whole-body insulin resistance and alterations in the plasma metabolome. In 6 carriers of a heterozygous lipoprotein lipase mutation (N291S) and 11 age-matched and weight-matched healthy controls, we examined insulin sensitivity and substrate metabolism by euglycemic-hyperinsulinemic clamps combined with indirect calorimetry. Plasma samples were taken before and after the clamp (4 hours of physiological hyperinsulinemia), and metabolites were measured enzymatically or by gas chromatography-mass spectrometry. Compared with healthy controls, heterozygous carriers of a defective lipoprotein lipase allele had elevated fasting plasma levels triglycerides (P < .006), and markedly impaired insulin-stimulated glucose disposal rates (P < .024) and nonoxidative glucose metabolism (P < .015). Plasma metabolite profiling demonstrated lower circulating levels of pyruvic acid and α-tocopherol in the N291S carriers than in controls both before and after stimulation with insulin (all >1.5-fold change and P < .05). Heterozygous carriers with a defective lipoprotein lipase allele are less insulin sensitive and have increased plasma levels of nonesterified fatty acids and triglycerides. The heterozygous N291S carriers also have a distinct plasma metabolomic signature, which may serve as a diagnostic tool for deficient lipoprotein lipase activity and as a marker of lipid-induced insulin resistance. Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.

  1. Breast Abscess Mimicking Breast Carcinoma in Male.

    PubMed

    Gochhait, Debasis; Dehuri, Priyadarshini; Umamahesweran, Sandyya; Kamat, Rohan

    2018-01-01

    Male breast can show almost all pathological entities described in female breast. Inflammatory conditions of the breast in male are not common; however, occasionally, it can be encountered in the form of an abscess. Clinically, gynecomastia always presents as a symmetric unilateral or bilateral lump in the retroareolar region, and any irregular asymmetric lump raises a possibility of malignancy. Radiology should be used as a part of the triple assessment protocol for breast lump along with fine-needle aspiration cytology for definite diagnosis and proper management.

  2. ED breast cases and other breast emergencies.

    PubMed

    Khadem, Nasim; Reddy, Sravanthi; Lee, Sandy; Larsen, Linda; Walker, Daphne

    2016-02-01

    Patients with pathologic processes of the breast commonly present in the Emergency Department (ED). Familiarity with the imaging and management of the most common entities is essential for the radiologist. Additionally, it is important to understand the limitations of ED imaging and management in the acute setting and to recognize when referrals to a specialty breast center are necessary. The goal of this article is to review the clinical presentations, pathophysiology, imaging, and management of emergency breast cases and common breast pathology seen in the ED.

  3. Heterozygous Mapping Strategy (HetMappS) for High Resolution Genotyping-By-Sequencing Markers: A Case Study in Grapevine

    PubMed Central

    Wang, Minghui; Londo, Jason P.; Acharya, Charlotte B.; Mitchell, Sharon E.; Sun, Qi; Reisch, Bruce; Cadle-Davidson, Lance

    2015-01-01

    Genotyping by sequencing (GBS) provides opportunities to generate high-resolution genetic maps at a low genotyping cost, but for highly heterozygous species, missing data and heterozygote undercalling complicate the creation of GBS genetic maps. To overcome these issues, we developed a publicly available, modular approach called HetMappS, which functions independently of parental genotypes and corrects for genotyping errors associated with heterozygosity. For linkage group formation, HetMappS includes both a reference-guided synteny pipeline and a reference-independent de novo pipeline. The de novo pipeline can be utilized for under-characterized or high diversity families that lack an appropriate reference. We applied both HetMappS pipelines in five half-sib F1 families involving genetically diverse Vitis spp. Starting with at least 116,466 putative SNPs per family, the HetMappS pipelines identified 10,440 to 17,267 phased pseudo-testcross (Pt) markers and generated high-confidence maps. Pt marker density exceeded crossover resolution in all cases; up to 5,560 non-redundant markers were used to generate parental maps ranging from 1,047 cM to 1,696 cM. The number of markers used was strongly correlated with family size in both de novo and synteny maps (r = 0.92 and 0.91, respectively). Comparisons between allele and tag frequencies suggested that many markers were in tandem repeats and mapped as single loci, while markers in regions of more than two repeats were removed during map curation. Both pipelines generated similar genetic maps, and genetic order was strongly correlated with the reference genome physical order in all cases. Independently created genetic maps from shared parents exhibited nearly identical results. Flower sex was mapped in three families and correctly localized to the known sex locus in all cases. The HetMappS pipeline could have wide application for genetic mapping in highly heterozygous species, and its modularity provides opportunities to

  4. Novel compound heterozygous mutations in MYO7A in a Chinese family with Usher syndrome type 1.

    PubMed

    Liu, Fei; Li, Pengcheng; Liu, Ying; Li, Weirong; Wong, Fulton; Du, Rong; Wang, Lei; Li, Chang; Jiang, Fagang; Tang, Zhaohui; Liu, Mugen

    2013-01-01

    To identify the disease-causing mutation(s) in a Chinese family with autosomal recessive Usher syndrome type 1 (USH1). An ophthalmic examination and an audiometric test were conducted to ascertain the phenotype of two affected siblings. The microsatellite marker D11S937, which is close to the candidate gene MYO7A (USH1B locus), was selected for genotyping. From the DNA of the proband, all coding exons and exon-intron boundaries of MYO7A were sequenced to identify the disease-causing mutation(s). Restriction fragment length polymorphism (RFLP) analysis was performed to exclude the alternative conclusion that the mutations are non-pathogenic rare polymorphisms. Based on severe hearing impairment, unintelligible speech, and retinitis pigmentosa, a clinical diagnosis of Usher syndrome type 1 was made. The genotyping results did not exclude the USH1B locus, which suggested that the MYO7A gene was likely the gene associated with the disease-causing mutation(s) in the family. With direct DNA sequencing of MYO7A, two novel compound heterozygous mutations (c.3742G>A and c.6051+1G>A) of MYO7A were identified in the proband. DNA sequence analysis and RFLP analysis of other family members showed that the mutations cosegregated with the disease. Unaffected members, including the parents, uncle, and sister of the proband, carry only one of the two mutations. The mutations were not present in the controls (100 normal Chinese subjects=200 chromosomes) according to the RFLP analysis. In this study, we identified two novel mutations, c.3742G>A (p.E1248K) and c.6051+1G>A (donor splice site mutation in intron 44), of MYO7A in a Chinese non-consanguineous family with USH1. The mutations cosegregated with the disease and most likely cause the phenotype in the two affected siblings who carry these mutations compound heterozygously. Our finding expands the mutational spectrum of MYO7A.

  5. Novel compound heterozygous mutations in MYO7A in a Chinese family with Usher syndrome type 1

    PubMed Central

    Liu, Fei; Li, Pengcheng; Liu, Ying; Li, Weirong; Wong, Fulton; Du, Rong; Wang, Lei; Li, Chang; Jiang, Fagang; Tang, Zhaohui

    2013-01-01

    Purpose To identify the disease-causing mutation(s) in a Chinese family with autosomal recessive Usher syndrome type 1 (USH1). Methods An ophthalmic examination and an audiometric test were conducted to ascertain the phenotype of two affected siblings. The microsatellite marker D11S937, which is close to the candidate gene MYO7A (USH1B locus), was selected for genotyping. From the DNA of the proband, all coding exons and exon-intron boundaries of MYO7A were sequenced to identify the disease-causing mutation(s). Restriction fragment length polymorphism (RFLP) analysis was performed to exclude the alternative conclusion that the mutations are non-pathogenic rare polymorphisms. Results Based on severe hearing impairment, unintelligible speech, and retinitis pigmentosa, a clinical diagnosis of Usher syndrome type 1 was made. The genotyping results did not exclude the USH1B locus, which suggested that the MYO7A gene was likely the gene associated with the disease-causing mutation(s) in the family. With direct DNA sequencing of MYO7A, two novel compound heterozygous mutations (c.3742G>A and c.6051+1G>A) of MYO7A were identified in the proband. DNA sequence analysis and RFLP analysis of other family members showed that the mutations cosegregated with the disease. Unaffected members, including the parents, uncle, and sister of the proband, carry only one of the two mutations. The mutations were not present in the controls (100 normal Chinese subjects=200 chromosomes) according to the RFLP analysis. Conclusions In this study, we identified two novel mutations, c.3742G>A (p.E1248K) and c.6051+1G>A (donor splice site mutation in intron 44), of MYO7A in a Chinese non-consanguineous family with USH1. The mutations cosegregated with the disease and most likely cause the phenotype in the two affected siblings who carry these mutations compound heterozygously. Our finding expands the mutational spectrum of MYO7A. PMID:23559863

  6. Novel compound heterozygous mutations in the OTOF Gene identified by whole-exome sequencing in auditory neuropathy spectrum disorder.

    PubMed

    Tang, Fengzhu; Ma, Dengke; Wang, Yulan; Qiu, Yuecai; Liu, Fei; Wang, Qingqing; Lu, Qiutian; Shi, Min; Xu, Liang; Liu, Min; Liang, Jianping

    2017-03-23

    Many hearing-loss diseases are demonstrated to have Mendelian inheritance caused by mutations in single gene. However, many deaf individuals have diseases that remain genetically unexplained. Auditory neuropathy is a sensorineural deafness in which sounds are able to be transferred into the inner ear normally but the transmission of the signals from inner ear to auditory nerve and brain is injured, also known as auditory neuropathy spectrum disorder (ANSD). The pathogenic mutations of the genes responsible for the Chinese ANSD population remain poorly understood. A total of 127 patients with non-syndromic hearing loss (NSHL) were enrolled in Guangxi Zhuang Autonomous Region. A hereditary deafness gene mutation screening was performed to identify the mutation sites in four deafness-related genes (GJB2, GJB3, 12S rRNA, and SLC26A4). In addition, whole-exome sequencing (WES) was applied to explore unappreciated mutation sites in the cases with the singularity of its phenotype. Well-characterized mutations were found in only 8.7% (11/127) of the patients. Interestingly, two mutations in the OTOF gene were identified in two affected siblings with ANSD from a Chinese family, including one nonsense mutation c.1273C > T (p.R425X) and one missense mutation c.4994 T > C (p.L1665P). Furthermore, we employed Sanger sequencing to confirm the mutations in each subject. Two compound heterozygous mutations in the OTOF gene were observed in the two affected siblings, whereas the two parents and unaffected sister were heterozygous carriers of c.1273C > T (father and sister) and c.4994 T > C (mother). The nonsense mutation p.R425X, contributes to a premature stop codon, may result in a truncated polypeptide, which strongly suggests its pathogenicity for ANSD. The missense mutation p.L1665P results in a single amino acid substitution in a highly conserved region. Two mutations in the OTOF gene in the Chinese deaf population were recognized for the first time. These

  7. A Novel Heterozygous Mutation in the T-box Protein 4 Gene in an Adult Case of Small Patella Syndrome.

    PubMed

    Oda, Tomoyuki; Matsushita, Masaki; Ono, Yohei; Kitoh, Hiroshi; Sakai, Tadahiro

    2018-01-01

    Small patella syndrome (SPS) is a rare skeletal dysplasia relating to the T-box protein 4 (TBX4) gene, which regulates the development of lower extremities. Patients typically present with recurrent patellar dislocation (RPD) in childhood or adolescence, leading to a diagnosis of SPS and subsequent treatment to improve activity levels. However, those with mild symptoms may not be diagnosed when young and present later after skeletal maturation, which might compromise treatment options. Further understanding of genetic mutations of SPS could possibly help early diagnosis and following adequate surgical treatment. In this case report, we present a surgically treated adult female case of RPD associated with SPS, carrying a novel heterozygous mutation in the TBX4 gene. A 19-year-old female presented with persistent right knee pain after an atraumatic episode ofpatellar dislocation during walking. The patient had a history of recurrent patella instability of the right knee with an onset at the age of 8 years due to a minor trauma. Patellar apprehension sign was positive bilaterally. There was radiological evidence of bilateral small patellae, hypoplastic femoral trochlea, and tibial tuberosity. A direct sequencing of the coding regions in the TBX4 gene had confirmed the diagnosis of SPS. A novel heterozygous mutation (p.L39PfsX35) was found in the patient and her father. Surgical treatment was indicated and the patient underwent an isolated medial patellofemoral ligament (MPFL) reconstruction while no distal realignment osteotomy was performed due to hypoplastic tibial tuberosity. Excellent subjective and objective outcomes were obtained at 1 year postoperatively. To the best of our knowledge, this is the first reported SPS case with a novel mutation in the TBX4 gene in an Asian population. While a satisfying short-term outcome was obtained by an isolated MPFL reconstruction, early genetic diagnosis in childhood with adequate surgical treatment (e.g., Roux

  8. High-throughput SNP genotyping in the highly heterozygous genome of Eucalyptus: assay success, polymorphism and transferability across species

    PubMed Central

    2011-01-01

    Background High-throughput SNP genotyping has become an essential requirement for molecular breeding and population genomics studies in plant species. Large scale SNP developments have been reported for several mainstream crops. A growing interest now exists to expand the speed and resolution of genetic analysis to outbred species with highly heterozygous genomes. When nucleotide diversity is high, a refined diagnosis of the target SNP sequence context is needed to convert queried SNPs into high-quality genotypes using the Golden Gate Genotyping Technology (GGGT). This issue becomes exacerbated when attempting to transfer SNPs across species, a scarcely explored topic in plants, and likely to become significant for population genomics and inter specific breeding applications in less domesticated and less funded plant genera. Results We have successfully developed the first set of 768 SNPs assayed by the GGGT for the highly heterozygous genome of Eucalyptus from a mixed Sanger/454 database with 1,164,695 ESTs and the preliminary 4.5X draft genome sequence for E. grandis. A systematic assessment of in silico SNP filtering requirements showed that stringent constraints on the SNP surrounding sequences have a significant impact on SNP genotyping performance and polymorphism. SNP assay success was high for the 288 SNPs selected with more rigorous in silico constraints; 93% of them provided high quality genotype calls and 71% of them were polymorphic in a diverse panel of 96 individuals of five different species. SNP reliability was high across nine Eucalyptus species belonging to three sections within subgenus Symphomyrtus and still satisfactory across species of two additional subgenera, although polymorphism declined as phylogenetic distance increased. Conclusions This study indicates that the GGGT performs well both within and across species of Eucalyptus notwithstanding its nucleotide diversity ≥2%. The development of a much larger array of informative SNPs across

  9. Heterozygous Mutations in BMP6 Pro-peptide Lead to Inappropriate Hepcidin Synthesis and Moderate Iron Overload in Humans.

    PubMed

    Daher, Raed; Kannengiesser, Caroline; Houamel, Dounia; Lefebvre, Thibaud; Bardou-Jacquet, Edouard; Ducrot, Nicolas; de Kerguenec, Caroline; Jouanolle, Anne-Marie; Robreau, Anne-Marie; Oudin, Claire; Le Gac, Gerald; Moulouel, Boualem; Loustaud-Ratti, Veronique; Bedossa, Pierre; Valla, Dominique; Gouya, Laurent; Beaumont, Carole; Brissot, Pierre; Puy, Hervé; Karim, Zoubida; Tchernitchko, Dimitri

    2016-03-01

    Hereditary hemochromatosis is a heterogeneous group of genetic disorders characterized by parenchymal iron overload. It is caused by defective expression of liver hepcidin, the main regulator of iron homeostasis. Iron stimulates the gene encoding hepcidin (HAMP) via the bone morphogenetic protein (BMP)6 signaling to SMAD. Although several genetic factors have been found to cause late-onset hemochromatosis, many patients have unexplained signs of iron overload. We investigated BMP6 function in these individuals. We sequenced the BMP6 gene in 70 consecutive patients with a moderate increase in serum ferritin and liver iron levels who did not carry genetic variants associated with hemochromatosis. We searched for BMP6 mutations in relatives of 5 probands and in 200 healthy individuals (controls), as well as in 2 other independent cohorts of hyperferritinemia patients. We measured serum levels of hepcidin by liquid chromatography-tandem mass spectrometry and analyzed BMP6 in liver biopsy specimens from patients by immunohistochemistry. The functions of mutant and normal BMP6 were assessed in transfected cells using immunofluorescence, real-time quantitative polymerase chain reaction, and immunoblot analyses. We identified 3 heterozygous missense mutations in BMP6 (p.Pro95Ser, p.Leu96Pro, and p.Gln113Glu) in 6 unrelated patients with unexplained iron overload (9% of our cohort). These mutations were detected in less than 1% of controls. p.Leu96Pro also was found in 2 patients from the additional cohorts. Family studies indicated dominant transmission. Serum levels of hepcidin were inappropriately low in patients. A low level of BMP6, compared with controls, was found in a biopsy specimen from 1 patient. In cell lines, the mutated residues in the BMP6 propeptide resulted in defective secretion of BMP6; reduced signaling via SMAD1, SMAD5, and SMAD8; and loss of hepcidin production. We identified 3 heterozygous missense mutations in BMP6 in patients with unexplained iron

  10. Breast Reconstruction After Mastectomy

    MedlinePlus

    ... reconstruct the breast? In autologous tissue reconstruction, a piece of tissue containing skin, fat, blood vessels, and ... body and used to rebuild the breast. This piece of tissue is called a flap. Different sites ...

  11. Breast cancer staging

    MedlinePlus

    ... this page: //medlineplus.gov/ency/patientinstructions/000911.htm Breast cancer staging To use the sharing features on this ... Once your health care team knows you have breast cancer , they will do more tests to stage it. ...

  12. Stereotactic Image-Guided Navigation During Breast Reconstruction in Patients With Breast Cancer

    ClinicalTrials.gov

    2017-04-12

    Ductal Breast Carcinoma in Situ; Lobular Breast Carcinoma in Situ; Recurrent Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer

  13. Broccoli Sprout Extract in Treating Patients With Breast Cancer

    ClinicalTrials.gov

    2018-06-04

    Ductal Breast Carcinoma; Ductal Breast Carcinoma In Situ; Estrogen Receptor Negative; Estrogen Receptor Positive; Invasive Breast Carcinoma; Lobular Breast Carcinoma; Postmenopausal; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer

  14. Breast oedema following free flap breast reconstruction.

    PubMed

    Greenhowe, Jennifer; Stephen, Christopher; McClymont, Liusaidh; Munnoch, D Alex

    2017-08-01

    Breast oedema causes significant morbidity and is historically difficult to quantify. The aim of this study was to identify changes in breast tissue water content from pre-operative levels in the native breast to post-operative levels in mastectomy skin flaps and free flaps in the reconstructed breast. One hundred patients undergoing unilateral mastectomy and immediate free flap breast reconstruction were examined pre-operatively and at three post-operative appointments. A validated moisture meter was used to record dermal water percentages of each breast quadrant and areola in both breasts pre-operatively, then four quadrants of both breasts plus the unaffected areola and free flap at each post-operative review. Native skin of the reconstructed breast showed significant, persistent increase in MWC from 45.6% ± 0.5% to 72.8% ± 0.9% at 1st follow up (p < 0.001), decreasing only to 67.6% ± 0.8% by 3rd follow up. There was a marked difference (p < 0.001) in the mean water content (MWC) of the initial free flap (39.7% ± 0.6%) compared to 61.8% ± 1.7% at 1st follow up, then 55.1% ± 1.4% at 2nd and 53.7% ± 1.3% at 3rd follow ups. The unaffected breast showed a small but significant increase in MWC of all quadrants at subsequent follow up (greatest difference 3.1% at 1st follow up). This patient group demonstrates significant, persistent oedema of the reconstructed breast, which can be monitored using a non-invasive moisture meter. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

  15. Breast Diseases - Multiple Languages

    MedlinePlus

    ... Breast Biopsy - العربية (Arabic) Bilingual PDF Health Information Translations Chinese, Simplified (Mandarin dialect) (简体中文) Expand Section Breast ... Chinese, Simplified (Mandarin dialect)) Bilingual PDF Health Information Translations Chinese, Traditional (Cantonese dialect) (繁體中文) Expand Section Breast ...

  16. Breast Cancer (For Kids)

    MedlinePlus

    ... Staying Safe Videos for Educators Search English Español Breast Cancer KidsHealth / For Kids / Breast Cancer What's in this ... for it when they are older. What Is Breast Cancer? The human body is made of tiny building ...

  17. Haemangiosarcoma of breast

    PubMed Central

    Kessler, E.; Kozenitzky, I. L.

    1971-01-01

    This is a report of a haemangiosarcoma involving the breast, spleen, liver, lungs, and subcutaneous tissue. There appears to be evidence that the tumour arose in the breast with the other sites representing metastases rather than a malignant transformation of multiple haemangiomatoses. Histologically the primary breast tumour appeared deceptively innocuous. Images PMID:5106732

  18. Identifying Breast Cancer Oncogenes

    DTIC Science & Technology

    2010-10-01

    08-1-0767 TITLE: Identifying Breast Cancer Oncogenes PRINCIPAL INVESTIGATOR: Yashaswi Shrestha... Breast Cancer Oncogenes 5a. CONTRACT NUMBER W81XWH-08-1-0767 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Yashaswi...SUPPLEMENTARY NOTES 14. ABSTRACT Breast cancer is attributed to genetic alterations, the majority of which are yet to be characterized. Oncogenic

  19. Utility of whole exome sequencing in the diagnosis of Usher syndrome: Report of novel compound heterozygous MYO7A mutations.

    PubMed

    Ramzan, Khushnooda; Al-Owain, Mohammed; Huma, Rozeena; Al-Hazzaa, Selwa A F; Al-Ageel, Sarah; Imtiaz, Faiqa; Al-Sayed, Moeenaldeen

    2018-05-01

    Next generation sequencing (NGS), such as targeted panel sequencing, whole-exome sequencing and whole-genome sequencing has led to an exponential increase of elucidated genetic causes in both rare diseases, and common but heterogeneous disorders. NGS is applied in both research and clinical settings, and the clinical exome sequencing (CES), which provides not only the sequence variation data but also clinical interpretation, aids in reaching a final conclusion with regards to a genetic diagnosis. Usher syndrome is a group of disorders, characterized by bilateral sensorineural hearing loss, with or without vestibular dysfunction and retinitis pigmentosa. The index patient, a 2-year-old child was initially diagnosed with nonsyndromic hearing impairment. Homozygosity mapping followed by CES was utilized as a diagnostic tool to identify the genetic basis of his hearing loss. A paternally inherited novel insertion, c.198_199insA (p.Val67Serfs*73) and a maternally inherited novel deletion, c.1219_1226del (p.Phe407Aspfs*33) in gene MYO7A were found in compound heterozygous state in the index patient. The result expands the mutational spectrum of MYO7A. In addition it helped in early diagnosis of the syndrome, for planning and adjustments for the patient, and as well as for future family planning. This study highlights the clinical effectiveness of CES for Usher syndrome diagnosis in a child presented with congenital hearing loss. Copyright © 2018. Published by Elsevier B.V.

  20. Two novel compound heterozygous mutations in the BCKDHB gene that cause the intermittent form of maple syrup urine disease.

    PubMed

    Guo, Yi; Liming, Liu; Jiang, Li

    2015-12-01

    Intermittent maple syrup urine disease (MSUD) is a potentially life-threatening metabolic disorder caused by a deficiency of branched chain α-ketoacid dehydrogenase (BCKD) complex. In contrast to classic MSUD, children with the intermittent form usually have an atypical clinical manifestation. Here, we describe the presenting symptoms and clinical course of a Chinese boy with intermittent MSUD. Mutation analysis identified two previously unreported mutations in exon 7 of the BCKDHB gene: c.767A > G (p.Y256C) and c.768C > G (p.Y256X); the parents were each heterozygous for one of these mutations. In silico analysis predicted Y256C probably affects protein structure; Y256X leads to a premature stop codon. This case demonstrates intermittent MSUD should be suspected in cases with symptoms of recurrent encephalopathy, especially ataxia or marked drowsiness, which usually present after the neonatal period and in conjunction with infection. symmetrical basal ganglia damage but normal myelination in the posterior limb will assist differential diagnosis; alloisoleucine is a useful diagnostic marker and mutation analysis may be of prognostic value. These novel mutations Y256C and Y256X result in the clinical manifestation of a variant form of MSUD, expanding the mutation spectrum of this disease.

  1. Effect of LDL cholesterol, statins and presence of mutations on the prevalence of type 2 diabetes in heterozygous familial hypercholesterolemia.

    PubMed

    Climent, Elisenda; Pérez-Calahorra, Sofía; Marco-Benedí, Victoria; Plana, Nuria; Sánchez, Rosa; Ros, Emilio; Ascaso, Juan F; Puzo, Jose; Almagro, Fátima; Lahoz, Carlos; Civeira, Fernando; Pedro-Botet, Juan

    2017-07-17

    Patients with heterozygous familial hypercholesterolemia (HeFH) have been reported to be less vulnerable to type 2 diabetes mellitus (T2DM), although the mechanism is unknown. The aims of the present study were to assess the effects of low density lipoprotein (LDL) cholesterol concentration and the presence of FH-causing mutations on T2DM prevalence in HeFH. Data were collected from the Dyslipidemia Registry of the Spanish Arteriosclerosis Society. Inclusion criteria were definite or probable HeFH in patients aged ≥18 years. T2DM prevalence in HeFH patients was compared with data of the general population. 1732 patients were included. The prevalence of T2DM was lower in patients with HeFH compared with the general population (5.94% vs 9.44%; OR: 0.606, 95% CI 0.486-0.755, p < 0.001). Risk factors for developing T2DM were male sex, age, body mass index, hypertension, baseline triglyceride levels and years on statin therapy. The prevalence of T2DM in HeFH patients was 40% lower than that observed in the general population. Gene mutations and LDL cholesterol concentrations were not risk factors associated with the prevalence of T2DM in patients with HeFH. The prevalence of T2DM in patients with HeFH was 40% lower than in the general population matched for age and sex.

  2. Heterozygous Pathogenic Variant in DACT1 Causes an Autosomal-Dominant Syndrome with Features Overlapping Townes–Brocks Syndrome

    PubMed Central

    Webb, Bryn D.; Metikala, Sanjeeva; Wheeler, Patricia G.; Sherpa, Mingma D.; Houten, Sander M.; Horb, Marko E.; Schadt, Eric E.

    2017-01-01

    A heterozygous nonsense variant was identified in dapper, antagonist of beta-catenin, 1 (DACT1) via whole-exome sequencing in family members with imperforate anus, structural renal abnormalities, genitourinary anomalies, and/or ear anomalies. The DACT1 c.1256G>A;p.Trp419* variant segregated appropriately in the family consistent with an autosomal dominant mode of inheritance. DACT1 is a member of the Wnt-signaling pathway, and mice homozygous for null alleles display multiple congenital anomalies including absent anus with blind-ending colon and genitourinary malformations. To investigate the DACT1 c.1256G>A variant, HEK293 cells were transfected with mutant DACT1 cDNA plasmid, and immunoblotting revealed stability of the DACT1 p.Trp419* protein. Overexpression of DACT1 c.1256G>A mRNA in Xenopus embryos revealed a specific gastrointestinal phenotype of enlargement of the proctodeum. Together, these findings suggest that the DACT1 c.1256G>A nonsense variant is causative of a specific genetic syndrome with features overlapping Townes–Brocks syndrome. PMID:28054444

  3. Heterozygous Pathogenic Variant in DACT1 Causes an Autosomal-Dominant Syndrome with Features Overlapping Townes-Brocks Syndrome.

    PubMed

    Webb, Bryn D; Metikala, Sanjeeva; Wheeler, Patricia G; Sherpa, Mingma D; Houten, Sander M; Horb, Marko E; Schadt, Eric E

    2017-04-01

    A heterozygous nonsense variant was identified in dapper, antagonist of beta-catenin, 1 (DACT1) via whole-exome sequencing in family members with imperforate anus, structural renal abnormalities, genitourinary anomalies, and/or ear anomalies. The DACT1 c.1256G>A;p.Trp419 * variant segregated appropriately in the family consistent with an autosomal dominant mode of inheritance. DACT1 is a member of the Wnt-signaling pathway, and mice homozygous for null alleles display multiple congenital anomalies including absent anus with blind-ending colon and genitourinary malformations. To investigate the DACT1 c.1256G>A variant, HEK293 cells were transfected with mutant DACT1 cDNA plasmid, and immunoblotting revealed stability of the DACT1 p.Trp419 * protein. Overexpression of DACT1 c.1256G>A mRNA in Xenopus embryos revealed a specific gastrointestinal phenotype of enlargement of the proctodeum. Together, these findings suggest that the DACT1 c.1256G>A nonsense variant is causative of a specific genetic syndrome with features overlapping Townes-Brocks syndrome. © 2017 WILEY PERIODICALS, INC.

  4. Multiplex primer extension reaction screening and oxidative challenge of glucose-6-phosphate dehydrogenase mutants in hemizygous and heterozygous subjects.

    PubMed

    Ko, Chun Hay; Yung, Edmund; Li, Karen; Li, Chung Leung; Ng, Pak Cheung; Fung, Kwok Pui; Wong, Raymond Pui-On; Chui, Kit Man; Gu, Goldie Jia-Shi; Fok, Tai Fai

    2006-01-01

    The primary objective of our study was to provide a simple and reliable assay for identifying the majority of G6PD genetic variants in the Chinese population. We optimized the multiplex primer extension reaction (MPER) assay for simultaneous screening of 14-point mutations in 98 G6PD-deficient subjects. Our data demonstrated that this method is precise, cost-effective and has successfully identified mutations in 97 out of 98 subjects, including all heterozygous mutants. We also detected a relatively high incidence (12.3%) of c.871G > A, and all of them harbored the silent mutation c.1311C > T. Apart from the screening program, the pharmacogenetic relationship between G6PD level and residual reduced glutathione (GSH) level was studied upon oxidative challenge by alpha-naphthol. The GSH levels were correlated with their status of G6PD deficiency, but no significant difference was observed between individual G6PD-deficient groups. Our data demonstrated the potentials of the MPER assay for characterization of G6PD deficiency and other genetic diseases.

  5. [Identification of novel compound heterozygous mutations of USH2A gene in a family with Usher syndrome type II].

    PubMed

    Jiang, Haiou; Ge, Chuanqin; Wang, Yiwang; Tang, Genyun; Quan, Qingli

    2015-06-01

    To identify potential mutations in a Chinese family with Usher syndrome type II. Genomic DNA was obtained from two affected and four unaffected members of the family and subjected to amplification of the entire coding sequence and splicing sites of USH2A gene. Mutation detection was conducted by direct sequencing of the PCR products. A total of 100 normal unrelated individuals were used as controls. The patients were identified to be a compound heterozygote for two mutations: c.8272G>T (p.E2758X) in exon 42 from his mother and c.12376-12378ACT>TAA(p.T4126X) in exon 63 of the USH2A gene from his father. Both mutations were not found in either of the two unaffected family members or 100 unrelated controls, and had completely co-segregated with the disease phenotype in the family. Neither mutation has been reported in the HGMD database. The novel compound heterozygous mutations c.8272G>T and c.12376-12378ACT>TAA within the USH2A gene may be responsible for the disease. This result may provide new clues for molecular diagnosis of this disease.

  6. The use of high resolution melting analysis to detect Fabry mutations in heterozygous females via dry bloodspots.

    PubMed

    Tai, Chang-Long; Liu, Mei-Ying; Yu, Hsiao-Chi; Chiang, Chiang-Chuan; Chiang, Hung; Suen, Jeng-Hung; Kao, Shu-Min; Huang, Yu-Hsiu; Wu, Tina Jui-Ting; Yang, Chia-Feng; Tsai, Fang-Chih; Lin, Ching-Yuang; Chang, Jan-Gowth; Chen, Hong-Duo; Niu, Dau-Ming

    2012-02-18

    As an X-linked genetic disorder, Fabry disease was first thought to affect males only, and females were generally considered to be asymptomatic carriers. However, recent research suggests that female carriers of Fabry disease may still develop vital organ damage causing severe morbidity and mortality. In the previous newborn screening, from 299,007 newborns, we identified a total of 20 different Fabry mutations and 121 newborns with Fabry mutations. However, we found that most female carriers are not detected by enzyme assays. A streamlined method for high resolution melting (HRM) analysis was designed to screen for GLA gene mutations using a same PCR and melting program. Primer sets were designed to cover the 7 exons and the Chinese common intronic mutation, IVS4+919G>A of GLA gene. The HRM analysis was successful in identifying heterozygous and hemizygous patients with the 20 surveyed mutations. We were also successful in using this method to test dry blood spots of newborns afflicted with Fabry mutations without having to determine DNA concentration before PCR amplification. The results of this study show that HRM could be a reliable and sensitive method for use in the rapid screening of females for GLA mutations. Copyright © 2011 Elsevier B.V. All rights reserved.

  7. Identification of two novel compound heterozygous mutations of ADGRV1 in a Chinese family with Usher syndrome type IIC.

    PubMed

    Zhang, Nian; Wang, Juan; Liu, Shuting; Liu, Mugen; Jiang, Fagang

    2018-08-01

    To describe the clinical and genetic findings in a Chinese family with three sibs diagnosed with Usher syndrome type IIC. Four members received ophthalmic and otologic tests to ascertain the clinical characteristics. According to the clinical phenotype, we focused attention on a total of 658 genes associated with them. We screened the possible pathogenic mutation sites, used Sanger to exclude the false positive and verified whether there were co-segregated among the family members. Typical fundus features found in the proband supported the diagnosis of retinitis pigmentosa (RP). Audiometric test indicated moderate to severe sensorineural hearing impairment while the vestibular function was normal. Whole-exome sequencing identified the presence of two novel compound heterozygous mutations in ADGRV1, a known gene responsible for Usher syndrome type IIC. Mutationc.15008delG/p.Gly5003AlafsTer13 was inherited from the mother while c.18383_18386dupACAG/p.His6130GlnfsTer84 was inherited from the father, and they were co-segregated with the disease phenotype in the family. The mutations found in our study not only broaden the mutation spectrum of ADGRV1, but also provide assistances for future genetic diagnosis and treatment for Usher syndrome patients.

  8. Dent Disease in Chinese Children and Findings from Heterozygous Mothers: Phenotypic Heterogeneity, Fetal Growth, and 10 Novel Mutations.

    PubMed

    Li, Fucheng; Yue, Zhihui; Xu, Tingting; Chen, Minghui; Zhong, Liangying; Liu, Ting; Jing, Xiangyi; Deng, Jia; Hu, Bin; Liu, Yuling; Wang, Haiyan; Lai, Kar N; Sun, Liangzhong; Liu, Jinsong; Maxwell, Patrick H; Wang, Yiming

    2016-07-01

    To characterize the phenotypes of Dent disease in Chinese children and their heterozygous mothers and to establish genetic diagnoses. Using a modified protocol, we screened 1288 individuals with proteinuria. A diagnosis of Dent disease was established in 19 boys from 16 families by the presence of loss of function/deleterious mutations in CLCN5 or OCRL1. We also analyzed 16 available patients' mothers and examined their pregnancy records. We detected 14 loss of function/deleterious mutations of CLCN5 in 15 boys and 2 mutations of OCRL1 in 4 boys. Of the patients, 16 of 19 had been wrongly diagnosed with other diseases and 11 of 19 had incorrect or unnecessary treatment. None of the patients, but 6 of 14 mothers, had nephrocalcinosis or nephrolithiasis at diagnosis. Of the patients, 8 of 14 with Dent disease 1 were large for gestational age (>90th percentile); 8 of 15 (53.3%) had rickets. We also present predicted structural changes for 4 mutant proteins. Pediatric Dent disease often is misdiagnosed; genetic testing achieves a correct diagnosis. Nephrocalcinosis or nephrolithiasis may not be sensitive diagnostic criteria. We identified 10 novel mutations in CLCN5 and OCRL1. The possibility that altered CLCN5 function could affect fetal growth and a possible link between a high rate of rickets and low calcium intake are discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. A novel heterozygous intronic mutation in POU1F1 is associated with combined pituitary hormone deficiency.

    PubMed

    Takagi, Masaki; Kamasaki, Hotaka; Yagi, Hiroko; Fukuzawa, Ryuji; Narumi, Satoshi; Hasegawa, Tomonobu

    2017-02-27

    POU class 1 homeobox 1 (POU1F1) regulates pituitary cell-specific gene expression of somatotropes, lactotropes, and thyrotropes. In humans, two POU1F1 isoforms (long and short isoform), which are generated by the alternative use of the splice acceptor site for exon 2, have been identified. To date, more than 30 POU1F1 mutations in patients with combined pituitary hormone deficiency (CPHD) have been described. All POU1F1 variants reported to date affect both the short and long isoforms of the POU1F1 protein; therefore, it is unclear at present whether a decrease in the function of only one of these two isoforms is sufficient for disease onset in humans. Here, we described a sibling case of CPHD carrying a heterozygous mutation in intron 1 of POU1F1. In vitro experiments showed that this mutation resulted in exon 2-skipping of only in the short isoform of POU1F1, while the long isoform remained intact. This result strongly suggests the possibility, for the first time, that isolated mutations in the short isoform of POU1F1 could be sufficient for induction of POU1F1-related CPHD. This finding improves our understanding of the molecular mechanisms, and developmental course associated with mutations in POU1F1.

  10. Heterozygous deletion of FOXA2 segregates with disease in a family with heterotaxy, panhypopituitarism, and biliary atresia.

    PubMed

    Tsai, Ellen A; Grochowski, Christopher M; Falsey, Alexandra M; Rajagopalan, Ramakrishnan; Wendel, Danielle; Devoto, Marcella; Krantz, Ian D; Loomes, Kathleen M; Spinner, Nancy B

    2015-06-01

    Biliary atresia (BA) is a pediatric cholangiopathy with unknown etiology occurring in isolated and syndromic forms. Laterality defects affecting the cardiovascular and gastrointestinal systems are the most common features present in syndromic BA. Most cases are sporadic, although reports of familial cases have led to the hypothesis of genetic susceptibility in some patients. We identified a child with BA, malrotation, and interrupted inferior vena cava whose father presented with situs inversus, polysplenia, panhypopituitarism, and mildly dysmorphic facial features. Chromosomal microarray analysis demonstrated a 277 kb heterozygous deletion on chromosome 20, which included a single gene, FOXA2, in the proband and her father. This deletion was confirmed to be de novo in the father. The proband and her father share a common diagnosis of heterotaxy, but they also each presented with a variety of other issues. Further genetic screening revealed that the proband carried an additional protein-altering polymorphism (rs1904589; p.His165Arg) in the NODAL gene that is not present in the father, and this variant has been shown to decrease expression of the gene. As FOXA2 can be a regulator of NODAL expression, we propose that haploinsufficiency for FOXA2 combined with a decreased expression of NODAL is the likely cause for syndromic BA in this proband. © 2015 WILEY PERIODICALS, INC.

  11. Heterozygous Deletion of FOXA2 Segregates with Disease in a Family with Heterotaxy, Panhypopituitarism, and Biliary Atresia

    PubMed Central

    Tsai, Ellen A.; Grochowski, Christopher M.; Falsey, Alexandra M.; Rajagopalan, Ramakrishnan; Wendel, Danielle; Devoto, Marcella; Krantz, Ian D.; Loomes, Kathleen M.; Spinner, Nancy B.

    2015-01-01

    Biliary atresia (BA) is a pediatric cholangiopathy with unknown etiology occurring in isolated and syndromic forms. Laterality defects affecting the cardiovascular and gastrointestinal systems are the most common features present in syndromic BA. Most cases are sporadic, although reports of familial cases have led to the hypothesis of genetic susceptibility in some patients. We identified a child with BA, malrotation, and interrupted inferior vena cava whose father presented with situs inversus, polysplenia, panhypopituitarism, and mildly dysmorphic facial features. Chromosomal microarray analysis demonstrated a 277kb heterozygous deletion on chromosome 20 which included a single gene, FOXA2, in the proband and her father. This deletion was confirmed to be de novo in the father. The proband and her father share a common diagnosis of heterotaxy, but they also each presented with a variety of other issues. Further genetic screening revealed that the proband carried an additional protein-altering polymorphism (rs1904589; p.His165Arg) in the NODAL gene that is not present in the father, and this variant has been shown to decrease expression of the gene. As FOXA2 can be a regulator of NODAL expression, we propose that haploinsufficiency for FOXA2 combined with a decreased expression of NODAL is the likely cause for syndromic BA in this proband. PMID:25765999

  12. Heterozygous variants in ACTL6A, encoding a component of the BAF complex, are associated with intellectual disability.

    PubMed

    Marom, Ronit; Jain, Mahim; Burrage, Lindsay C; Song, I-Wen; Graham, Brett H; Brown, Chester W; Stevens, Servi J C; Stegmann, Alexander P A; Gunter, Andrew T; Kaplan, Julie D; Gavrilova, Ralitza H; Shinawi, Marwan; Rosenfeld, Jill A; Bae, Yangjin; Tran, Alyssa A; Chen, Yuqing; Lu, James T; Gibbs, Richard A; Eng, Christine; Yang, Yaping; Rousseau, Justine; de Vries, Bert B A; Campeau, Philippe M; Lee, Brendan

    2017-10-01

    Pathogenic variants in genes encoding components of the BRG1-associated factor (BAF) chromatin remodeling complex have been associated with intellectual disability syndromes. We identified heterozygous, novel variants in ACTL6A, a gene encoding a component of the BAF complex, in three subjects with varying degrees of intellectual disability. Two subjects have missense variants affecting highly conserved amino acid residues within the actin-like domain. Missense mutations in the homologous region in yeast actin were previously reported to be dominant lethal and were associated with impaired binding of the human ACTL6A to β-actin and BRG1. A third subject has a splicing variant that creates an in-frame deletion. Our findings suggest that the variants identified in our subjects may have a deleterious effect on the function of the protein by disturbing the integrity of the BAF complex. Thus, ACTL6A gene mutation analysis should be considered in patients with intellectual disability, learning disabilities, or developmental language disorder. © 2017 Wiley Periodicals, Inc.

  13. Heterozygous Germline Mutations in the CBL Tumor-Suppressor Gene Cause a Noonan Syndrome-like Phenotype

    PubMed Central

    Martinelli, Simone; De Luca, Alessandro; Stellacci, Emilia; Rossi, Cesare; Checquolo, Saula; Lepri, Francesca; Caputo, Viviana; Silvano, Marianna; Buscherini, Francesco; Consoli, Federica; Ferrara, Grazia; Digilio, Maria C.; Cavaliere, Maria L.; van Hagen, Johanna M.; Zampino, Giuseppe; van der Burgt, Ineke; Ferrero, Giovanni B.; Mazzanti, Laura; Screpanti, Isabella; Yntema, Helger G.; Nillesen, Willy M.; Savarirayan, Ravi; Zenker, Martin; Dallapiccola, Bruno; Gelb, Bruce D.; Tartaglia, Marco

    2010-01-01

    RAS signaling plays a key role in controlling appropriate cell responses to extracellular stimuli and participates in early and late developmental processes. Although enhanced flow through this pathway has been established as a major contributor to oncogenesis, recent discoveries have revealed that aberrant RAS activation causes a group of clinically related developmental disorders characterized by facial dysmorphism, a wide spectrum of cardiac disease, reduced growth, variable cognitive deficits, ectodermal and musculoskeletal anomalies, and increased risk for certain malignancies. Here, we report that heterozygous germline mutations in CBL, a tumor-suppressor gene that is mutated in myeloid malignancies and encodes a multivalent adaptor protein with E3 ubiquitin ligase activity, can underlie a phenotype with clinical features fitting or partially overlapping Noonan syndrome (NS), the most common condition of this disease family. Independent CBL mutations were identified in two sporadic cases and two families from among 365 unrelated subjects who had NS or suggestive features and were negative for mutations in previously identified disease genes. Phenotypic heterogeneity and variable expressivity were documented. Mutations were missense changes altering evolutionarily conserved residues located in the RING finger domain or the linker connecting this domain to the N-terminal tyrosine kinase binding domain, a known mutational hot spot in myeloid malignancies. Mutations were shown to affect CBL-mediated receptor ubiquitylation and dysregulate signal flow through RAS. These findings document that germline mutations in CBL alter development to cause a clinically variable condition that resembles NS and that possibly predisposes to malignancies. PMID:20619386

  14. Compound heterozygous deletions in pseudoautosomal region 1 in an infant with mild manifestations of langer mesomelic dysplasia.

    PubMed

    Tsuchiya, Takayoshi; Shibata, Minoru; Numabe, Hironao; Jinno, Tomoko; Nakabayashi, Kazuhiko; Nishimura, Gen; Nagai, Toshiro; Ogata, Tsutomu; Fukami, Maki

    2014-02-01

    Haploinsufficiency of SHOX on the short arm pseudoautosomal region (PAR1) leads to Leri-Weill dyschondrosteosis (LWD), and nullizygosity of SHOX results in Langer mesomelic dysplasia (LMD). Molecular defects of LWD/LMD include various microdeletions in PAR1 that involve exons and/or the putative upstream or downstream enhancer regions of SHOX, as well as several intragenic mutations. Here, we report on a Japanese male infant with mild manifestations of LMD and hitherto unreported microdeletions in PAR1. Clinical analysis revealed mesomelic short stature with various radiological findings indicative of LMD. Molecular analyses identified compound heterozygous deletions, that is, a maternally inherited ∼46 kb deletion involving the upstream region and exons 1-5 of SHOX, and a paternally inherited ∼500 kb deletion started from a position ∼300 kb downstream from SHOX. In silico analysis revealed that the downstream deletion did not affect the known putative enhancer regions of SHOX, although it encompassed several non-coding elements which were well conserved among various species with SHOX orthologs. These results provide the possibility of the presence of a novel enhancer for SHOX in the genomic region ∼300 to ∼800 kb downstream of the start codon. © 2013 Wiley Periodicals, Inc.

  15. Clonal evolution following chemotherapy-induced stem cell depletion in cats heterozygous for glucose-6-phosphate dehydrogenase

    SciTech Connect

    Abkowitz, J.L.; Ott, R.M.; Holly, R.D.

    The number of hematopoietic stem cells necessary to support normal hematopoiesis is not known but may be small. If so, the depletion or damage of such cells could result in apparent clonal dominance. To test this hypothesis, dimethylbusulfan (2 to 4 mg/kg intravenously (IV) x 3) was given to cats heterozygous for the X-linked enzyme glucose-6-phosphate dehydrogenase (G-6-PD). These cats were the daughters of domestic X Geoffroy parents. After the initial drug-induced cytopenias (2 to 4 weeks), peripheral blood counts and the numbers of marrow progenitors detected in culture remained normal, although the percentages of erythroid burst-forming cells (BFU-E) andmore » granulocyte/macrophage colony-forming cells (CFU-GM) in DNA synthesis increased, as determined by the tritiated thymidine suicide technique. In three of six cats treated, a dominance of Geoffroy-type G-6-PD emerged among the progenitor cells, granulocytes, and RBCs. These skewed ratios of domestic to Geoffroy-type G-6-PD have persisted greater than 3 years. No changes in cell cycle kinetics or G-6-PD phenotypes were noted in similar studies in six control cats. These data suggest that clonal evolution may reflect the depletion or damage of normal stem cells and not only the preferential growth and dominance of neoplastic cells.« less

  16. A Case of Beta-propeller Protein-associated Neurodegeneration due to a Heterozygous Deletion of WDR45.

    PubMed

    Hermann, Andreas; Kitzler, Hagen H; Pollack, Tobias; Biskup, Saskia; Krüger, Stefanie; Funke, Claudia; Terrile, Caterina; Haack, Tobias B

    2017-01-01

    Static encephalopathy of childhood with neurodegeneration in adulthood is a phenotypically distinctive, X-linked dominant subtype of neurodegeneration with brain iron accumulation (NBIA). WDR45 mutations were recently identified as causal. WDR45 encodes a beta-propeller scaffold protein with a putative role in autophagy, and the disease has been renamed beta-propeller protein-associated neurodegeneration (BPAN). Here we describe a female patient suffering from a classical BPAN phenotype due to a novel heterozygous deletion of WDR45 . An initial gene panel and Sanger sequencing approach failed to uncover the molecular defect. Based on the typical clinical and neuroimaging phenotype, quantitative polymerase chain reaction of the WDR45 coding regions was undertaken, and this showed a reduction of the gene dosage by 50% compared with controls. An extended search for deletions should be performed in apparently WDR45- negative cases presenting with features of NBIA and should also be considered in young patients with predominant intellectual disabilities and hypertonia/parkinsonism/dystonia.

  17. Compound heterozygous PNPLA6 mutations cause Boucher-Neuhäuser syndrome with late-onset ataxia.

    PubMed

    Deik, A; Johannes, B; Rucker, J C; Sánchez, E; Brodie, S E; Deegan, E; Landy, K; Kajiwara, Y; Scelsa, S; Saunders-Pullman, R; Paisán-Ruiz, C

    2014-12-01

    PNPLA6 mutations, known to be associated with the development of motor neuron phenotypes, have recently been identified in families with Boucher-Neuhäuser syndrome. Boucher-Neuhäuser is a rare autosomal recessive syndrome characterized by the co-occurrence of cerebellar ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy. Gait ataxia in Boucher-Neuhäuser usually manifests before early adulthood, although onset in the third or fourth decade has also been reported. However, given the recent identification of PNPLA6 mutations as the cause of this condition, the determining factors of age of symptom onset still need to be established. Here, we have identified a sporadic Boucher-Neuhäuser case with late-onset gait ataxia and relatively milder retinal changes due to compound heterozygous PNPLA6 mutations. Compound heterozygosity was confirmed by cloning and sequencing the patient's genomic DNA from coding exons 26-29. Furthermore, both mutations (one novel and one known) fell in the phospholipase esterase domain, where most pathogenic mutations seem to cluster. Taken together, we herein confirm PNPLA6 mutations as the leading cause of Boucher-Neuhäuser syndrome and suggest inquiring about a history of hypogonadism or visual changes in patients presenting with late-onset gait ataxia. We also advocate for neuroophthalmologic evaluation in suspected cases.

  18. Identification of FASTKD2 compound heterozygous mutations as the underlying cause of autosomal recessive MELAS-like syndrome.

    PubMed

    Yoo, Da Hye; Choi, Young-Chul; Nam, Da Eun; Choi, Sun Seong; Kim, Ji Won; Choi, Byung-Ok; Chung, Ki Wha

    2017-07-01

    Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a condition that affects many parts of the body, particularly the brain and muscles. This study examined a Korean MELAS-like syndrome patient with seizure, stroke-like episode, and optic atrophy. Target sequencing of whole mtDNA and 73 nuclear genes identified compound heterozygous mutations p.R205X and p.L255P in the FASTKD2. Each of his unaffected parents has one of the two mutations, and both mutations were not found in 302 controls. FASTKD2 encodes a FAS-activated serine-threonine (FAST) kinase domain 2 which locates in the mitochondrial inner compartment. A FASTKD2 nonsense mutation was once reported as the cause of a recessive infantile mitochondrial encephalomyopathy. The present case showed relatively mild symptoms with a late onset age, compared to a previous patient with FASTKD2 mutation, implicating an inter-allelic clinical heterogeneity. Because this study is the second report of an autosomal recessive mitochondrial encephalomyopathy patient with a FASTKD2 mutation, it will extend the phenotypic spectrum of the FASTKD2 mutation. Copyright © 2017. Published by Elsevier B.V.

  19. Atypical generalized lipoatrophy and severe insulin resistance due to a heterozygous LMNA p.T10I mutation.

    PubMed

    Mory, Patricia B; Crispim, Felipe; Kasamatsu, Teresa; Gabbay, Monica A L; Dib, Sergio A; Moisés, Regina S

    2008-11-01

    Lipodystrophies are a group of heterogeneous disorders characterized by the loss of adipose tissue and metabolic complications. The main familial forms of lipodystrophy are Congenital Generalized Lipodystrophy and Familial Partial Lipodystrophy (FPLD). FPLD may result from mutations in the LMNA gene. Besides FPLD, mutations in LMNA have been shown to be responsible for other inherited diseases called laminopathies. Here we describe the case of a 15-year-old girl who was referred to our service due to diabetes mellitus and severe hypertriglyceridemia. Physical examination revealed generalized loss of subcutaneous fat, confirmed by DEXA (total body fat 8.6%). As the patient presented with pubertal-onset of generalized lipodystrophy and insulin resistance, molecular analysis of the LMNA gene was performed. We identified a heterozygous substitution in exon 1 (c.29C>T) predicting a p.T10I mutation. In summary, we describe an atypical phenotype of lipodistrophy associated with a de novo appearance of the p.T10I mutation in LMNA gene.

  20. Comparative molecular dynamics studies of heterozygous open reading frames of DNA polymerase eta (η) in pathogenic yeast Candida albicans

    NASA Astrophysics Data System (ADS)

    Satpati, Suresh; Manohar, Kodavati; Acharya, Narottam; Dixit, Anshuman

    2017-01-01

    Genomic instability in Candida albicans is believed to play a crucial role in fungal pathogenesis. DNA polymerases contribute significantly to stability of any genome. Although Candida Genome database predicts presence of S. cerevisiae DNA polymerase orthologs; functional and structural characterizations of Candida DNA polymerases are still unexplored. DNA polymerase eta (Polη) is unique as it promotes efficient bypass of cyclobutane pyrimidine dimers. Interestingly, C. albicans is heterozygous in carrying two Polη genes and the nucleotide substitutions were found only in the ORFs. As allelic differences often result in functional differences of the encoded proteins, comparative analyses of structural models and molecular dynamic simulations were performed to characterize these orthologs of DNA Polη. Overall structures of both the ORFs remain conserved except subtle differences in the palm and PAD domains. The complementation analysis showed that both the ORFs equally suppressed UV sensitivity of yeast rad30 deletion strain. Our study has predicted two novel molecular interactions, a highly conserved molecular tetrad of salt bridges and a series of π-π interactions spanning from thumb to PAD. This study suggests these ORFs as the homologues of yeast Polη, and due to its heterogeneity in C. albicans they may play a significant role in pathogenicity.

  1. Hearing dysfunction in heterozygous Mitf(Mi-wh) /+ mice, a model for Waardenburg syndrome type 2 and Tietz syndrome.

    PubMed

    Ni, Christina; Zhang, Deming; Beyer, Lisa A; Halsey, Karin E; Fukui, Hideto; Raphael, Yehoash; Dolan, David F; Hornyak, Thomas J

    2013-01-01

    The human deafness-pigmentation syndromes, Waardenburg syndrome (WS) type 2a, and Tietz syndrome are characterized by profound deafness but only partial cutaneous pigmentary abnormalities. Both syndromes are caused by mutations in MITF. To illuminate differences between cutaneous and otic melanocytes in these syndromes, their development and survival in heterozygous Microphthalmia-White (Mitf(Mi-wh) /+) mice were studied and hearing function of these mice characterized. Mitf(Mi-wh) /+ mice have a profound hearing deficit, characterized by elevated auditory brainstem response thresholds, reduced distortion product otoacoustic emissions, absent endocochlear potential, loss of outer hair cells, and stria vascularis abnormalities. Mitf(Mi-wh) /+ embryos have fewer melanoblasts during embryonic development than their wild-type littermates. Although cochlear melanocytes are present at birth, they disappear from the Mitf(Mi-wh) /+ cochlea between P1 and P7. These findings may provide insight into the mechanism of melanocyte and hearing loss in human deafness-pigmentation syndromes such as WS and Tietz syndrome and illustrate differences between otic and follicular melanocytes. © 2012 John Wiley & Sons A/S.

  2. Impaired Angiogenesis and Mobilization of Circulating Angiogenic Cells in HIF-1α Heterozygous-Null Mice after Burn Wounding

    PubMed Central

    Zhang, Xianjie; Liu, Lixin; Wei, Xiaofei; Tan, Yee Sun; Tong, Lana; Chang, Ryan; Ghanamah, Mohammed S.; Reinblatt, Maura; Marti, Guy P.; Harmon, John W.; Semenza, Gregg L.

    2014-01-01

    Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that controls vascular responses to hypoxia and ischemia. In this study, mice that were heterozygous for a null allele at the locus encoding the HIF-1α subunit (HET mice) and their wild type (WT) littermates were subjected to thermal injury involving 10% of body surface area. HIF-1α protein levels were increased in burn wounds of WT but not of HET mice on day 2. Serum levels of stromal-derived factor 1α, which binds to CXCR4, were increased on day 2 in WT but not in HET mice. Circulating angiogenic cells were also increased on day 2 in WT but not in HET mice and included CXCR4+Sca1+ cells. Laser Doppler perfusion imaging demonstrated increased blood flow in burn wounds of WT but not HET mice on day 7. Immunohistochemistry on day 7 revealed a reduced number of CD31+ vessels at the healing margin of burn wounds in HET as compared to WT mice. Vessel maturation was also impaired in wounds of HET mice as determined by the number of α-smooth muscle actin-positive vessels on day 21. The remaining wound area on day 14 was significantly increased in HET mice compared to WT littermates. The percentage of healed wounds on day 14 was significantly decreased in HET mice. These data delineate a signaling pathway by which HIF-1 promotes angiogenesis during burn wound healing. PMID:20163569

  3. Brain-derived neurotrophic factor heterozygous mutant rats show selective cognitive changes and vulnerability to chronic corticosterone treatment.

    PubMed

    Gururajan, A; Hill, R A; van den Buuse, M

    2015-01-22

    Brain-derived neurotrophic factor (BDNF) is a widely expressed neurotrophin involved in neurodevelopment, neuroprotection and synaptic plasticity. It is also implicated in a range of psychiatric disorders such as schizophrenia, depression and post-traumatic stress disorder. Stress during adolescence/young adulthood can have long-term psychiatric and cognitive consequences, however it is unknown how altered BDNF signaling is involved in such effects. Here we investigated whether a congenital deficit in BDNF availability in rats increases vulnerability to the long-term effects of the stress hormone, corticosterone (CORT). Compared to wildtype (WT) littermates, BDNF heterozygous (HET) rats showed higher body weights and minor developmental changes, such as reduced relative brain and pituitary weight. These animals furthermore showed deficits in short-term spatial memory in the Y-maze and in prepulse inhibition and startle, but not in object-recognition memory. CORT treatment induced impairments in novel-object recognition memory in both genotypes but disrupted fear conditioning extinction learning in BDNF HET rats only. These results show selective behavioral changes in BDNF HET rats, at baseline or after chronic CORT treatment and add to our understanding of the role of BDNF and its interaction with stress. Importantly, this study demonstrates the utility of the BDNF HET rat in investigations into the pathophysiology of various psychiatric disorders. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  4. Cognitive assessment of mice strains heterozygous for cell-adhesion genes reveals strain-specific alterations in timing.

    PubMed

    Gallistel, C R; Tucci, Valter; Nolan, Patrick M; Schachner, Melitta; Jakovcevski, Igor; Kheifets, Aaron; Barboza, Luendro

    2014-03-05

    We used a fully automated system for the behavioural measurement of physiologically meaningful properties of basic mechanisms of cognition to test two strains of heterozygous mutant mice, Bfc (batface) and L1, and their wild-type littermate controls. Both of the target genes are involved in the establishment and maintenance of synapses. We find that the Bfc heterozygotes show reduced precision in their representation of interval duration, whereas the L1 heterozygotes show increased precision. These effects are functionally specific, because many other measures made on the same mice are unaffected, namely: the accuracy of matching temporal investment ratios to income ratios in a matching protocol, the rate of instrumental and classical conditioning, the latency to initiate a cued instrumental response, the trials on task and the impulsivity in a switch paradigm, the accuracy with which mice adjust timed switches to changes in the temporal constraints, the days to acquisition, and mean onset time and onset variability in the circadian anticipation of food availability.

  5. Cognitive assessment of mice strains heterozygous for cell-adhesion genes reveals strain-specific alterations in timing

    PubMed Central

    Gallistel, C. R.; Tucci, Valter; Nolan, Patrick M.; Schachner, Melitta; Jakovcevski, Igor; Kheifets, Aaron; Barboza, Luendro

    2014-01-01

    We used a fully automated system for the behavioural measurement of physiologically meaningful properties of basic mechanisms of cognition to test two strains of heterozygous mutant mice, Bfc (batface) and L1, and their wild-type littermate controls. Both of the target genes are involved in the establishment and maintenance of synapses. We find that the Bfc heterozygotes show reduced precision in their representation of interval duration, whereas the L1 heterozygotes show increased precision. These effects are functionally specific, because many other measures made on the same mice are unaffected, namely: the accuracy of matching temporal investment ratios to income ratios in a matching protocol, the rate of instrumental and classical conditioning, the latency to initiate a cued instrumental response, the trials on task and the impulsivity in a switch paradigm, the accuracy with which mice adjust timed switches to changes in the temporal constraints, the days to acquisition, and mean onset time and onset variability in the circadian anticipation of food availability. PMID:24446498

  6. Breast Tumor Specific Peptides: Development of Breast Carcinoma Diagnostic and Therapeutic Agents

    DTIC Science & Technology

    2000-11-01

    Columbia, Missouri 65211; La Jolla Institute for Allergy and Inmunology [M. E. H.], San Diego, California 92121; and Sidney Kimmel Cancer Center and...spontaneous homotypic aggregation of breast The costs of publication of this article were defrayed in part by the payment of page cancer cells, then a T...antigen-binding peptide may likewise inhibit charges. This article must therefore be hereby marked advertisement in accordance with this aggregation

  7. Breast-feeding and benign breast disease.

    PubMed

    Bernardi, S; Londero, A P; Bertozzi, S; Driul, L; Marchesoni, D; Petri, R

    2012-01-01

    Benign breast disease (BBD) is very common among women in their fertile age, but its correlation with breast reproductive function remains unclear. Our study aimed to investigate the relation between BBD and breast-feeding. We collected data on 105 women with BBD and 98 controls, focusing on their reproductive history and breast-feeding. We analysed data by R (version 2.12.1) considering p < 0.05 as significant. The results showed that fibroadenoma represented the most frequent BBD (55%), followed by fibrocystic changes (19%), intraductal papilloma (6%) and inflammatory breast disorders (5%). The mean age was 31.5 years (± 6.1), BMI 21.2 kg/m² (± 3.4) and age at menarche 13.0 years (± 1.5). Duration of breast-feeding was not significantly different between controls and BBD types (p = NS). Selecting women with fibroadenoma breast-feeding duration directly correlated with the number of benign lesions (p < 0.05), which remains significant also by multivariate analysis. It was concluded that there seemed to be no difference in breast-feeding among BBDs types, but lactation may influence the number of fibroadenomas. Moreover, prospective studies would better define the correlation between lactation and BBDs.

  8. Breast-Conserving Surgery Followed by Radiation Therapy With MRI-Detected Stage I or Stage II Breast Cancer

    ClinicalTrials.gov

    2011-12-07

    Ductal Breast Carcinoma in Situ; Estrogen Receptor-negative Breast Cancer; Estrogen Receptor-positive Breast Cancer; HER2-negative Breast Cancer; HER2-positive Breast Cancer; Invasive Ductal Breast Carcinoma; Invasive Lobular Breast Carcinoma; Male Breast Cancer; Medullary Ductal Breast Carcinoma With Lymphocytic Infiltrate; Mucinous Ductal Breast Carcinoma; Papillary Ductal Breast Carcinoma; Progesterone Receptor-negative Breast Cancer; Progesterone Receptor-positive Breast Cancer; Stage I Breast Cancer; Stage II Breast Cancer; Tubular Ductal Breast Carcinoma

  9. Docosahexaenoic Acid in Preventing Recurrence in Breast Cancer Survivors

    ClinicalTrials.gov

    2016-06-20

    Benign Breast Neoplasm; Ductal Breast Carcinoma In Situ; Invasive Breast Carcinoma; Lobular Breast Carcinoma In Situ; Paget Disease of the Breast; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  10. Breast Implants: Saline vs. Silicone

    MedlinePlus

    ... sticky fluid that closely mimics the feel of human fat. Most women feel that silicone breast implants look and feel more like natural breast tissue. Silicone breast implants are available to women 22 and older for breast augmentation and to women of any age for breast ...

  11. Electroclinical presentation and genotype-phenotype relationships in patients with Unverricht-Lundborg disease carrying compound heterozygous CSTB point and indel mutations.

    PubMed

    Canafoglia, Laura; Gennaro, Elena; Capovilla, Giuseppe; Gobbi, Giuseppe; Boni, Antonella; Beccaria, Francesca; Viri, Maurizio; Michelucci, Roberto; Agazzi, Pamela; Assereto, Stefania; Coviello, Domenico A; Di Stefano, Maria; Rossi Sebastiano, Davide; Franceschetti, Silvana; Zara, Federico

    2012-12-01

    Unverricht-Lundborg disease (EPM1A) is frequently due to an unstable expansion of a dodecamer repeat in the CSTB gene, whereas other types of mutations are rare. EPM1A due to homozygous expansion has a rather stereotyped presentation with prominent action myoclonus. We describe eight patients with five different compound heterozygous CSTB point or indel mutations in order to highlight their particular phenotypical presentations and evaluate their genotype-phenotype relationships. We screened CSTB mutations by means of Southern blotting and the sequencing of the genomic DNA of each proband. CSTB messenger RNA (mRNA) aberrations were characterized by sequencing the complementary DNA (cDNA) of lymphoblastoid cells, and assessing the protein concentrations in the lymphoblasts. The patient evaluations included the use of a simplified myoclonus severity rating scale, multiple neurophysiologic tests, and electroencephalography (EEG)-polygraphic recordings. To highlight the particular clinical features and disease time-course in compound heterozygous patients, we compared some of their characteristics with those observed in a series of 40 patients carrying the common homozygous expansion mutation observed at the C. Besta Foundation, Milan, Italy. The eight compound heterozygous patients belong to six EPM1A families (out of 52; 11.5%) diagnosed at the Laboratory of Genetics of the Galliera Hospitals in Genoa, Italy. They segregated five different heterozygous point or indel mutations in association with the common dodecamer expansion. Four patients from three families had previously reported CSTB mutations (c.67-1G>C and c.168+1_18del); one had a novel nonsense mutation at the first exon (c.133C>T) leading to a premature stop codon predicting a short peptide; the other three patients from two families had a complex novel indel mutation involving the donor splice site of intron 2 (c.168+2_169+21delinsAA) and leading to an aberrant transcript with a partially retained intron

  12. Heterozygous Hfe gene deletion leads to impaired glucose homeostasis, but not liver injury in mice fed a high-calorie diet.

    PubMed

    Britton, Laurence; Jaskowski, Lesley; Bridle, Kim; Santrampurwala, Nishreen; Reiling, Janske; Musgrave, Nick; Subramaniam, V Nathan; Crawford, Darrell

    2016-06-01

    Heterozygous mutations of the Hfe gene have been proposed as cofactors in the development and progression of nonalcoholic fatty liver disease (NAFLD). Homozygous Hfe deletion previously has been shown to lead to dysregulated hepatic lipid metabolism and accentuated liver injury in a dietary mouse model of NAFLD We sought to establish whether heterozygous deletion of Hfe is sufficient to promote liver injury when mice are exposed to a high-calorie diet (HCD). Eight-week-old wild-type and Hfe(+/-) mice received 8 weeks of a control diet or HCD Liver histology and pathways of lipid and iron metabolism were analyzed. Liver histology demonstrated that mice fed a HCD had increased NAFLD activity score (NAS), steatosis, and hepatocyte ballooning. However, liver injury was unaffected by Hfe genotype. Hepatic iron concentration (HIC) was increased in Hfe(+/-) mice of both dietary groups. HCD resulted in a hepcidin-independent reduction in HIC Hfe(+/-) mice demonstrated raised fasting serum glucose concentrations and HOMA-IR score, despite unaltered serum adiponectin concentrations. Downstream regulators of hepatic de novo lipogenesis (pAKT, SREBP-1, Fas, Scd1) and fatty acid oxidation (AdipoR2, Pparα, Cpt1) were largely unaffected by genotype. In summary, heterozygous Hfe gene deletion is associated with impaired iron and glucose metabolism. However, unlike homozygous Hfe deletion, heterozygous gene deletion did not affect lipid metabolism pathways or liver injury in this model. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  13. Comparison of Spectrophotometry, Chromate Inhibition, and Cytofluorometry Versus Gene Sequencing for Detection of Heterozygously Glucose-6-Phosphate Dehydrogenase-Deficient Females.

    PubMed

    Peters, Anna L; Veldthuis, Martijn; van Leeuwen, Karin; Bossuyt, Patrick M M; Vlaar, Alexander P J; van Bruggen, Robin; de Korte, Dirk; Van Noorden, Cornelis J F; van Zwieten, Rob

    2017-11-01

    Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme deficiency worldwide. Detection of heterozygously deficient females can be difficult as residual activity in G6PD-sufficient red blood cells (RBCs) can mask deficiency. In this study, we compared accuracy of 4 methods for detection of G6PD deficiency in females. Blood samples from females more than 3 months of age were used for spectrophotometric measurement of G6PD activity and for determination of the percentage G6PD-negative RBCs by cytofluorometry. An additional sample from females suspected to have G6PD deficiency based on the spectrophotometric G6PD activity was used for measuring chromate inhibition and sequencing of the G6PD gene. Of 165 included females, 114 were suspected to have heterozygous deficiency. From 75 females, an extra sample was obtained. In this group, mutation analysis detected 27 heterozygously deficient females. The sensitivity of spectrophotometry, cytofluorometry, and chromate inhibition was calculated to be 0.52 (confidence interval [CI]: 0.32-0.71), 0.85 (CI: 0.66-0.96), and 0.96 (CI: 0.71-1.00, respectively, and the specificity was 1.00 (CI: 0.93-1.00), 0.88 (CI: 0.75-0.95), and 0.98 (CI: 0.89-1.00), respectively. Heterozygously G6PD-deficient females with a larger percentage of G6PD-sufficient RBCs are missed by routine methods measuring total G6PD activity. However, the majority of these females can be detected with both chromate inhibition and cytofluorometry.

  14. Improved motor performance in Dyt1 ΔGAG heterozygous knock-in mice by cerebellar Purkinje-cell specific Dyt1 conditional knocking-out.

    PubMed

    Yokoi, Fumiaki; Dang, Mai Tu; Li, Yuqing

    2012-05-01

    Early-onset generalized torsion dystonia (dystonia 1) is an inherited movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Most patients have a 3-base pair deletion (ΔGAG) in one allele of DYT1, corresponding to a loss of a glutamic acid residue (ΔE) in the C-terminal region of the protein. Functional alterations in basal ganglia circuits and the cerebellum have been reported in dystonia. Pharmacological manipulations or mutations in genes that result in functional alterations of the cerebellum have been reported to have dystonic symptoms and have been used as phenotypic rodent models. Additionally, structural lesions in the abnormal cerebellar circuits, such as cerebellectomy, have therapeutic effects in these models. A previous study has shown that the Dyt1 ΔGAG heterozygous knock-in (KI) mice exhibit motor deficits in the beam-walking test. Both Dyt1 ΔGAG heterozygous knock-in (KI) and Dyt1 Purkinje cell-specific knockout (Dyt1 pKO) mice exhibit dendritic alterations of cerebellar Purkinje cells. Here, Dyt1 pKO mice exhibited significantly less slip numbers in the beam-walking test, suggesting better motor performance than control littermates, and normal gait. Furthermore, Dyt1 ΔGAG KI/Dyt1 pKO double mutant mice exhibited significantly lower numbers of slips than Dyt1 ΔGAG heterozygous KI mice, suggesting Purkinje-cell specific knockout of Dyt1 wild-type (WT) allele in Dyt1 ΔGAG heterozygous KI mice rescued the motor deficits. The results suggest that molecular lesions of torsinA in Purkinje cells by gene therapy or intervening in the signaling pathway downstream of the cerebellar Purkinje cells may rescue motor symptoms in dystonia 1. Copyright © 2012 Elsevier B.V. All rights reserved.

  15. Improved motor performance in Dyt1 ΔGAG heterozygous knock-in mice by cerebellar Purkinje-cell specific Dyt1 conditional knocking-out

    PubMed Central

    Yokoi, Fumiaki; Dang, Mai Tu; Li, Yuqing

    2012-01-01

    Early-onset generalized torsion dystonia (dystonia 1) is an inherited movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Most patients have a 3-base pair deletion (ΔGAG) in one allele of DYT1, corresponding to a loss of a glutamic acid residue (ΔE) in the C-terminal region of the protein. Functional alterations in basal ganglia circuits and the cerebellum have been reported in dystonia. Pharmacological manipulations or mutations in genes that result in functional alterations of the cerebellum have been reported to have dystonic symptoms and have been used as phenotypic rodent models. Additionally, structural lesions in the abnormal cerebellar circuits, such as cerebellectomy, have therapeutic effects in these models. A previous study has shown that the Dyt1 ΔGAG heterozygous knock-in (KI) mice exhibit motor deficits in the beam-walking test. Both Dyt1 ΔGAG heterozygous knock-in (KI) and Dyt1 Purkinje cell-specific knockout (Dyt1 pKO) mice exhibit dendritic alterations of cerebellar Purkinje cells. Here, Dyt1 pKO mice exhibited significantly less slip numbers in the beam-walking test, suggesting better motor performance than control littermates, and normal gait. Furthermore, Dyt1 ΔGAG KI/Dyt1 pKO double mutant mice exhibited significantly lower numbers of slips than Dyt1 ΔGAG heterozygous KI mice, suggesting Purkinje-cell specific knockout of Dyt1 wild-type (WT) allele in Dyt1 ΔGAG heterozygous KI mice rescued the motor deficits. The results suggest that molecular lesions of torsinA in Purkinje cells by gene therapy or intervening in the signaling pathway downstream of the cerebellar Purkinje cells may rescue motor symptoms in dystonia 1. PMID:22391119

  16. Atp1a3-deficient heterozygous mice show lower rank in the hierarchy and altered social behavior.

    PubMed

    Sugimoto, H; Ikeda, K; Kawakami, K

    2018-06-01

    Atp1a3 is the Na-pump alpha3 subunit gene expressed mainly in neurons of the brain. Atp1a3-deficient heterozygous mice (Atp1a3 +/- ) show altered neurotransmission and deficits of motor function after stress loading. To understand the function of Atp1a3 in a social hierarchy, we evaluated social behaviors (social interaction, aggression, social approach and social dominance) of Atp1a3 +/- and compared the rank and hierarchy structure between Atp1a3 +/- and wild-type mice within a housing cage using the round-robin tube test and barbering observations. Formation of a hierarchy decreases social conflict and promote social stability within the group. The hierarchical rank is a reflection of social dominance within a cage, which is heritable and can be regulated by specific genes in mice. Here we report: (1) The degree of social interaction but not aggression was lower in Atp1a3 +/- than wild-type mice, and Atp1a3 +/- approached Atp1a3 +/- mice more frequently than wild type. (2) The frequency of barbering was lower in the Atp1a3 +/- group than in the wild-type group, while no difference was observed in the mixed-genotype housing condition. (3) Hierarchy formation was not different between Atp1a3 +/- and wild type. (4) Atp1a3 +/- showed a lower rank in the mixed-genotype housing condition than that in the wild type, indicating that Atp1a3 regulates social dominance. In sum, Atp1a3 +/- showed unique social behavior characteristics of lower social interaction and preference to approach the same genotype mice and a lower ranking in the hierarchy. © 2017 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  17. Molecular Pathogenesis of EBV Susceptibility in XLP as Revealed by Analysis of Female Carriers with Heterozygous Expression of SAP

    PubMed Central

    Palendira, Umaimainthan; Low, Carol; Chan, Anna; Hislop, Andrew D.; Ho, Edwin; Phan, Tri Giang; Deenick, Elissa; Cook, Matthew C.; Riminton, D. Sean; Choo, Sharon; Loh, Richard; Alvaro, Frank; Booth, Claire; Gaspar, H. Bobby; Moretta, Alessandro; Khanna, Rajiv; Rickinson, Alan B.; Tangye, Stuart G.

    2011-01-01

    X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency caused by mutations in SH2D1A which encodes SAP. SAP functions in signalling pathways elicited by the SLAM family of leukocyte receptors. A defining feature of XLP is exquisite sensitivity to infection with EBV, a B-lymphotropic virus, but not other viruses. Although previous studies have identified defects in lymphocytes from XLP patients, the unique role of SAP in controlling EBV infection remains unresolved. We describe a novel approach to this question using female XLP carriers who, due to random X-inactivation, contain both SAP+ and SAP− cells. This represents the human equivalent of a mixed bone marrow chimera in mice. While memory CD8+ T cells specific for CMV and influenza were distributed across SAP+ and SAP− populations, EBV-specific cells were exclusively SAP+. The preferential recruitment of SAP+ cells by EBV reflected the tropism of EBV for B cells, and the requirement for SAP expression in CD8+ T cells for them to respond to Ag-presentation by B cells, but not other cell types. The inability of SAP− clones to respond to Ag-presenting B cells was overcome by blocking the SLAM receptors NTB-A and 2B4, while ectopic expression of NTB-A on fibroblasts inhibited cytotoxicity of SAP− CD8+ T cells, thereby demonstrating that SLAM receptors acquire inhibitory function in the absence of SAP. The innovative XLP carrier model allowed us to unravel the mechanisms underlying the unique susceptibility of XLP patients to EBV infection in the absence of a relevant animal model. We found that this reflected the nature of the Ag-presenting cell, rather than EBV itself. Our data also identified a pathological signalling pathway that could be targeted to treat patients with severe EBV infection. This system may allow the study of other human diseases where heterozygous gene expression from random X-chromosome inactivation can be exploited. PMID:22069374

  18. Viable phenotype of ILNEB syndrome without nephrotic impairment in siblings heterozygous for unreported integrin alpha3 mutations.

    PubMed

    Colombo, Elisa Adele; Spaccini, Luigina; Volpi, Ludovica; Negri, Gloria; Cittaro, Davide; Lazarevic, Dejan; Zirpoli, Salvatore; Farolfi, Andrea; Gervasini, Cristina; Cubellis, Maria Vittoria; Larizza, Lidia

    2016-10-07

    Integrin α3 (ITGA3) gene mutations are associated with Interstitial Lung disease, Nephrotic syndrome and Epidermolysis bullosa (ILNEB syndrome). To date only six patients are reported: all carried homozygous ITGA3 mutations and presented a dramatically severe phenotype leading to death before age 2 years, from multi-organ failure due to interstitial lung disease and congenital nephrotic syndrome. The involvement of skin and cutaneous adnexa was variable with sparse hair and nail dysplasia combined or not to skin lesions ranging from skin fragility to epidermolysis bullosa-like blistering. We report on two siblings of 13 and 9 years born to non-consanguineous healthy parents, who display growth delay, severe pulmonary fibrosis with fatigue, dyspnea on exertion and wheezing, atrophic skin with erythematosus lesions, rare eyelashes/eyebrows and pachyonychia. By exome sequencing, we identified two unreported ITGA3 missense mutations, c.373G>A (p.(G125R)) in exon 3 and c.821G>A (p.(R274Q)) in exon 6, affecting highly conserved residues in the integrin α3 extracellular N-terminal β-propeller domain. Homology modelling of α3β1 heterodimer fragment, encompassing the mutation sites, showed that G125 plays a pivotal structural role in the β-propeller, while R274 might prevent the interaction between integrin and urokinase complex. We report a variant of ILNEB syndrome in two siblings differing from the previously reported patients in the lack of nephrotic impairment and survival beyond childhood. Our siblings are the first reported compound heterozygous for ITGA3 mutations; this state as well as the hypomorphic nature of their p.(R274Q) mutation likely account for their survival.

  19. Three cases of congenital dysfibrinogenemia in unrelated Chinese families: heterozygous missense mutation in fibrinogen alpha chain Argl6His

    PubMed Central

    Luo, Meiling; Deng, Donghong; Xiang, Liqun; Cheng, Peng; Liao, Lin; Deng, Xuelian; Yan, Jie; Lin, Faquan

    2016-01-01

    Abstract Congenital dysfibrinogenemia (CD) is a qualitative fibrinogen disorder caused by an abnormal fibrinogen molecule structure, leading to dysfunctional blood coagulation. This study describes 3 cases of dysfibrinogenemia identified in the unrelated Chinese pedigrees. Routine coagulation screening tests were performed on the probands and their families. The antigens and functionality of fibrinogen was measured using an immunoturbidimetry assay and the Clauss method, respectively. To identify the genetic mutation responsible for these dysfibrinogens, genomic DNA extracted from the blood was analyzed using PCR amplification and direct sequencing. The presence of the mutant chains was determined using matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectroscopy. Purified plasma fibrinogen of 3 probands was analyzed using SDS–PAGE, fibrinogen clottability, fibrin polymerization, fibrinopeptide release, and scanning electron microscopy (SEM). The 3 probands had a long thrombin time. Levels of functional fibrinogen were found to be very low, while the fibrinogen antigen was within the normal range. DNA sequencing revealed a heterozygous Arg16His substitution in the fibrinogen Aα chain (FGA). The mutant chains were found to be expressed using MALDI-TOF mass spectroscopy. SDS–PAGE did not reveal any difference in the molecular weights of 3 polypeptide chains between normal and abnormal fibrinogens. Fibrinogen clottability showed a slower fibrin clot formation than the healthy control. Fibrin polymerization, after addition of thrombin, showed a prolonged lag phase and decreased final turbidity. The kinetics of fibrinopeptides release revealed a decreased amount of the released fibrinopeptide A. SEM of the patient's fibrin clot was found to be abnormal. Results indicate that the 3 probands with dysfibrinogenemia were caused by mutations of Aα chain Arg16His. Mutation of this fibrinogen induced dysfunction of plasma fibrinogen. PMID

  20. Anxiety, depression, and health-related quality of life in heterozygous familial hypercholesterolemia: A systematic review and meta-analysis.

    PubMed

    Akioyamen, Leo E; Genest, Jacques; Shan, Shubham D; Inibhunu, Happy; Chu, Anna; Tu, Jack V

    2018-06-01

    Heterozygous familial hypercholesterolemia (FH) is a common genetic disease predisposing affected individuals to a high risk of cardiovascular disease. Yet, considerable uncertainty exists regarding its impact on psychosocial wellbeing. We performed a systematic review and meta-analysis of the association between FH and symptoms of anxiety and depression, and health-related quality of life (HRQL). We searched MEDLINE, EMBASE, Global Health, the Cochrane Library, PsycINFO, and PubMed for peer-reviewed literature published in English between January 1, 1990 and January 1, 2018. Quantitative and qualitative studies were eligible if they included patients with confirmed FH and evaluated its association with symptoms of anxiety or depression, or HRQL. We performed a narrative synthesis of studies, including thematic analysis of qualitative studies, and where data permitted, random-effects meta-analysis reporting standardized mean differences (SMD) and 95% confidence intervals. We found 10 eligible studies measuring HRQL, depression and anxiety. Random-effects meta-analysis of 4 (n = 4293) and 5 studies (n = 5098), respectively, showed that patients with FH had slightly lower symptoms of anxiety (SMD: -0.29 [95% CI: -0.53, -0.04]) and mental HRQL (SMD: -0.10 [95% -0.20, -0.00]) relative to general population controls. No significant differences existed in depressive symptoms (SMD: 0.04 [95% CI: -0.12, 0.19]) or physical HRQL scores (SMD: 0.02 [95% CI: -0.09, 0.12]). Our systematic review suggests that patients with FH may report small but measurable differences in anxiety symptoms and mental HRQL. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. Placental Glucose and Amino Acid Transport in Calorie-Restricted Wild-Type and Glut3 Null Heterozygous Mice

    PubMed Central

    Ganguly, Amit; Collis, Laura

    2012-01-01

    Calorie restriction (CR) decreased placenta and fetal weights in wild-type (wt) and glucose transporter (Glut) 3 heterozygous null (glut3+/−) mice. Because placental nutrient transport is a primary energy determinant of placentofetal growth, we examined key transport systems. Maternal CR reduced intra- and transplacental glucose and leucine transport but enhanced system A amino acid transport in wt mice. These transport perturbations were accompanied by reduced placental Glut3 and leucine amino acid transporter (LAT) family member 2, no change in Glut1 and LAT family member 1, but increased sodium coupled neutral amino acid transporter (SNAT) and SNAT2 expression. We also noted decreased total and active phosphorylated forms of mammalian target of rapamycin, which is the intracellular nutrient sensor, the downstream total P70S6 kinase, and pS6 ribosomal protein with no change in total and phosphorylated 4E-binding protein 1. To determine the role of placental Glut3 in mediating CR-induced placental transport changes, we next investigated the effect of gestational CR in glut3+/− mice. In glut3+/− mice, a key role of placental Glut3 in mediating transplacental and intraplacental glucose transport was established. In addition, reduced Glut3 results in a compensatory increase of leucine and system A transplacental transport. On the other hand, diminished Glut3-mediated intraplacental glucose transport reduced leucine transport and mammalian target of rapamycin and preserved LAT and enhancing SNAT. CR in glut3+/− mice further reduced transplacental glucose transport and enhanced system A amino acid transport, although the increased leucine transport was lost. In addition, increased Glut3 was seen and preserved Glut1, LAT, and SNAT. These placental changes collectively protect survival of wt and glut3+/− fetuses against maternal CR-imposed reduction of macromolecular nutrients. PMID:22700768

  2. Placental glucose and amino acid transport in calorie-restricted wild-type and Glut3 null heterozygous mice.

    PubMed

    Ganguly, Amit; Collis, Laura; Devaskar, Sherin U

    2012-08-01

    Calorie restriction (CR) decreased placenta and fetal weights in wild-type (wt) and glucose transporter (Glut) 3 heterozygous null (glut3(+/-)) mice. Because placental nutrient transport is a primary energy determinant of placentofetal growth, we examined key transport systems. Maternal CR reduced intra- and transplacental glucose and leucine transport but enhanced system A amino acid transport in wt mice. These transport perturbations were accompanied by reduced placental Glut3 and leucine amino acid transporter (LAT) family member 2, no change in Glut1 and LAT family member 1, but increased sodium coupled neutral amino acid transporter (SNAT) and SNAT2 expression. We also noted decreased total and active phosphorylated forms of mammalian target of rapamycin, which is the intracellular nutrient sensor, the downstream total P70S6 kinase, and pS6 ribosomal protein with no change in total and phosphorylated 4E-binding protein 1. To determine the role of placental Glut3 in mediating CR-induced placental transport changes, we next investigated the effect of gestational CR in glut3(+/-) mice. In glut3(+/-) mice, a key role of placental Glut3 in mediating transplacental and intraplacental glucose transport was established. In addition, reduced Glut3 results in a compensatory increase of leucine and system A transplacental transport. On the other hand, diminished Glut3-mediated intraplacental glucose transport reduced leucine transport and mammalian target of rapamycin and preserved LAT and enhancing SNAT. CR in glut3(+/-) mice further reduced transplacental glucose transport and enhanced system A amino acid transport, although the increased leucine transport was lost. In addition, increased Glut3 was seen and preserved Glut1, LAT, and SNAT. These placental changes collectively protect survival of wt and glut3(+/-) fetuses against maternal CR-imposed reduction of macromolecular nutrients.

  3. Loss of corticostriatal and thalamostriatal synaptic terminals precedes striatal projection neuron pathology in heterozygous Q140 Huntington's disease mice.

    PubMed

    Deng, Y P; Wong, T; Bricker-Anthony, C; Deng, B; Reiner, A

    2013-12-01

    Motor slowing, forebrain white matter loss, and striatal shrinkage have been reported in premanifest Huntington's disease (HD) prior to overt striatal neuron loss. We carried out detailed LM and EM studies in a genetically precise HD mimic, heterozygous Q140 HD knock-in mice, to examine the possibility that loss of corticostriatal and thalamostriatal terminals prior to striatal neuron loss underlies these premanifest HD abnormalities. In our studies, we used VGLUT1 and VGLUT2 immunolabeling to detect corticostriatal and thalamostriatal (respectively) terminals in dorsolateral (motor) striatum over the first year of life, prior to striatal projection neuron pathology. VGLUT1+ axospinous corticostriatal terminals represented about 55% of all excitatory terminals in striatum, and VGLUT2+ axospinous thalamostriatal terminals represented about 35%, with VGLUT1+ and VGLUT2+ axodendritic terminals accounting for the remainder. In Q140 mice, a significant 40% shortfall in VGLUT2+ axodendritic thalamostriatal terminals and a 20% shortfall in axospinous thalamostriatal terminals were already observed at 1 month of age, but VGLUT1+ terminals were normal in abundance. The 20% deficiency in VGLUT2+ thalamostriatal axospinous terminals persisted at 4 and 12 months in Q140 mice, and an additional 30% loss of VGLUT1+ corticostriatal terminals was observed at 12 months. The early and persistent deficiency in thalamostriatal axospinous terminals in Q140 mice may reflect a development defect, and the impoverishment of this excitatory drive to striatum may help explain early motor defects in Q140 mice and in premanifest HD. The loss of corticostriatal terminals at 1 year in Q140 mice is consistent with prior evidence from other mouse models of corticostriatal disconnection early during progression, and can explain both the measurable bradykinesia and striatal white matter loss in late premanifest HD. © 2013.

  4. Further delineation of COG8-CDG: A case with novel compound heterozygous mutations diagnosed by targeted exome sequencing.

    PubMed

    Yang, Aram; Cho, Sung Yoon; Jang, Ja-Hyun; Kim, Jinsup; Kim, Sook Za; Lee, Beom Hee; Yoo, Han-Wook; Jin, Dong-Kyu

    2017-08-01

    Congenital disorders of glycosylation (CDG) are a rapidly expanding group of inherited metabolic disorders with highly variable clinical presentations caused by deficient glycosylation of proteins and/or lipids. CDG-IIh is a very rare subgroup of CDG caused by mutations in the conserved oligomeric Golgi (COG) complex gene, COG8, and so far, only two cases have been reported in the medical literature. Here, we describe an 8-year-old Korean boy with psychomotor retardation, hypotonia, failure to thrive, elevated serum liver enzymes, microcephaly, and talipes equinovarus. A liver biopsy of the patient showed only interface hepatitis with mild lobular activity, and brain magnetic resonance imaging revealed cerebellar atrophy. Compared with the previous two reported cases, our patient showed relatively mild psychomotor retardation without a seizure history. The transferrin isoelectric focusing profiles in the patient showed a CDG type II pattern with increased disialo- and trisialo-transferrin. Targeted exome sequencing was performed to screen all CDG type II-related genes, and two novel frameshift mutations were found: c.171dupG (p.Leu58Alafs*29) and c.1656dupC (p.Ala553Argfs*15) in COG8. The parents were heterozygous carriers of each variant. CDG should be included in the initial differential diagnosis for children with a suspected unknown syndrome or unclassified inherited metabolic disorder or children with diverse clinical presentations, such as psychomotor retardation, hypotonia, skeletal deformity, microcephaly, cerebellar atrophy, and unexplained transient elevated liver enzyme. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Severe Early-Onset Combined Immunodeficiency due to Heterozygous Gain-of-Function Mutations in STAT1.

    PubMed

    Baris, Safa; Alroqi, Fayhan; Kiykim, Ayca; Karakoc-Aydiner, Elif; Ogulur, Ismail; Ozen, Ahmet; Charbonnier, Louis-Marie; Bakır, Mustafa; Boztug, Kaan; Chatila, Talal A; Barlan, Isil B

    2016-10-01

    Loss and gain-of-function (GOF) mutations in human signal transducer and activator of transcription 1 (STAT1) lead to distinct phenotypes. Although recurrent infections are common to both types of STAT1 mutations, GOF mutations are distinguished by chronic mucocutaneous candidiasis and autoimmunity. However, the clinical spectra of STAT1 GOF mutations continue to expand. We here describe two patients with STAT1 GOF mutations presenting early in life with combined immunodeficiency (CID). Clinical data and laboratory findings including immunophenotyping, level of interferon (IFN)-γ/IL-17(+) T cells, interferon-induced STAT1 phosphorylation, and JAK inhibitor assays were evaluated. Sequencing of STAT1 gene was performed by Sanger sequencer. Patient 1 (P1) had persistent oral candidiasis and cytomegalovirus (CMV) infection since 2 months of age and later developed cavitary lung lesions due to Mycobacterium tuberculosis. Patient 2 (P2) presented with oral candidiasis and recurrent pneumonia at 4 months of age and subsequently developed CMV pneumonitis. Both patients suffered heterozygous missense mutations in STAT1, leading to deleterious amino acid substitutions in the DNA binding domain (P1: c.1154C > T; p.T385M; P2. c.971G > T; p.C324F). Circulating CD4(+) T cells of both patients exhibited increased interferon-γ and decreased IL-17 expression as compared to controls. They also exhibited increased IFN-β and -γ-induced STAT1 phosphorylation that was reversed upon treatment with the JAK kinase inhibitor ruxolitinib. STAT1 GOF mutations may present early in life with CID, consistent with the clinical heterogeneity of the disease. JAK kinase inhibitors may potentially be useful in some patients as adjunct therapy pending definitive treatment with bone marrow transplantation.

  6. A case report of heterozygous TINF2 gene mutation associated with pulmonary fibrosis in a patient with dyskeratosis congenita.

    PubMed

    Du, Hongchun; Guo, Yubiao; Ma, Di; Tang, Kejing; Cai, Decheng; Luo, Yifeng; Xie, Canmao

    2018-05-01

    Dyskeratosis congenita (DC) is a rare inherited disease characterized by the classical mucocutaneous triad. Pulmonary fibrosis, bone marrow failure, and solid tumors are the main causes of mortality in DC. Pathogenic variants in TERT, TERC, and DKC1 have been identified in individuals with familial pulmonary fibrosis. Mutations in TINF2 gene have been reported to be associated with bone marrow failure in most cases. However, the relationship between TINF2 mutation and pulmonary fibrosis is not yet clear. Here, we report the case of a 32-year-old woman presented with irritating cough for 2 years and progressive breathlessness for 6 months. The patient was diagnosed with DC based on the following clinical evidences. Along with some family members, she had the typical mucocutaneous triad and pulmonary fibrosis. A heterozygous mutation (c.844C>T), located in exon 6 of TINF2 gene, that changed arginine to cysteine (Arg282Cys) was identified in this proband by whole exome sequencing. The patient received corticosteroid therapy but refused to receive lung transplantation. The proband died of respiratory failure 4 months after the diagnosis. The missense mutation was located in the conserved region of TINF2 gene and predicted to be deleterious by altering the protein structure. Lung transplantation should be considered for improved survival of patients with DC, and pulmonary fibrosis. Whole exome and whole genome sequencing should be widely used in the identification of such rare genetic variants for clinical diagnosis. The study of DC with pulmonary fibrosis can provide a more appropriate means of clinical research and therapy to the unfortunate patients who suffer from this rare disorder.

  7. A heterozygous IDH1R132H/WT mutation induces genome-wide alterations in DNA methylation.

    PubMed

    Duncan, Christopher G; Barwick, Benjamin G; Jin, Genglin; Rago, Carlo; Kapoor-Vazirani, Priya; Powell, Doris R; Chi, Jen-Tsan; Bigner, Darell D; Vertino, Paula M; Yan, Hai

    2012-12-01

    Monoallelic point mutations of the NADP(+)-dependent isocitrate dehydrogenases IDH1 and IDH2 occur frequently in gliomas, acute myeloid leukemias, and chondromas, and display robust association with specific DNA hypermethylation signatures. Here we show that heterozygous expression of the IDH1(R132H) allele is sufficient to induce the genome-wide alterations in DNA methylation characteristic of these tumors. Using a gene-targeting approach, we knocked-in a single copy of the most frequently observed IDH1 mutation, R132H, into a human cancer cell line and profiled changes in DNA methylation at over 27,000 CpG dinucleotides relative to wild-type parental cells. We find that IDH1(R132H/WT) mutation induces widespread alterations in DNA methylation, including hypermethylation of 2010 and hypomethylation of 842 CpG loci. We demonstrate that many of these alterations are consistent with those observed in IDH1-mutant and G-CIMP+ primary gliomas and can segregate IDH wild-type and mutated tumors as well as those exhibiting the G-CIMP phenotype in unsupervised analysis of two primary glioma cohorts. Further, we show that the direction of IDH1(R132H/WT)-mediated DNA methylation change is largely dependent upon preexisting DNA methylation levels, resulting in depletion of moderately methylated loci. Additionally, whereas the levels of multiple histone H3 and H4 methylation modifications were globally increased, consistent with broad inhibition of histone demethylation, hypermethylation at H3K9 in particular accompanied locus-specific DNA hypermethylation at several genes down-regulated in IDH1(R132H/WT) knock-in cells. These data provide insight on epigenetic alterations induced by IDH1 mutations and support a causal role for IDH1(R132H/WT) mutants in driving epigenetic instability in human cancer cells.

  8. Heterozygous Ambra1 Deficiency in Mice: A Genetic Trait with Autism-Like Behavior Restricted to the Female Gender

    PubMed Central

    Dere, Ekrem; Dahm, Liane; Lu, Derek; Hammerschmidt, Kurt; Ju, Anes; Tantra, Martesa; Kästner, Anne; Chowdhury, Kamal; Ehrenreich, Hannelore

    2014-01-01

    Autism-spectrum disorders (ASD) are heterogeneous, highly heritable neurodevelopmental conditions affecting around 0.5% of the population across cultures, with a male/female ratio of approximately 4:1. Phenotypically, ASD are characterized by social interaction and communication deficits, restricted interests, repetitive behaviors, and reduced cognitive flexibility. Identified causes converge at the level of the synapse, ranging from mutation of synaptic genes to quantitative alterations in synaptic protein expression, e.g., through compromised transcriptional or translational control. We wondered whether reduced turnover and degradation of synapses, due to deregulated autophagy, would lead to similar phenotypical consequences. Ambra1, strongly expressed in cortex, hippocampus, and striatum, is a positive regulator of Beclin1, a principal player in autophagosome formation. While homozygosity of the Ambra1 null mutation causes embryonic lethality, heterozygous mice with reduced Ambra1 expression are viable, reproduce normally, and lack any immediately obvious phenotype. Surprisingly, comprehensive behavioral characterization of these mice revealed an autism-like phenotype in Ambra1+/− females only, including compromised communication and social interactions, a tendency of enhanced stereotypies/repetitive behaviors, and impaired cognitive flexibility. Reduced ultrasound communication was found in adults as well as pups, which achieved otherwise normal neurodevelopmental milestones. These features were all absent in male Ambra1+/− mice. As a first hint explaining this gender difference, we found a much stronger reduction of Ambra1 protein in the cortex of Ambra1+/− females compared to males. To conclude, Ambra1 deficiency can induce an autism-like phenotype. The restriction to the female gender of autism-generation by a defined genetic trait is unique thus far and warrants further investigation. PMID:24904333

  9. Heterozygous ambra1 deficiency in mice: a genetic trait with autism-like behavior restricted to the female gender.

    PubMed

    Dere, Ekrem; Dahm, Liane; Lu, Derek; Hammerschmidt, Kurt; Ju, Anes; Tantra, Martesa; Kästner, Anne; Chowdhury, Kamal; Ehrenreich, Hannelore

    2014-01-01

    Autism-spectrum disorders (ASD) are heterogeneous, highly heritable neurodevelopmental conditions affecting around 0.5% of the population across cultures, with a male/female ratio of approximately 4:1. Phenotypically, ASD are characterized by social interaction and communication deficits, restricted interests, repetitive behaviors, and reduced cognitive flexibility. Identified causes converge at the level of the synapse, ranging from mutation of synaptic genes to quantitative alterations in synaptic protein expression, e.g., through compromised transcriptional or translational control. We wondered whether reduced turnover and degradation of synapses, due to deregulated autophagy, would lead to similar phenotypical consequences. Ambra1, strongly expressed in cortex, hippocampus, and striatum, is a positive regulator of Beclin1, a principal player in autophagosome formation. While homozygosity of the Ambra1 null mutation causes embryonic lethality, heterozygous mice with reduced Ambra1 expression are viable, reproduce normally, and lack any immediately obvious phenotype. Surprisingly, comprehensive behavioral characterization of these mice revealed an autism-like phenotype in Ambra1 (+/-) females only, including compromised communication and social interactions, a tendency of enhanced stereotypies/repetitive behaviors, and impaired cognitive flexibility. Reduced ultrasound communication was found in adults as well as pups, which achieved otherwise normal neurodevelopmental milestones. These features were all absent in male Ambra1 (+/-) mice. As a first hint explaining this gender difference, we found a much stronger reduction of Ambra1 protein in the cortex of Ambra1 (+/-) females compared to males. To conclude, Ambra1 deficiency can induce an autism-like phenotype. The restriction to the female gender of autism-generation by a defined genetic trait is unique thus far and warrants further investigation.

  10. Probing the Effect of Two Heterozygous Mutations in Codon 723 of SLC26A4 on Deafness Phenotype Based on Molecular Dynamics Simulations.

    PubMed

    Yao, Jun; Qian, Xuli; Bao, Jingxiao; Wei, Qinjun; Lu, Yajie; Zheng, Heng; Cao, Xin; Xing, Guangqian

    2015-06-02

    A Chinese family was identified with clinical features of enlarged vestibular aqueduct syndrome (EVAS). The mutational analysis showed that the proband (III-2) had EVAS with bilateral sensorineural hearing loss and carried a rare compound heterozygous mutation of SLC26A4 (IVS7-2A>G, c.2167C>G), which was inherited from the same mutant alleles of IVS7-2A>G heterozygous father and c.2167C>G heterozygous mother. Compared with another confirmed pathogenic biallelic mutation in SLC26A4 (IVS7-2A>G, c.2168A>G), these two biallelic mutations shared one common mutant allele and the same codon of the other mutant allele, but led to different changes of amino acid (p.H723D, p.H723R) and both resulted in the deafness phenotype. Structure-modeling indicated that these two mutant alleles changed the shape of pendrin protein encoded by SLC26A4 with increasing randomness in conformation, and might impair pendrin's ability as an anion transporter. The molecular dynamics simulations also revealed that the stability of mutant pendrins was reduced with increased flexibility of backbone atoms, which was consistent with the structure-modeling results. These evidences indicated that codon 723 was a hot-spot region in SLC26A4 with a significant impact on the structure and function of pendrin, and acted as one of the genetic factors responsible for the development of hearing loss.

  11. Waardenburg syndrome type 3 (Klein-Waardenburg syndrome) segregating with a heterozygous deletion in the paired box domain of PAX3: a simple variant or a true syndrome?

    PubMed

    Tekin, M; Bodurtha, J N; Nance, W E; Pandya, A

    2001-10-01

    Klein-Waardenburg syndrome or Waardenburg syndrome type 3 (WS-III; MIM 148820) is characterized by the presence of musculoskeletal abnormalities in association with clinical features of Waardenburg syndrome type 1 (WS-I). Since the description of the first patient in 1947 (D. Klein, Arch Klaus Stift Vererb Forsch 1947: 22: 336-342), a few cases have been reported. Only occasional families have demonstrated autosomal-dominant inheritance of WS-III. In a previous report, a missense mutation in the paired domain of the PAX3 gene has been described in a family with dominant segregation of WS-III. In this report, we present a second family (mother and son) with typical clinical findings of WS-III segregating with a heterozygous 13-bp deletion in the paired domain of the PAX3 gene. Although homozygosity or compound heterozygosity has also been documented in patients with severe limb involvement, a consistent genotype-phenotype correlation for limb abnormalities associated with heterozygous PAX3 mutations has not previously been apparent. Heterozygous mutations could either reflect a unique dominant-negative effect or possibly the contribution of other unlinked genetic modifiers in determining the phenotype.

  12. Comparative analyses of lung transcriptomes in patients with alveolar capillary dysplasia with misalignment of pulmonary veins and in foxf1 heterozygous knockout mice.

    PubMed

    Sen, Partha; Dharmadhikari, Avinash V; Majewski, Tadeusz; Mohammad, Mahmoud A; Kalin, Tanya V; Zabielska, Joanna; Ren, Xiaomeng; Bray, Molly; Brown, Hannah M; Welty, Stephen; Thevananther, Sundararajah; Langston, Claire; Szafranski, Przemyslaw; Justice, Monica J; Kalinichenko, Vladimir V; Gambin, Anna; Belmont, John; Stankiewicz, Pawel

    2014-01-01

    Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV) is a developmental disorder of the lungs, primarily affecting their vasculature. FOXF1 haploinsufficiency due to heterozygous genomic deletions and point mutations have been reported in most patients with ACDMPV. The majority of mice with heterozygous loss-of-function of Foxf1 exhibit neonatal lethality with evidence of pulmonary hemorrhage in some of them. By comparing transcriptomes of human ACDMPV lungs with control lungs using expression arrays, we found that several genes and pathways involved in lung development, angiogenesis, and in pulmonary hypertension development, were deregulated. Similar transcriptional changes were found in lungs of the postnatal day 0.5 Foxf1+/- mice when compared to their wildtype littermate controls; 14 genes, COL15A1, COL18A1, COL6A2, ESM1, FSCN1, GRINA, IGFBP3, IL1B, MALL, NOS3, RASL11B, MATN2, PRKCDBP, and SIRPA, were found common to both ACDMPV and Foxf1 heterozygous lungs. Our results advance knowledge toward understanding of the molecular mechanism of ACDMPV, lung development, and its vasculature pathology. These data may also be useful for understanding etiologies of other lung disorders, e.g. pulmonary hypertension, bronchopulmonary dysplasia, or cancer.

  13. G6PD/PK ratio: a reliable parameter to identify glucose-6-phosphate dehydrogenase deficiency associated with microcytic anemia in heterozygous subjects.

    PubMed

    Tagarelli, Antonio; Piro, Anna; Tagarelli, Giuseppe; Bastone, Loredana; Paleari, Renata; Mosca, Andrea

    2004-10-01

    To determine if measuring the ratio of glucose-6-phosphate dehydrogenase (G6PD) to pyruvate kinase (PK) is more reliable than only measuring G6PD activity to identify heterozygous G6PD- individuals with associated microcytic anemia in the Calabrian population, which shows high frequencies of both the thalassaemia (thal) trait and G6PD deficiency. Measurement of G6PD and PK activities was carried out on 205 samples of whole blood from Calabrian subjects of both sexes (age range 10-50 years) using a double starter differential pH-metry technique. The G6PD/PK ratio is able to differentiate G6PD- heterozygous individuals from the normal population. G6PD/PK values also allowed us to easily identify the G6PD- heterozygous subjects with microcytic anaemia. Student's t test shows that G6PD/PK ratio is more reliable in both sample groups, relative to G6PD activity in normal subjects. G6PD/PK ratio is a reliable diagnostic parameter for mass screening for G6PD deficiency.

  14. Disruption of NBS1 gene leads to early embryonic lethality in homozygous null mice and induces specific cancer in heterozygous mice

    SciTech Connect

    Kurimasa, Akihiro; Burma, Sandeep; Henrie, Melinda

    2002-04-15

    Nijmegen breakage syndrome (NBS) is a rare autosomal recessive chromosome instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition, with cellular features similar to that of ataxia telangiectasia (AT). NBS results from mutations in the mammalian gene Nbs1 that codes for a 95-kDa protein called nibrin, NBS1, or p95. To establish an animal model for NBS, we attempted to generate NBS1 knockout mice. However, NBS1 gene knockouts were lethal at an early embryonic stage. NBS1 homozygous(-/-) blastocyst cells cultured in vitro showed retarded growth and subsequently underwent growth arrest within 5 days of culture. Apoptosis, assayed by TUNELmore » staining, was observed in NBSI homozygous(-/-) blastocyst cells cultured for four days. NBSI heterozygous(+/-) mice were normal, and exhibited no specific phenotype for at least one year. However, fibroblast cells from NBSI heterozygous(+/-) mice displayed an enhanced frequency of spontaneous transformation to anchorage-independent growth as compared to NBS1 wild-type(+/+) cells. Furthermore, heterozygous(+/-) mice exhibited a high incidence of hepatocellular carcinoma after one year compared to wild-type mice, even though no significant differences in the incidence of other tumors such as lung adenocarcinoma and lymphoma were observed. Taken together, these results strongly suggest that NBS1 heterozygosity and reduced NBSI expression induces formation of specific tumors in mice.« less

  15. High-resolution melting (HRM) re-analysis of a polyposis patients cohort reveals previously undetected heterozygous and mosaic APC gene mutations.

    PubMed

    Out, Astrid A; van Minderhout, Ivonne J H M; van der Stoep, Nienke; van Bommel, Lysette S R; Kluijt, Irma; Aalfs, Cora; Voorendt, Marsha; Vossen, Rolf H A M; Nielsen, Maartje; Vasen, Hans F A; Morreau, Hans; Devilee, Peter; Tops, Carli M J; Hes, Frederik J

    2015-06-01

    Familial adenomatous polyposis is most frequently caused by pathogenic variants in either the APC gene or the MUTYH gene. The detection rate of pathogenic variants depends on the severity of the phenotype and sensitivity of the screening method, including sensitivity for mosaic variants. For 171 patients with multiple colorectal polyps without previously detectable pathogenic variant, APC was reanalyzed in leukocyte DNA by one uniform technique: high-resolution melting (HRM) analysis. Serial dilution of heterozygous DNA resulted in a lowest detectable allelic fraction of 6% for the majority of variants. HRM analysis and subsequent sequencing detected pathogenic fully heterozygous APC variants in 10 (6%) of the patients and pathogenic mosaic variants in 2 (1%). All these variants were previously missed by various conventional scanning methods. In parallel, HRM APC scanning was applied to DNA isolated from polyp tissue of two additional patients with apparently sporadic polyposis and without detectable pathogenic APC variant in leukocyte DNA. In both patients a pathogenic mosaic APC variant was present in multiple polyps. The detection of pathogenic APC variants in 7% of the patients, including mosaics, illustrates the usefulness of a complete APC gene reanalysis of previously tested patients, by a supplementary scanning method. HRM is a sensitive and fast pre-screening method for reliable detection of heterozygous and mosaic variants, which can be applied to leukocyte and polyp derived DNA.

  16. Breast Cancer and Bone Loss

    MedlinePlus

    ... Resource Find an Endocrinologist Search Breast Cancer and Bone Loss July 2010 Download PDFs English Espanol Editors ... What is the link between breast cancer and bone loss? Certain treatments for breast cancer can lead ...

  17. Genetics Home Reference: breast cancer

    MedlinePlus

    ... Email Facebook Twitter Home Health Conditions Breast cancer Breast cancer Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Breast cancer is a disease in which certain cells in ...

  18. Breast Cancer—Patient Version

    Cancer.gov

    Breast cancer is the second most common cancer in women after skin cancer. Mammograms can detect breast cancer early, possibly before it has spread. Start here to find information on breast cancer treatment, causes and prevention, screening, research, and statistics.

  19. 6 Common Cancers - Breast Cancer

    MedlinePlus

    ... Bar Home Current Issue Past Issues 6 Common Cancers - Breast Cancer Past Issues / Spring 2007 Table of Contents For ... her down. Photo: AP Photo/Brett Flashnick Breast Cancer Breast cancer is a malignant (cancerous) growth that ...

  20. Accelerated Radiation Therapy After Surgery in Treating Patients With Breast Cancer

    ClinicalTrials.gov

    2017-11-15

    Inflammatory Breast Cancer; Invasive Ductal Breast Carcinoma; Invasive Lobular Breast Carcinoma; Mucinous Ductal Breast Carcinoma; Papillary Ductal Breast Carcinoma; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Tubular Ductal Breast Carcinoma

  1. Personalized Stem Cell Therapy to Correct Corneal Defects Due to a Unique Homozygous-Heterozygous Mosaicism of Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome.

    PubMed

    Barbaro, Vanessa; Nasti, Annamaria Assunta; Raffa, Paolo; Migliorati, Angelo; Nespeca, Patrizia; Ferrari, Stefano; Palumbo, Elisa; Bertolin, Marina; Breda, Claudia; Miceli, Francesco; Russo, Antonella; Caenazzo, Luciana; Ponzin, Diego; Palù, Giorgio; Parolin, Cristina; Di Iorio, Enzo

    2016-08-01

    : Ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome is a rare autosomal dominant disease caused by mutations in the p63 gene. To date, approximately 40 different p63 mutations have been identified, all heterozygous. No definitive treatments are available to counteract and resolve the progressive corneal degeneration due to a premature aging of limbal epithelial stem cells. Here, we describe a unique case of a young female patient, aged 18 years, with EEC and corneal dysfunction, who was, surprisingly, homozygous for a novel and de novo R311K missense mutation in the p63 gene. A detailed analysis of the degree of somatic mosaicism in leukocytes from peripheral blood and oral mucosal epithelial stem cells (OMESCs) from biopsies of buccal mucosa showed that approximately 80% were homozygous mutant cells and 20% were heterozygous. Cytogenetic and molecular analyses excluded genomic alterations, thus suggesting a de novo mutation followed by an allelic gene conversion of the wild-type allele by de novo mutant allele as a possible mechanism to explain the homozygous condition. R311K-p63 OMESCs were expanded in vitro and heterozygous holoclones selected following clonal analysis. These R311K-p63 OMESCs were able to generate well-organized and stratified epithelia in vitro, resembling the features of healthy tissues. This study supports the rationale for the development of cultured autologous oral mucosal epithelial stem cell sheets obtained by selected heterozygous R311K-p63 stem cells, as an effective and personalized therapy for reconstructing the ocular surface of this unique case of EEC syndrome, thus bypassing gene therapy approaches. This case demonstrates that in a somatic mosaicism context, a novel homozygous mutation in the p63 gene can arise as a consequence of an allelic gene conversion event, subsequent to a de novo mutation. The heterozygous mutant R311K-p63 stem cells can be isolated by means of clonal analysis and given their good regenerative

  2. Secondary Breast Augmentation.

    PubMed

    Brown, Mitchell H; Somogyi, Ron B; Aggarwal, Shagun

    2016-07-01

    After studying this article, the participant should be able to: 1. Assess common clinical problems in the secondary breast augmentation patient. 2. Describe a treatment plan to correct the most common complications of breast augmentation. 3. Provide surgical and nonsurgical options for managing complications of breast augmentation. 4. Decrease the incidence of future complications through accurate assessment, preoperative planning, and precise surgical technique. Breast augmentation has been increasing steadily in popularity over the past three decades. Many of these patients present with secondary problems or complications following their primary breast augmentation. Two of the most common complications are capsular contracture and implant malposition. Familiarity and comfort with the assessment and management of these complications is necessary for all plastic surgeons. An up-to-date understanding of current devices and techniques may decrease the need to manage future complications from the current cohort of breast augmentation patients.

  3. Identifying Breast Cancer Oncogenes

    DTIC Science & Technology

    2009-10-01

    study by Boehm et al. (2007) identified IKBKE as a breast cancer oncogene that cooperates with HMLE -MEKDD to replace the function of myr-AKT in...1-0767 TITLE: Identifying Breast Cancer Oncogenes ~ PRINCIPAL INVESTIGATOR: Yashaswi Shrestha...Identifying Breast Cancer Oncogenes 5a. CONTRACT NUMBER W81XWH-08-1-0767 5b. GRANT NUMBER BC083061 - PreDoc 5c. PROGRAM ELEMENT NUMBER 6

  4. Prevention of breast cancer.

    PubMed

    Olver, Ian N

    2016-11-21

    Modifiable lifestyle factors may reduce the risk of developing breast cancer. Obesity is associated particularly with post-menopausal breast cancer. Diet is important, and exercise equivalent to running for up to 8 hours each week reduces the risk of breast cancer, both in its own right and through reducing obesity. Alcohol consumption may be responsible for 5.8% of breast cancers in Australia and it is recommended to reduce this to two standard drinks per day. Drinking alcohol and smoking increases the risk for breast cancer and, therefore, it is important to quit tobacco smoking. Prolonged use of combined oestrogen and progesterone hormone replacement therapy and oral contraceptives may increase breast cancer risk and this must be factored into individual decisions about their use. Ionising radiation, either from diagnostic or therapeutic radiation or through occupational exposure, is associated with a high incidence of breast cancer and exposure may be reduced in some cases. Tamoxifen chemoprevention may reduce the incidence of oestrogen receptor positive cancer in 51% of women with high risk of breast cancer. Uncommon but serious side effects include thromboembolism and uterine cancer. Raloxifene, which can also reduce osteoporosis, can be used in post-menopausal women and is not associated with the development of uterine cancer. Surgical prophylaxis with bilateral mastectomy and salpingo-oophorectomy can reduce the risk of breast cancer in patients carrying BRCA1 or BRCA2 mutations. For preventive treatments, mammographic screening can identify other women at high risk.

  5. Breast cancer prevention.

    PubMed

    Euhus, David M; Diaz, Jennifer

    2015-01-01

    Breast cancer is the most common cancer in women with 232,670 new cases estimated in the USA for 2014. Approaches for reducing breast cancer risk include lifestyle modification, chemoprevention, and prophylactic surgery. Lifestyle modification has a variety of health benefits with few associated risks and is appropriate for all women regardless of breast cancer risk. Chemoprevention options have expanded rapidly, but most are directed at estrogen receptor positive breast cancer and uptake is low. Prophylactic surgery introduces significant additional risks of its own and is generally reserved for the highest risk women. © 2014 Wiley Periodicals, Inc.

  6. Prion infectivity in the spleen of a PRNP heterozygous individual with subclinical variant Creutzfeldt–Jakob disease

    PubMed Central

    Bishop, Matthew T.; Diack, Abigail B.; Ritchie, Diane L.; Ironside, James W.; Will, Robert G.

    2013-01-01

    Blood transfusion has been identified as a source of human-to-human transmission of variant Creutzfeldt–Jakob disease. Three cases of variant Creutzfeldt–Jakob disease have been identified following red cell transfusions from donors who subsequently developed variant Creutzfeldt–Jakob disease and an asymptomatic red cell transfusion recipient, who did not die of variant Creutzfeldt–Jakob disease, has been identified with prion protein deposition in the spleen and a lymph node, but not the brain. This individual was heterozygous (MV) at codon 129 of the prion protein gene (PRNP), whereas all previous definite and probable cases of variant Creutzfeldt–Jakob disease have been methionine homozygotes (MM). A critical question for public health is whether the prion protein deposition reported in peripheral tissues from this MV individual correlates with infectivity. Additionally it is important to establish whether the PRNP codon 129 genotype has influenced the transmission characteristics of the infectious agent. Brain and spleen from the MV blood recipient were inoculated into murine strains that have consistently demonstrated transmission of the variant Creutzfeldt–Jakob disease agent. Mice were assessed for clinical and pathological signs of disease and transmission data were compared with other transmission studies in variant Creutzfeldt–Jakob disease, including those on the spleen and brain of the donor to the index case. Transmission of variant Creutzfeldt–Jakob disease was observed from the MV blood recipient spleen, but not from the brain, whereas there was transmission from both spleen and brain tissues from the red blood cell donor. Longer incubation times were observed for the blood donor spleen inoculum compared with the blood donor brain inoculum, suggesting lower titres of infectivity in the spleen. The distribution of vacuolar pathology and abnormal prion protein in infected mice were similar following inoculation with both donor and

  7. Wild-type offspring of heterozygous prolactin receptor-null female mice have maladaptive β-cell responses during pregnancy.

    PubMed

    Huang, Carol

    2013-03-01

    Abstract  β-Cell mass increases during pregnancy in adaptation to the insulin resistance of pregnancy. This increase is accompanied by an increase in β-cell proliferation, a process that requires intact prolactin receptor (Prlr) signalling. Previously, it was found that during pregnancy, heterozygous prolactin receptor-null (Prlr(+/-)) mice had lower number of β-cells, lower serum insulin and higher blood glucose levels than wild-type (Prlr(+/+)) mice. An unexpected observation was that the glucose homeostasis of the experimental mouse depends on the genotype of her mother, such that within the Prlr(+/+) group, the Prlr(+/+) offspring derived from Prlr(+/+) mothers (Prlr(+/+(+/+))) had higher β-cell mass and lower blood glucose than those derived from Prlr(+/-) mothers (Prlr(+/+(+/-))). Pathways that are known to regulate β-cell proliferation during pregnancy include insulin receptor substrate-2, Akt, menin, the serotonin synthetic enzyme tryptophan hydroxylase-1, Forkhead box M1 and Forkhead box D3. The aim of the present study was to determine whether dysregulation in these signalling molecules in the islets could explain the maternal effect on the phenotype of the offspring. It was found that the pregnancy-induced increases in insulin receptor substrate-2 and Akt expression in the islets were attenuated in the Prlr(+/+(+/-)) mice in comparison to the Prlr(+/+(+/+)) mice. The expression of Forkhead box D3, which plays a permissive role for β-cell proliferation during pregnancy, was also lower in the Prlr(+/+(+/-)) mice. In contrast, the pregnancy-induced increases in phospho-Jak2, tryptophan hydroxylase-1 and FoxM1, as well as the pregnancy-associated reduction in menin expression, were comparable between the two groups. There was also no difference in expression levels of genes that regulate insulin synthesis and secretion (i.e. glucose transporter 2, glucokinase and pancreatic and duodenal homeobox-1) between these two groups. Taken together, these

  8. Mature proprotein convertase subtilisin/kexin type 9, coronary atheroma burden, and vessel remodeling in heterozygous familial hypercholesterolemia.

    PubMed

    Kataoka, Yu; Harada-Shiba, Mariko; Nakao, Kazuhiro; Nakashima, Takahiro; Kawakami, Shoji; Fujino, Masashi; Kanaya, Tomoaki; Nagai, Toshiyuki; Tahara, Yoshio; Asaumi, Yasuhide; Hori, Mika; Ogura, Masatsune; Goto, Yoichi; Noguchi, Teruo; Yasuda, Satoshi

    Proprotein convertase subtilisin/kexin type 9 (PCSK9), an important contributor to low-density lipoprotein metabolism in heterozygous familial hypercholesterolemia (HeFH), exhibits direct proatherogenic effects. PCSK9 circulates as mature and furin-cleaved forms, which differ in its biological activity. However, it remains to be elucidated whether each PCSK9 subtype has different atherogenic properties. To investigate the association of each PCSK9 subtype with coronary atherosclerosis in HeFH. About 204 nonculprit segments in 138 HeFH subjects with coronary artery disease were evaluated by using intravascular ultrasound. Mature, furin-cleaved PCSK9 and total concentration of PCSK9 subtypes were measured by using enzyme-linked immunosorbent assay (BML Inc., Tokyo, Japan). The relationship of these PCSK9 values with intravascular ultrasound measures was investigated. Mature PCSK9 level was positively associated with percent atheroma volume (PAV: r = 0.78, P = .003). Despite extensive atheroma under a higher mature PCSK9 level, vessel volume did not change across any mature PCSK9 levels (r = 0.05, P = .78). These responses resulted in smaller lumen volume, which was negatively correlated to mature PCSK9 level (r = 0.65, P = .009). By contrast, there were no significant relationships of PAV with furin-cleaved (r = 0.12, P = .45) and total PCSK9 (r = 0.37, P = .25) levels. On multivariate analysis, mature PCSK9 level independently contributed to PAV (odds ratio: 1.45, 95% confidence interval: 1.11-1.67, P = .01). Even in subjects with low-density lipoprotein cholesterol level <2.6 mmol/L, greater PAV was still observed in association with an elevated mature PCSK9 level (P = .003). Mature PCSK9 associated with atheroma volume and impaired vessel remodeling in HeFH patients with coronary artery disease. These findings suggest the potential role of mature PCSK9 in propagation of coronary atherosclerosis in HeFH. Copyright © 2017 National Lipid

  9. Heterozygous Vangl2Looptail mice reveal novel roles for the planar cell polarity pathway in adult lung homeostasis and repair

    PubMed Central

    Poobalasingam, Thanushiyan; Yates, Laura L.; Walker, Simone A.; Pereira, Miguel; Gross, Nina Y.; Ali, Akmol; Kolatsi-Joannou, Maria; Jarvelin, Marjo-Riitta; Pekkanen, Juha; Papakrivopoulou, Eugenia; Long, David A.; Griffiths, Mark; Wagner, Darcy; Königshoff, Melanie; Hind, Matthew; Minelli, Cosetta; Lloyd, Clare M.

    2017-01-01

    ABSTRACT Lung diseases impose a huge economic and health burden worldwide. A key aspect of several adult lung diseases, such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD), including emphysema, is aberrant tissue repair, which leads to an accumulation of damage and impaired respiratory function. Currently, there are few effective treatments available for these diseases and their incidence is rising. The planar cell polarity (PCP) pathway is critical for the embryonic development of many organs, including kidney and lung. We have previously shown that perturbation of the PCP pathway impairs tissue morphogenesis, which disrupts the number and shape of epithelial tubes formed within these organs during embryogenesis. However, very little is known about the role of the PCP pathway beyond birth, partly because of the perinatal lethality of many PCP mouse mutant lines. Here, we investigate heterozygous Looptail (Lp) mice, in which a single copy of the core PCP gene, Vangl2, is disrupted. We show that these mice are viable but display severe airspace enlargement and impaired adult lung function. Underlying these defects, we find that Vangl2Lp/+ lungs exhibit altered distribution of actin microfilaments and abnormal regulation of the actin-modifying protein cofilin. In addition, we show that Vangl2Lp/+ lungs exhibit many of the hallmarks of tissue damage, including an altered macrophage population, abnormal elastin deposition and elevated levels of the elastin-modifying enzyme, Mmp12, all of which are observed in emphysema. In vitro, disruption of VANGL2 impairs directed cell migration and reduces the rate of repair following scratch wounding of human alveolar epithelial cells. Moreover, using population data from a birth cohort of young adults, all aged 31, we found evidence of an interactive effect between VANGL2 and smoking on lung function. Finally, we show that PCP genes VANGL2 and SCRIB are significantly downregulated in lung

  10. Dense Breasts: Answers to Commonly Asked Questions

    Cancer.gov

    Mammograms detect breast density, breast cancer, and breast changes that are not cancer (benign breast changes). Breast density describes the amount of glandular and fibrous tissue, as compared to fatty tissue. Learn what factors are associated with breast density and about other risk factors for breast cancer.

  11. Breast cancer statistics, 2011.

    PubMed

    DeSantis, Carol; Siegel, Rebecca; Bandi, Priti; Jemal, Ahmedin

    2011-01-01

    In this article, the American Cancer Society provides an overview of female breast cancer statistics in the United States, including trends in incidence, mortality, survival, and screening. Approximately 230,480 new cases of invasive breast cancer and 39,520 breast cancer deaths are expected to occur among US women in 2011. Breast cancer incidence rates were stable among all racial/ethnic groups from 2004 to 2008. Breast cancer death rates have been declining since the early 1990s for all women except American Indians/Alaska Natives, among whom rates have remained stable. Disparities in breast cancer death rates are evident by state, socioeconomic status, and race/ethnicity. While significant declines in mortality rates were observed for 36 states and the District of Columbia over the past 10 years, rates for 14 states remained level. Analyses by county-level poverty rates showed that the decrease in mortality rates began later and was slower among women residing in poor areas. As a result, the highest breast cancer death rates shifted from the affluent areas to the poor areas in the early 1990s. Screening rates continue to be lower in poor women compared with non-poor women, despite much progress in increasing mammography utilization. In 2008, 51.4% of poor women had undergone a screening mammogram in the past 2 years compared with 72.8% of non-poor women. Encouraging patients aged 40 years and older to have annual mammography and a clinical breast examination is the single most important step that clinicians can take to reduce suffering and death from breast cancer. Clinicians should also ensure that patients at high risk of breast cancer are identified and offered appropriate screening and follow-up. Continued progress in the control of breast cancer will require sustained and increased efforts to provide high-quality screening, diagnosis, and treatment to all segments of the population. Copyright © 2011 American Cancer Society, Inc.

  12. Educating Normal Breast Mucosa to Prevent Breast Cancer

    DTIC Science & Technology

    2016-12-01

    prevention of breast cancer and the feasibility of translating this approach into preventive breast cancer vaccine setting. 15. SUBJECT TERMS...immunity. Our overall goal is to develop a preventative vaccination strategy to reduce the incidence and mortality from breast cancer based on...thorough understanding of the immunity in breast mucosa will enable the design of appropriate vaccination strategies aimed at generating persistent

  13. BREAST CANCER AND EXERCISE

    ClinicalTrials.gov

    2008-03-19

    Prevent Osteoporosis and Osteoporotic Fractures; Improve Quality of Life; Improve Weight Control, and Muscular and Cardiovascular Fitness; Help the Patients to Return to Working Life; Reduce the Risk of Breast Cancer Recurrence; Prevent Other Diseases and Reduce All-Cause Mortality in Patients With Primary Breast Cancer.

  14. Partial breast brachytherapy

    MedlinePlus

    ... 11, 2016. www.cancer.gov/types/breast/hp/breast-treatment-pdq . Accessed September 13, 2016. National Cancer Institute. Radiation therapy and you: support for people who have cancer. Cancer.gov Web site. www.cancer.gov/publications/patient-education/radiation-therapy-and-you . Accessed September 13, ...

  15. Whole breast radiation therapy

    MedlinePlus

    ... 11, 2016. www.cancer.gov/types/breast/hp/breast-treatment-pdq . Accessed September 13, 2016. National Cancer Institute. Radiation therapy and you: support for people who have cancer. Cancer.gov Web site. www.cancer.gov/publications/patient-education/radiation-therapy-and-you . Accessed September 13, ...

  16. Theranostics Targeting Metastatic Breast Cancer

    DTIC Science & Technology

    2017-10-01

    AWARD NUMBER: W81XWH-15-1-0389 TITLE: Theranostics Targeting Metastatic Breast Cancer PRINCIPAL INVESTIGATOR: Kevin Burgess CONTRACTING...ADDRESS. 1. REPORT DATE October 2017 2. REPORT TYPE Annual 3. DATES COVERED 4. TITLE AND SUBTITLE Theranostics Targeting Metastatic Breast Cancer 5a...safe and effective interventions; (ii) elimination of mortality associated with metastatic breast cancer ; and, (iii) distinguishing aggressive breast

  17. [Management of breast cancer in a woman with breast implants].

    PubMed

    Remacle, S; Lifrange, E; Nizet, J-L

    2015-01-01

    The incidence of breast cancer, currently one woman on eight, also concerns patients who underwent augmentation surgery. Breast implants have already been the subject of numerous publications concerning the risk of inducing breast cancer or of delaying its diagnosis; however, no significant causal relationship has been established. The purpose of this article is to assess the diagnostic and therapeutic consequences when breast cancer is identified in a patient with breast implants.

  18. Age- and Tumor Subtype–Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers

    PubMed Central

    Hogervorst, Frans; van Hien, Richard; Cornelissen, Sten; Broeks, Annegien; Adank, Muriel A.; Meijers, Hanne; Waisfisz, Quinten; Hollestelle, Antoinette; Schutte, Mieke; van den Ouweland, Ans; Hooning, Maartje; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia N.; Antoniou, Antonis C.; Arndt, Volker; Bermisheva, Marina; Bogdanova, Natalia V.; Bolla, Manjeet K.; Brauch, Hiltrud; Brenner, Hermann; Brüning, Thomas; Burwinkel, Barbara; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Dunning, Alison M.; Fasching, Peter A.; Figueroa, Jonine; Fletcher, Olivia; Flyger, Henrik; Galle, Eva; García-Closas, Montserrat; Giles, Graham G.; Haeberle, Lothar; Hall, Per; Hillemanns, Peter; Hopper, John L.; Jakubowska, Anna; John, Esther M.; Jones, Michael; Khusnutdinova, Elza; Knight, Julia A.; Kosma, Veli-Matti; Kristensen, Vessela; Lee, Andrew; Lindblom, Annika; Lubinski, Jan; Mannermaa, Arto; Margolin, Sara; Meindl, Alfons; Milne, Roger L.; Muranen, Taru A.; Newcomb, Polly A.; Offit, Kenneth; Park-Simon, Tjoung-Won; Peto, Julian; Pharoah, Paul D.P.; Robson, Mark; Rudolph, Anja; Sawyer, Elinor J.; Schmutzler, Rita K.; Seynaeve, Caroline; Soens, Julie; Southey, Melissa C.; Spurdle, Amanda B.; Surowy, Harald; Swerdlow, Anthony; Tollenaar, Rob A.E.M.; Tomlinson, Ian; Trentham-Dietz, Amy; Vachon, Celine; Wang, Qin; Whittemore, Alice S.; Ziogas, Argyrios; van der Kolk, Lizet; Nevanlinna, Heli; Dörk, Thilo; Bojesen, Stig; Easton, Douglas F.

    2016-01-01

    Purpose CHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtype- and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC. Patients and Methods CHEK2*1100delC genotyping was mostly done by a custom Taqman assay. Breast cancer odds ratios (ORs) for CHEK2*1100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population- and hospital-based studies. Results Proportions of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population- and hospital-based studies, and in patients with breast cancer from familial- and clinical genetics center–based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69; P = 2.3 × 10−20). The OR was higher for estrogen receptor (ER)–positive disease (2.55 [95%CI, 2.10 to 3.10; P = 4.9 × 10−21]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88; P = .12]; P interaction = 9.9 × 10−4). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom. Conclusion These CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into

  19. Age- and Tumor Subtype-Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers.

    PubMed

    Schmidt, Marjanka K; Hogervorst, Frans; van Hien, Richard; Cornelissen, Sten; Broeks, Annegien; Adank, Muriel A; Meijers, Hanne; Waisfisz, Quinten; Hollestelle, Antoinette; Schutte, Mieke; van den Ouweland, Ans; Hooning, Maartje; Andrulis, Irene L; Anton-Culver, Hoda; Antonenkova, Natalia N; Antoniou, Antonis C; Arndt, Volker; Bermisheva, Marina; Bogdanova, Natalia V; Bolla, Manjeet K; Brauch, Hiltrud; Brenner, Hermann; Brüning, Thomas; Burwinkel, Barbara; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Couch, Fergus J; Cox, Angela; Cross, Simon S; Czene, Kamila; Dunning, Alison M; Fasching, Peter A; Figueroa, Jonine; Fletcher, Olivia; Flyger, Henrik; Galle, Eva; García-Closas, Montserrat; Giles, Graham G; Haeberle, Lothar; Hall, Per; Hillemanns, Peter; Hopper, John L; Jakubowska, Anna; John, Esther M; Jones, Michael; Khusnutdinova, Elza; Knight, Julia A; Kosma, Veli-Matti; Kristensen, Vessela; Lee, Andrew; Lindblom, Annika; Lubinski, Jan; Mannermaa, Arto; Margolin, Sara; Meindl, Alfons; Milne, Roger L; Muranen, Taru A; Newcomb, Polly A; Offit, Kenneth; Park-Simon, Tjoung-Won; Peto, Julian; Pharoah, Paul D P; Robson, Mark; Rudolph, Anja; Sawyer, Elinor J; Schmutzler, Rita K; Seynaeve, Caroline; Soens, Julie; Southey, Melissa C; Spurdle, Amanda B; Surowy, Harald; Swerdlow, Anthony; Tollenaar, Rob A E M; Tomlinson, Ian; Trentham-Dietz, Amy; Vachon, Celine; Wang, Qin; Whittemore, Alice S; Ziogas, Argyrios; van der Kolk, Lizet; Nevanlinna, Heli; Dörk, Thilo; Bojesen, Stig; Easton, Douglas F

    2016-08-10

    CHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtype- and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC. CHEK2*1100delC genotyping was mostly done by a custom Taqman assay. Breast cancer odds ratios (ORs) for CHEK2*1100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population- and hospital-based studies. Proportions of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population- and hospital-based studies, and in patients with breast cancer from familial- and clinical genetics center-based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69; P = 2.3 × 10(-20)). The OR was higher for estrogen receptor (ER)-positive disease (2.55 [95%CI, 2.10 to 3.10; P = 4.9 × 10(-21)]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88; P = .12]; P interaction = 9.9 × 10(-4)). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom. These CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into guidelines for intensified screening and follow-up. © 2016

  20. Heterozygous Submicroscopic Inversions Involving Olfactory Receptor–Gene Clusters Mediate the Recurrent t(4;8)(p16;p23) Translocation

    PubMed Central

    Giglio, Sabrina; Calvari, Vladimiro; Gregato, Giuliana; Gimelli, Giorgio; Camanini, Silvia; Giorda, Roberto; Ragusa, Angela; Guerneri, Silvana; Selicorni, Angelo; Stumm, Marcus; Tonnies, Holger; Ventura, Mario; Zollino, Marcella; Neri, Giovanni; Barber, John; Wieczorek, Dagmar; Rocchi, Mariano; Zuffardi, Orsetta

    2002-01-01

    The t(4;8)(p16;p23) translocation, in either the balanced form or the unbalanced form, has been reported several times. Taking into consideration the fact that this translocation may be undetected in routine cytogenetics, we find that it may be the most frequent translocation after t(11q;22q), which is the most common reciprocal translocation in humans. Case subjects with der(4) have the Wolf-Hirschhorn syndrome, whereas case subjects with der(8) show a milder spectrum of dysmorphic features. Two pairs of the many olfactory receptor (OR)–gene clusters are located close to each other, on both 4p16 and 8p23. Previously, we demonstrated that an inversion polymorphism of the OR region at 8p23 plays a crucial role in the generation of chromosomal imbalances through unusual meiotic exchanges. These findings prompted us to investigate whether OR-related inversion polymorphisms at 4p16 and 8p23 might also be involved in the origin of the t(4;8)(p16;p23) translocation. In seven case subjects (five of whom both represented de novo cases and were of maternal origin), including individuals with unbalanced and balanced translocations, we demonstrated that the breakpoints fell within the 4p and 8p OR-gene clusters. FISH experiments with appropriate bacterial-artificial-chromosome probes detected heterozygous submicroscopic inversions of both 4p and 8p regions in all the five mothers of the de novo case subjects. Heterozygous inversions on 4p16 and 8p23 were detected in 12.5% and 26% of control subjects, respectively, whereas 2.5% of them were scored as doubly heterozygous. These novel data emphasize the importance of segmental duplications and large-scale genomic polymorphisms in the evolution and pathology of the human genome. PMID:12058347

  1. Long-term response to growth hormone therapy in a patient with short stature caused by a novel heterozygous mutation in NPR2.

    PubMed

    Vasques, Gabriela A; Hisado-Oliva, Alfonso; Funari, Mariana F A; Lerario, Antonio M; Quedas, Elisangela P S; Solberg, Paulo; Heath, Karen E; Jorge, Alexander A L

    2017-01-01

    Heterozygous loss-of-function mutations in the natriuretic peptide receptor B gene (NPR2) are responsible for short stature in patients without a distinct phenotype. Some of these patients have been treated with recombinant human growth hormone (rhGH) therapy with a variable response. The proband was a healthy boy who presented at the age of 5.1 years with familial short stature (height SDS of -3.1). He had a prominent forehead, a depressed nasal bridge, centripetal fat distribution and a high-pitched voice resembling that of children with GH deficiency. His hormonal evaluation showed low insulin-like growth factor-1 (IGF-1) but a normal GH peak at a stimulation test. During the first year of rhGH treatment, his growth velocity increased from 3.4 to 10.4 cm/year (height SDS change of +1.1). At the last visit, he was 8.8 years old and still on treatment, his growth velocity was 6.4 cm/year and height SDS was -1.8. We identified through exome sequencing a novel heterozygous loss-of-function NPR2 mutation (c.2905G>C; p.Val969Leu). Cells cotransfected with the p.Val969Leu mutant showed a significant decrease in cyclic guanosine monophosphate (cGMP) production compared to the wild type (WT), suggesting a dominant negative effect. This case reveals a novel heterozygous loss-of-function NPR2 mutation responsible for familial short stature and the good response of rhGH therapy in this patient.

  2. Bexarotene in Preventing Breast Cancer in Patients at High Risk for Breast Cancer

    ClinicalTrials.gov

    2018-05-16

    Atypical Ductal Breast Hyperplasia; Atypical Lobular Breast Hyperplasia; BRCA1 Gene Mutation; BRCA2 Gene Mutation; Ductal Breast Carcinoma In Situ; Invasive Breast Carcinoma; Lobular Breast Carcinoma In Situ; No Evidence of Disease

  3. Epigenomics and breast cancer

    PubMed Central

    Lo, Pang-Kuo

    2009-01-01

    Breast carcinogenesis involves genetic and epigenetic alterations that cause aberrant gene function. Recent progress in the knowledge of epigenomics has had a profound impact on the understanding of mechanisms leading to breast cancer, and consequently the development of new strategies for diagnosis and treatment of breast cancer. Epigenetic regulation has been known to involve three mutually interacting events – DNA methylation, histone modifications and nucleosomal remodeling. These processes modulate chromatin structure to form euchromatin or heterochromatin, and in turn activate or silence gene expression. Alteration in expression of key genes through aberrant epigenetic regulation in breast cells can lead to initiation, promotion and maintenance of carcinogenesis, and is even implicated in the generation of drug resistance. We currently review known roles of the epigenetic machinery in the development and recurrence of breast cancer. Furthermore, we highlight the significance of epigenetic alterations as predictive biomarkers and as new targets of anticancer therapy. PMID:19072646

  4. Use of deep whole-genome sequencing data to identify structure risk variants in breast cancer susceptibility genes.

    PubMed

    Guo, Xingyi; Shi, Jiajun; Cai, Qiuyin; Shu, Xiao-Ou; He, Jing; Wen, Wanqing; Allen, Jamie; Pharoah, Paul; Dunning, Alison; Hunter, David J; Kraft, Peter; Easton, Douglas F; Zheng, Wei; Long, Jirong

    2018-03-01

    Functional disruptions of susceptibility genes by large genomic structure variant (SV) deletions in germlines are known to be associated with cancer risk. However, few studies have been conducted to systematically search for SV deletions in breast cancer susceptibility genes. We analysed deep (> 30x) whole-genome sequencing (WGS) data generated in blood samples from 128 breast cancer patients of Asian and European descent with either a strong family history of breast cancer or early cancer onset disease. To identify SV deletions in known or suspected breast cancer susceptibility genes, we used multiple SV calling tools including Genome STRiP, Delly, Manta, BreakDancer and Pindel. SV deletions were detected by at least three of these bioinformatics tools in five genes. Specifically, we identified heterozygous deletions covering a fraction of the coding regions of BRCA1 (with approximately 80kb in two patients), and TP53 genes (with ∼1.6 kb in two patients), and of intronic regions (∼1 kb) of the PALB2 (one patient), PTEN (three patients) and RAD51C genes (one patient). We confirmed the presence of these deletions using real-time quantitative PCR (qPCR). Our study identified novel SV deletions in breast cancer susceptibility genes and the identification of such SV deletions may improve clinical testing.

  5. The Potential Contribution of BRCA Mutations to Early Onset and Familial Breast Cancer in Uzbekistan.

    PubMed

    Abdikhakimov, Abdulla; Tukhtaboeva, Mukaddas; Adilov, Bakhtiyar; Turdikulova, Shahlo

    2016-01-01

    Breast cancer is the most common malignancy in women and affects approximately 1 out of 8 females in the US. Risk of developing breast cancer is strongly influenced by genetic factors. Germ-line mutations in BRCA1 and BRCA2 genes are associated with 5-10% of breast cancer incidence. To reduce the risk of developing cancer and to increase the likelihood of early detection, carriers of BRCA1 or BRCA2 mutations are offered surveillance programs and effective preventive medical interventions. Identification of founder mutations of BRCA1/2 in high risk communities can have a significant impact on the management of hereditary cancer at the level of the national healthcare systems, making genetic testing more affordable and cost-effective. BRCA1 and BRCA2 mutations in breast cancer patients have not been characterized in the Uzbek population. This pilot study aimed to investigate the contribution of BRCA1 and BRCA2 mutation to early onset and familial cases of breast cancer in Uzbekistan. A total of 67 patients with breast cancer and 103 age-matched disease free controls were included in this study. Utilizing SYBR Green based real-time allele-specific PCR, we have analyzed DNA samples of patients with breast cancer and disease free controls to identify the following BRCA1 and BRCA2 mutations: BRCA1 5382insC, BRCA1 4153delA, BRCA1 185delAG, BRCA1 300T>G, BRCA2 6174delT. Three unrelated samples (4.5%) were found to be positive for the heterozygous 5382insCBRCA1 mutation, representing a possible founder mutation in the Uzbek population, supporting the need for larger studies examining the contribution of this mutation to breast cancer incidence in Uzbekistan. We did not find BRCA1 4153delA, BRCA1 185delAG, BRCA1 300T>G, and BRCA2 6174delT mutations. This preliminary evidence suggests a potential contribution of BRCA1 5382insC mutation to breast cancer development in Uzbek population. Taking into account a high disease penetrance in carriers of BRCA1 mutation, it seems

  6. Hypofractionated Radiation Therapy in Treating Patients With Stage 0-IIB Breast Cancer

    ClinicalTrials.gov

    2018-05-11

    Ductal Breast Carcinoma In Situ; Invasive Breast Carcinoma; Stage 0 Breast Cancer; Stage I Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer

  7. Omega-3 Fatty Acid in Treating Patients With Stage I-III Breast Cancer

    ClinicalTrials.gov

    2018-06-25

    Ductal Breast Carcinoma in Situ; Lobular Breast Carcinoma in Situ; Male Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  8. Herpesviruses and breast milk.

    PubMed

    Pietrasanta, C; Ghirardi, B; Manca, M F; Uccella, S; Gualdi, C; Tota, E; Pugni, L; Mosca, F

    2014-06-30

    Breast milk has always been the best source of nourishment for newborns. However, breast milk can carry a risk of infection, as it can be contaminated with bacterial or viral pathogens. This paper reviews the risk of acquisition of varicella-zoster virus (VZV) and cytomegalovirus (CMV), herpesviruses frequently detected in breastfeeding mothers, via breast milk, focusing on the clinical consequences of this transmission and the possible strategies for preventing it. Maternal VZV infections are conditions during which breastfeeding may be temporarily contraindicated, but expressed breast milk should always be given to the infant. CMV infection acquired through breast milk rarely causes disease in healthy term newborns; an increased risk of CMV disease has been documented in preterm infants. However, the American Academy of Pediatrics (AAP) does not regard maternal CMV seropositivity as a contraindication to breastfeeding; according to the AAP, in newborns weighing less than 1500 g, the decision should be taken after weighing the benefits of breast milk against the risk of transmission of infection. The real efficacy of the different methods of inactivating CMV in breast milk should be compared in controlled clinical trials, rigorously examining the negative consequences that each of these methods can have on the immunological and nutritional properties of the milk itself, with a view to establish the best risk-benefit ratio of these strategies before they are recommended for use in clinical practice.

  9. Breast surface estimation for radar-based breast imaging systems.

    PubMed

    Williams, Trevor C; Sill, Jeff M; Fear, Elise C

    2008-06-01

    Radar-based microwave breast-imaging techniques typically require the antennas to be placed at a certain distance from or on the breast surface. This requires prior knowledge of the breast location, shape, and size. The method proposed in this paper for obtaining this information is based on a modified tissue sensing adaptive radar algorithm. First, a breast surface detection scan is performed. Data from this scan are used to localize the breast by creating an estimate of the breast surface. If required, the antennas may then be placed at specified distances from the breast surface for a second tumor-sensing scan. This paper introduces the breast surface estimation and antenna placement algorithms. Surface estimation and antenna placement results are demonstrated on three-dimensional breast models derived from magnetic resonance images.

  10. Targeted next-generation sequencing reveals that a compound heterozygous mutation in phosphodiesterase 6a gene leads to retinitis pigmentosa in a Chinese family.

    PubMed

    Zhang, Shanshan; Li, Jie; Li, Shujin; Yang, Yeming; Yang, Mu; Yang, Zhenglin; Zhu, Xianjun; Zhang, Lin

    2018-04-25

    Retinitis pigmentosa (RP) is a genetically heterogeneous disease with over 70 causative genes identified to date. However, approximately 40% of RP cases remain genetically unsolved, suggesting that many novel disease-causing mutations are yet to be identified. The purpose of this study is to identify the causative mutations of a Chinese RP family. Targeted next-generation sequencing (NGS) for a total of 163 genes which involved in inherited retinal disorders were used to screen the possible causative mutations. Sanger sequencing was used to verify the mutations. As results, we identified two heterozygous mutations: a splicing site mutation c.1407 + 1G>C and a nonsense mutation c. 1957C>T (p.R653X) in phosphodiesterase 6A (PDE6A) gene in the RP patient. These two mutations are inherited from his father and mother, respectively. Furthermore, these mutations are unique in our in-house database and are rare in human genome databases, implicating that these two mutations are pathological. By using targeted NGS method, we identified a compound heterozygous mutation in PDE6A gene that is associated with RP in a Chinese family.

  11. Genetic background has a major effect on the penetrance and severity of craniofacial defects in mice heterozygous for the gene encoding the nucleolar protein Treacle.

    PubMed

    Dixon, Jill; Dixon, Michael James

    2004-04-01

    Treacher Collins syndrome (TCS) is a craniofacial disorder that results from mutations in TCOF1, which encodes the nucleolar protein Treacle. The severity of the clinical features exhibits wide variation and includes hypoplasia of the mandible and maxilla, abnormalities of the external ears and middle ear ossicles, and cleft palate. To determine the in vivo function of Treacle, we previously generated Tcof1 heterozygous mice on a mixed C57BL/6 and 129 background. These mice exhibited a lethal phenotype, which included abnormal development of the maxilla, absence of the eyes and nasal passages, and neural tube defects. Here, we show that placing the mutation onto different genetic backgrounds has a major effect on the penetrance and severity of the craniofacial and other defects. The offspring exhibit markedly variable strain-dependent phenotypes that range from extremely severe and lethal in a mixed CBA/Ca and 129 background, to apparently normal and viable in a mixed BALB/c and 129 background. In the former case, in addition to a profoundly severe craniofacial phenotype, CBA-derived heterozygous mice also exhibited delayed ossification of the long bones, rib fusions, and digit anomalies. The results of our studies indicate that factors in the different genetic backgrounds contribute extensively to the Tcof1 phenotype. Copyright 2004 Wiley-Liss, Inc.

  12. Specific expression of FOXP2 in cerebellum improves ultrasonic vocalization in heterozygous but not in homozygous Foxp2 (R552H) knock-in pups.

    PubMed

    Fujita-Jimbo, Eriko; Momoi, Takashi

    2014-04-30

    The R553H mutation has been found in the FOXP2 gene of patients with speech-language disorder. Foxp2(R552H) knock-in (KI) mice exhibit poor dendritic development of Purkinje cells in the cerebellum and impaired ultrasonic vocalization (USV), which is related to human speech and language; compared with wild-type mice, heterozygous Foxp2(R552H)-KI pups exhibit the reduced number of whistle-type USVs and the increased short-type ones, while homozygous pups exhibit only click-type USVs but no whistle-type or short-type ones. To make clear the relationship between the role of Foxp2 in the cerebellum and whistle-type USVs activity, we prepared transgenic (Tg) mice specifically expressing human FOXP2-myc in cerebellum (Pcp2-FOXP2-myc-Tg mice) by using purkinje cell protein-2 (Pcp2) promoter. FOXP2-myc expression in the cerebellum increased the relative numbers of whistle-type USVs in the heterozygous Foxp2(R552H)-KI pups and recovered their USVs but did not in the homozygous ones. Foxp2 in the cerebellum may pertain to the brain network engaged in whistle-type USVs activities including modification, but not their production. There may be common molecular contribution of Purkinje cells to human FOXP2-mediated speech-language and mouse Foxp2-mediated USVs. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  13. A heterozygous mutation in RPGR associated with X-linked retinitis pigmentosa in a patient with Turner syndrome mosaicism (45,X/46,XX).

    PubMed

    Zhou, Qi; Yao, Fengxia; Wang, Feng; Li, Hui; Chen, Rui; Sui, Ruifang

    2018-01-01

    Turner syndrome with retinitis pigmentosa (RP) is rare, with only three cases reported based on clinical examination alone. We summarized the 4-year follow-up and molecular findings in a 28-year-old patient with Turner syndrome and the typical features of short stature and neck webbing, who also had X-linked RP. Her main complaints were night blindness and progressive loss of vision since the age of 9 years. Ophthalmologic examination, optical coherent tomographic imaging, and visual electrophysiology tests showed classic manifestations of RP. The karyotype of peripheral blood showed mosaicism (45,X [72%]/46,XX[28%]). A novel heterozygous frameshift mutation (c.2403_2406delAGAG, p.T801fsX812) in the RP GTPase regulator (RPGR) gene was detected using next generation sequencing and validated by Sanger sequencing. We believe that this is the first report of X-linked RP in a patient with Turner syndrome associated with mosaicism, and an RPGR heterozygous mutation. We hypothesize that X-linked RP in this woman is not related to Turner syndrome, but may be a manifestation of the lack of a normal paternal X chromosome with intact but mutated RPGR. © 2017 Wiley Periodicals, Inc.

  14. Follow-up Findings in a Turkish Girl with Pseudohypoparathyroidism Type Ia Caused by a Novel Heterozygous Mutation in the GNAS Gene.

    PubMed

    Şahin, Sezgin; Hiort, Olaf; Thiele, Susanne; Evliyaoğlu, Olcay; Tüysüz, Beyhan

    2017-03-01

    Pseudohypoparathyroidism type Ia (PHP-Ia) is characterized by multihormone resistance and an Albright hereditary osteodystrophy (AHO) phenotype. It is caused by heterozygous mutations in GNAS gene. Clinical and biochemical findings of a female PHP-Ia patient were evaluated from age of diagnosis (6.5 years) to 14.5 years of age. The patient had short stature, brachydactyly, and subcutaneous heterotopic ossifications. Serum calcium and phosphorus levels were normal, but parathyroid hormone levels were high. Based on the typical clinical findings of AHO phenotype and biochemical findings, she was diagnosed as having PHP-Ia. A novel heterozygous mutation (c.128T>C) was found in the GNAS gene. Follow-up examinations revealed resistance to thyroid-stimulating hormone and a bioinactive growth hormone. Clinicians should take into consideration PHP-Ia in patients referred with short stature, and patients with an AHO phenotype must be further evaluated for hormone resistance, GNAS gene mutation, Gsα activity. To our knowledge, this is the first case report describing bioinactive growth hormone in PHP-Ia.

  15. Targeted exome sequencing identifies novel compound heterozygous mutations in P3H1 in a fetus with osteogenesis imperfecta type VIII.

    PubMed

    Huang, Yanru; Mei, Libin; Lv, Weigang; Li, Haoxian; Zhang, Rui; Pan, Qian; Tan, Hu; Guo, Jing; Luo, Xiaomei; Chen, Chen; Liang, Desheng; Wu, Lingqian

    2017-01-01

    Osteogenesis imperfecta (OI) is a highly clinically and genetically heterogeneous group of disorders. It is difficult to identify severe OI in the perinatal period. Here, a Chinese woman with a suspected history of fetal OI was referred to our institution at 19weeks of gestation, due to ultrasound inspection during antenatal screening, which revealed bulbous metaphyses, short humeri, and short thick bent femora in the fetus. Using targeted exome sequencing of 248 genes known to be involved in skeletal system diseases, we identified novel compound heterozygous mutation in the P3H1 gene in the fetus with OI type VIII: c.105_120del (p.D36Rfs*16) and c.2164C>T (p.Q722*). These two mutations were inherited from the father and mother, respectively. The mRNA level of P3H1 wasn't changed suggested that mRNA with this mutation escaped from nonsense-mediated RNA decay. Besides, the level of P3H1 was absence while the CRTAP was mildly decreased. In conclusion, our findings imply this novel compound heterozygous mutation as the molecular pathogenetic in a Chinese fetus with OI type VIII, and demonstrate that targeted next-generation sequencing (NGS) is an accurate, rapid, and cost-effective method in the genetic diagnosis of fetal skeletal dysplasia with genetic and clinical heterogeneity, especially for autosomal recessive skeletal disorders. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Exome sequencing identifies novel compound heterozygous IFNA4 and IFNA10 mutations as a cause of impaired function in Crohn’s disease patients

    PubMed Central

    Xiao, Chuan-Xing; Xiao, Jing-Jing; Xu, Hong-Zhi; Wang, Huan-Huan; Chen, Xu; Liu, Yuan-Sheng; Li, Ping; Shi, Ying; Nie, Yong-Zhan; Li, Shao; Wu, Kai-Chun; Liu, Zhan-Ju; Ren, Jian-Lin; Guleng, Bayasi

    2015-01-01

    Previous studies have highlighted the role of genetic predispositions in disease, and several genes had been identified as important in Crohn’s disease (CD). However, many of these genes are likely rare and not associated with susceptibility in Chinese CD patients. We found 294 shared identical variants in the CD patients of which 26 were validated by Sanger sequencing. Two heterozygous IFN variants (IFNA10 c.60 T > A; IFNA4 c.60 A > T) were identified as significantly associated with CD susceptibility. The single-nucleotide changes alter a cysteine situated before the signal peptide cleavage site to a stop code (TGA) in IFNA10 result in the serum levels of IFNA10 were significantly decreased in the CD patients compared to the controls. Furthermore, the IFNA10 and IFNA4 mutants resulted in an impairment of the suppression of HCV RNA replication in HuH7 cells, and the administration of the recombinant IFN subtypes restored DSS-induced colonic inflammation through the upregulation of CD4+ Treg cells. We identified heterozygous IFNA10 and IFNA4 variants as a cause of impaired function and CD susceptibility genes in Chinese patients from multiple center based study. These findings might provide clues in the understanding of the genetic heterogeneity of CD and lead to better screening and improved treatment. PMID:26000985

  17. Hypogonadism in a patient with two novel mutations of the luteinizing hormone β-subunit gene expressed in a compound heterozygous form.

    PubMed

    Basciani, Sabrina; Watanabe, Mikiko; Mariani, Stefania; Passeri, Marina; Persichetti, Agnese; Fiore, Daniela; Scotto d'Abusco, Anna; Caprio, Massimiliano; Lenzi, Andrea; Fabbri, Andrea; Gnessi, Lucio

    2012-09-01

    LH gene mutations are rare; only four mutations have been described. The affected individuals are hypogonadal. We describe the clinical features of a 31-yr-old man who presented with delayed puberty and azoospermia and was found to have hypogonadism associated with an absence of circulating LH. The patient had a 12-bp deletion in exon 2 in the LH β-subunit gene and a mutation of the 5' splice site IVS2+1G→T in the same gene present in a compound heterozygous state. The first mutation predicts a deletion of four leucines of the hydrophobic core of the signal peptide. The second mutation disrupts the splicing of mRNA, generating a gross abnormality in the processing. The patient's heterozygous parents were clinically normal. The phenotype of a 16-yr-old sister of the proband, carrying the same mutations, was characterized by normal pubertal development and oligomenorrhea. This report unravels two novel mutations of the LH gene critical for synthesis and activity of the LH molecule. The insight gained from the study is that normal pubertal maturation in women can occur in a state of LH deficiency, whereas LH is essential for maturation of Leydig cells and thus steroidogenesis, puberty, and spermatogenesis in man. These mutations should be considered in girls and boys with selective deficiency of LH.

  18. Identification of a novel heterozygous missense mutation in the CACNA1F gene in a chinese family with retinitis pigmentosa by next generation sequencing.

    PubMed

    Zhou, Qi; Cheng, Jingliang; Yang, Weichan; Tania, Mousumi; Wang, Hui; Khan, Md Asaduzzaman; Duan, Chengxia; Zhu, Li; Chen, Rui; Lv, Hongbin; Fu, Junjiang

    2015-01-01

    Retinitis pigmentosa (RP) is an inherited retinal degenerative disease, which is clinically and genetically heterogeneous, and the inheritance pattern is complex. In this study, we have intended to study the possible association of certain genes with X-linked RP (XLRP) in a Chinese family. A Chinese family with RP was recruited, and a total of seven individuals were enrolled in this genetic study. Genomic DNA was isolated from peripheral leukocytes, and used for the next generation sequencing (NGS). The affected individual presented the clinical signs of XLRP. A heterozygous missense mutation (c.1555C>T, p.R519W) was identified by NGS in exon 13 of the CACNA1F gene on X chromosome, and was confirmed by Sanger sequencing. It showed perfect cosegregation with the disease in the family. The mutation at this position in the CACNA1F gene of RP was found novel by database searching. By using NGS, we have found a novel heterozygous missense mutation (c.1555C>T, p.R519W) in CACNA1F gene, which is probably associated with XLRP. The findings might provide new insights into the cause and diagnosis of RP, and have implications for genetic counseling and clinical management in this family.

  19. Identification of a Novel Heterozygous Missense Mutation in the CACNA1F Gene in a Chinese Family with Retinitis Pigmentosa by Next Generation Sequencing

    PubMed Central

    Tania, Mousumi; Wang, Hui; Khan, Md. Asaduzzaman; Duan, Chengxia; Zhu, Li; Chen, Rui; Lv, Hongbin

    2015-01-01

    Background. Retinitis pigmentosa (RP) is an inherited retinal degenerative disease, which is clinically and genetically heterogeneous, and the inheritance pattern is complex. In this study, we have intended to study the possible association of certain genes with X-linked RP (XLRP) in a Chinese family. Methods. A Chinese family with RP was recruited, and a total of seven individuals were enrolled in this genetic study. Genomic DNA was isolated from peripheral leukocytes, and used for the next generation sequencing (NGS). Results. The affected individual presented the clinical signs of XLRP. A heterozygous missense mutation (c.1555C>T, p.R519W) was identified by NGS in exon 13 of the CACNA1F gene on X chromosome, and was confirmed by Sanger sequencing. It showed perfect cosegregation with the disease in the family. The mutation at this position in the CACNA1F gene of RP was found novel by database searching. Conclusion. By using NGS, we have found a novel heterozygous missense mutation (c.1555C>T, p.R519W) in CACNA1F gene, which is probably associated with XLRP. The findings might provide new insights into the cause and diagnosis of RP, and have implications for genetic counseling and clinical management in this family. PMID:26075273

  20. Identification of a Novel De Novo Heterozygous Deletion in the SOX10 Gene in Waardenburg Syndrome Type II Using Next-Generation Sequencing.

    PubMed

    Li, Haonan; Jin, Peng; Hao, Qian; Zhu, Wei; Chen, Xia; Wang, Ping

    2017-11-01

    Waardenburg syndrome (WS) is a rare autosomal dominant disorder associated with pigmentation abnormalities and sensorineural hearing loss. In this study, we investigated the genetic cause of WSII in a patient and evaluated the reliability of the targeted next-generation exome sequencing method for the genetic diagnosis of WS. Clinical evaluations were conducted on the patient and targeted next-generation sequencing (NGS) was used to identify the candidate genes responsible for WSII. Multiplex ligation-dependent probe amplification (MLPA) and real-time quantitative polymerase chain reaction (qPCR) were performed to confirm the targeted NGS results. Targeted NGS detected the entire deletion of the coding sequence (CDS) of the SOX10 gene in the WSII patient. MLPA results indicated that all exons of the SOX10 heterozygous deletion were detected; no aberrant copy number in the PAX3 and microphthalmia-associated transcription factor (MITF) genes was found. Real-time qPCR results identified the mutation as a de novo heterozygous deletion. This is the first report of using a targeted NGS method for WS candidate gene sequencing; its accuracy was verified by using the MLPA and qPCR methods. Our research provides a valuable method for the genetic diagnosis of WS.

  1. Mice heterozygous for the ATM gene are more sensitive to both X-ray and heavy ion exposure than are wildtypes

    NASA Astrophysics Data System (ADS)

    Worgul, B. V.; Smilenov, L.; Brenner, D. J.; Vazquez, M.; Hall, E. J.

    Previous studies have shown that the eyes of ATM heterozygous mice exposed to low-LET radiation (X-rays) are significantly more susceptible to the development of cataracts than are those of wildtype mice. The findings, as well as others, run counter to the assumption underpinning current radiation safety guidelines, that individuals are all equally sensitive to the biological effects of radiation. A question, highly relevant to human space activities is whether or not, in similar fashion there may exist a genetic predisposition to high-LET radiation damage. Mice haplodeficient for the ATM gene and wildtypes were exposed to 325 mGy of 1 GeV/amu 56Fe ions at the AGS facility of Brookhaven National Laboratory. The fluence was equivalent to 1 ion per lens epithelial cell nuclear area. Controls consisted of irradiated wildtype as well as unirradiated wildtype and heterozygous mice. Prevalence analyses for stage 0.5-3.0 cataracts indicated that not only cataract onset but also progression were accelerated in the mice haplo-deficient for the ATM gene. The data show that heterozygosity for the ATM gene predisposes the eye to the cataractogenic influence of heavy ions and suggest that ATM heterozygotes in the human population may also be radiosensitive. This may have to be considered in the selection of individuals who will be exposed to both HZE particles and low-LET radiation as they may be predisposed to increased late normal tissue damage.

  2. Newborn screening of glucose-6-phosphate dehydrogenase deficiency in Guangxi, China: determination of optimal cutoff value to identify heterozygous female neonates.

    PubMed

    Fu, Chunyun; Luo, Shiyu; Li, Qifei; Xie, Bobo; Yang, Qi; Geng, Guoxing; Lin, Caijuan; Su, Jiasun; Zhang, Yue; Wang, Jin; Qin, Zailong; Luo, Jingsi; Chen, Shaoke; Fan, Xin

    2018-01-16

    The aim of this study is to assess the disease incidence and mutation spectrum of glucose-6-phosphate dehydrogenase (G6PD) deficiency in Guangxi, China, and to determine an optimal cutoff value to identify heterozygous female neonates. A total of 130, 635 neonates were screened from the year of 2013 to 2017. Neonates suspected for G6PD deficiency were further analyzed by quantitatively enzymatic assay and G6PD mutation analysis. The overall incidence of G6PD deficiency was 7.28%. A total of 14 G6PD mutations were identified, and different mutations lead to varying levels of G6PD enzymatic activities. The best cut-off value of G6PD activity in male subjects is 2.2 U/g Hb, same as conventional setting. In female population, however, the cut-off value is found to be 2.8 U/g Hb (sensitivity: 97.5%, specificity: 87.7%, AUC: 0.964) to best discriminate between normal and heterozygotes, and 1.6 U/g Hb (sensitivity: 82.2%, specificity: 85.9%, AUC: 0.871) between heterozygotes and deficient subjects. In conclusion, we have conducted a comprehensive newborn screening of G6PD deficiency in a large cohort of population from Guangxi, China, and first established a reliable cut-off value of G6PD activity to distinguish heterozygous females from either normal or deficient subjects.

  3. Partial breast radiation therapy - external beam

    MedlinePlus

    APBI is used to prevent breast cancer from coming back. When radiation therapy is given after breast- ... breast conservation therapy reduces the risk of cancer coming back, and possibly even death from breast cancer.

  4. Management of Breast Sarcoma.

    PubMed

    Hsu, Cary; McCloskey, Susan A; Peddi, Parvin F

    2016-10-01

    Breast sarcomas are exceptionally rare mesenchymal neoplasms composed of many histologic subtypes. Therapy is guided by principles established in the management of extremity sarcomas. The anatomic site does influence treatment decisions, particularly the surgical management. Surgery should be undertaken with the aim of achieving a widely negative margin. Selected patients can be managed with breast-conserving surgery. Breast reconstruction is increasingly being undertaken for selected patients. Radiation therapy and chemotherapy are used selectively for large, high-grade sarcomas for which there is significant concern for local and distant recurrence. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Pertuzumab, Trastuzumab, and Paclitaxel Albumin-Stabilized Nanoparticle Formulation in Treating Patients With HER2-Positive Advanced Breast Cancer

    ClinicalTrials.gov

    2018-03-15

    HER2-positive Breast Cancer; Recurrent Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Breast Adenocarcinoma; Inflammatory Breast Carcinoma

  6. Breast Cancer Translational Research Center of Excellence

    DTIC Science & Technology

    2017-11-01

    treating breast diseases and breast cancer. This multidisciplinary model integrates prevention, screening, diagnosis, treatment and continuing care...breast diseases and breast cancer. This approach integrates prevention, screening, diagnosis, treatment and continuing care, incorporation of...mammography and clinical breast examination have a very poor accuracy in the young active duty force in determining which breast abnormalities

  7. Obesity and Breast Cancer.

    PubMed

    Fortner, Renée T; Katzke, Verena; Kühn, Tilman; Kaaks, Rudolf

    The relationship between adiposity and breast cancer risk and prognosis is complex, with associations that differ depending on when body size is assessed (e.g., pre- vs. postmenopausal obesity) and when breast cancer is diagnosed (i.e., pre- vs. postmenopausal disease). Further, the impact of obesity on risk differs by tumor hormone receptor status (e.g., estrogen (ER) and progesterone (PR) receptor) and, among postmenopausal women, use of exogenous hormones (i.e., hormone replacement therapy (HRT)). In the context of these complexities, this review focuses on associations between childhood and adolescent adiposity, general adiposity, weight changes (i.e., loss and gain), abdominal adiposity, and breast cancer risk and survival. Finally, we discuss potential mechanisms linking adiposity to breast cancer.

  8. Breast MRI scan

    MedlinePlus

    ... heart valves Heart defibrillator or pacemaker Inner ear (cochlear) implants Kidney disease or dialysis (you may not ... that remains after surgery or chemotherapy Show blood flow through the breast area Guide a biopsy (not ...

  9. Premenstrual breast changes

    MedlinePlus

    ... occurs during the second half of the menstrual cycle. ... Hormone changes during the menstrual cycle likely lead to breast swelling. More estrogen is made early in the cycle and it peaks just before mid-cycle. This ...

  10. Breast Pain in Women

    MedlinePlus

    ... effective, some women feel better when changing bra styles and cutting back on salt and caffeine. Breast ... Childbirth Women Men Seniors Your Health Resources Healthcare Management End-of-Life Issues Insurance & Bills Self Care ...

  11. Breast augmentation - slideshow

    MedlinePlus

    ... page: //medlineplus.gov/ency/presentations/100205.htm Breast augmentation - series—Normal anatomy To use the sharing features ... Bethesda, MD 20894 U.S. Department of Health and Human Services National Institutes of Health Page last updated: ...

  12. TMIST Breast Screening Study

    Cancer.gov

    TMIST is a randomized breast screening trial that compares two Food and Drug Administration (FDA)-approved types of digital mammography, standard digital mammography (2-D) with a newer technology called tomosynthesis mammography (3-D).

  13. Breast radiation - discharge

    MedlinePlus

    ... underwire. Ask your provider about wearing your breast prosthesis, if you have one. Self-care You need ... swelling ( edema ) in your arm. You have a feeling of tightness in your arm. Rings on your ...

  14. Breast Reconstruction and Prosthesis

    MedlinePlus

    ... Does your health insurance cover breast reconstruction? The Women’s Health and Cancer Rights Act requires all health insurance providers and health maintenance organizations (HMOs) that pay for mastectomy to also pay ...

  15. Breast biopsy -- stereotactic

    MedlinePlus

    ... sent to a pathologist to be examined. Normal Results A normal result means there is no sign ... follow-up mammogram or other tests. What Abnormal Results Mean If the biopsy shows benign breast tissue ...

  16. Factors influencing breast feeding.

    PubMed Central

    McKean, K S; Baum, J D; Sloper, K

    1975-01-01

    A survey is reported of infant feeding practice at the time of discharge from a single maternity ward. It is shown that a change in the attitude of nursing staff increased the number of mothers breast feeding their infants and eliminated the practice of giving the infants formula feed complements. This change in attitude, however, did nothing to prevent the rapid decline in lactation after leaving hospital, such that 50% of mothers discharged breast feeding were no longer doing so by 2 months. The early introduction of solid feeds was common practice, 50% of mothers discharged breast feeding having introduced mixed feeds within 2 months. Successful lactation was found to be commoner in those mothers who had themselves been breast fed in infancy and in mothers from socioeconomic classes I and II. Successful lactation was not related to parity. The survey also shows the influential role of the health visitor, district nurse, and midwife upon mothers' decisions about infant feeding. PMID:1170810

  17. Breast Reconstruction with Implants

    MedlinePlus

    ... implants is a complex procedure performed by a plastic surgeon. The breast reconstruction process can start at ... doctor may recommend that you meet with a plastic surgeon. Consult a plastic surgeon who's board certified ...

  18. Cosmetic breast surgery - discharge

    MedlinePlus

    ... Higdon KK. Reduction mammaplasty. In: Neligan PC, ed. Plastic Surgery . 3rd ed. Philadelphia, PA: Elsevier Saunders; 2013: ... Gabriel A. Breast augmentation. In: Neligan PC, ed. Plastic Surgery . 3rd ed. Philadelphia, PA: Elsevier Saunders; 2013: ...

  19. Breast reduction (mammoplasty) - slideshow

    MedlinePlus

    ... page: //medlineplus.gov/ency/presentations/100189.htm Breast reduction (mammoplasty) - series—Indications To use the sharing features ... Lickstein, MD, FACS, specializing in cosmetic and reconstructive plastic surgery, Palm Beach Gardens, FL. Review provided by ...

  20. Breast lift (mastopexy) - slideshow

    MedlinePlus

    ... routine breast exam are required before surgery. Review Date 1/10/2017 Updated by: David A. Lickstein, MD, FACS, specializing in cosmetic and reconstructive plastic surgery, Palm Beach Gardens, FL. Review provided by VeriMed Healthcare ...

  1. Breast cancer and protein biomarkers

    PubMed Central

    Gam, Lay-Harn

    2012-01-01

    Breast cancer is a healthcare concern of women worldwide. Despite procedures being available for diagnosis, prognosis and treatment of breast cancer, researchers are working intensively on the disease in order to improve the life quality of breast cancer patients. At present, there is no single treatment known to bring a definite cure for breast cancer. One of the possible solutions for combating breast cancer is through identification of reliable protein biomarkers that can be effectively used for early detection, prognosis and treatments of the cancer. Therefore, the task of identification of biomarkers for breast cancer has become the focus of many researchers worldwide. PMID:24520539

  2. Relation of polymorphism C1236T and C3435T in ABCB1 gene with bone marrow suppression in chemotherapy-treated breast cancer patients

    NASA Astrophysics Data System (ADS)

    Syarifah, S.; Hamdi, T.; Widyawati, T.; Sari, M. I.; Anggraini, D. R.

    2018-03-01

    ABCB1 is agene that encoded P-glycoprotein (P-gp), a transmembrane active efflux pump for a variety of carcinogens and cytostatics.ABCB1 polymorphisms C1236T and C3435T contribute to the variability oftherapeutic outcome and side effects.The present study was conducted to investigatethe relation of C1236T and C3435T polymorphisms in ABCB1 gene with bone marrow suppression in breast cancer patients treated withchemotherapy72 Indonesian womens isolated DNA sampleswere amplified using the PCR method. The analysis process of ABCB1 C1236T and C3435T polymorphism was by using thePCR-RFLP method. The frequencies of ABCB1 C1236T genotype for homozygous CC,heterozygous CT and variant TT was 11(15.28%), 42(58.33%), 19(26.39%), respectively. No associationwas between ABCB1 C1236T and C3435T polymorphisms in both individually and haplotypes with bone marrow suppression event (p > 0.05). There was no specific deviation of allele and genotype frequency from Hardy-Weinberg Equilibrium. There was a linkage between heterozygous CT-heterozygous CT in position 1236 and 3435 within 25 people (35%).

  3. Aluminium and the human breast.

    PubMed

    Darbre, P D

    2016-06-01

    The human population is exposed to aluminium (Al) from diet, antacids and vaccine adjuvants, but frequent application of Al-based salts to the underarm as antiperspirant adds a high additional exposure directly to the local area of the human breast. Coincidentally the upper outer quadrant of the breast is where there is also a disproportionately high incidence of breast cysts and breast cancer. Al has been measured in human breast tissues/fluids at higher levels than in blood, and experimental evidence suggests that at physiologically relevant concentrations, Al can adversely impact on human breast epithelial cell biology. Gross cystic breast disease is the most common benign disorder of the breast and evidence is presented that Al may be a causative factor in formation of breast cysts. Evidence is also reviewed that Al can enable the development of multiple hallmarks associated with cancer in breast cells, in particular that it can cause genomic instability and inappropriate proliferation in human breast epithelial cells, and can increase migration and invasion of human breast cancer cells. In addition, Al is a metalloestrogen and oestrogen is a risk factor for breast cancer known to influence multiple hallmarks. The microenvironment is established as another determinant of breast cancer development and Al has been shown to cause adverse alterations to the breast microenvironment. If current usage patterns of Al-based antiperspirant salts contribute to causation of breast cysts and breast cancer, then reduction in exposure would offer a strategy for prevention, and regulatory review is now justified. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  4. Prolonged breast-feeding is an independent risk factor for postmenopausal osteoporosis.

    PubMed

    Okyay, Duygu Ozkale; Okyay, Emre; Dogan, Erbil; Kurtulmus, Secil; Acet, Ferruh; Taner, Cuneyt Eftal

    2013-03-01

    This study investigated the effects of parity and age at first pregnancy and breast-feeding, as well as duration of BF for total and per child on postmenopausal osteoporosis. The study was conducted among 542 cases who were divided based on the presence or absence of osteoporosis. Patients were separated according to their first pregnancy and breast-feeding age as before or after 27 years. Osteoporosis was defined as a T score of -2.5 or lower. Parity, age at first pregnancy and breast-feeding, breast-feeding period for total and average duration per child according to a questionnaire were assessed. Osteoporosis group had significantly lower parity compared to non-osteoporosis group. The age at first pregnancy and breast-feeding<27 age were significantly more frequent in osteoporosis group. They also had prolonged breast-feeding period. Women who had a breast-feeding period per child>1 year under age 27 was higher in osteoporosis group. In multivariate analysis, women who breast-fed>1 year per child had the highest risk for osteoporosis (odds ratio: 12.92; 95% confidence interval, 3.1-52.6) and osteoporosis risk for women who breast-fed>1 year per child under age 27 was 7.1. Increased parity was associated with a significant protective effect for osteoporosis. Extended breast-feeding period per child>1 year is the highest risk factor for osteoporosis independent of first breast-feeding age. However, high parity has a protective effect. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  5. Compound heterozygous mutations in the SRD5A2 gene exon 4 in a male pseudohermaphrodite patient of Chinese origin.

    PubMed

    Fernández-Cancio, Mónica; Nistal, Manuel; Gracia, Ricardo; Molina, M Antonia; Tovar, Juan Antonio; Esteban, Cristina; Carrascosa, Antonio; Audí, Laura

    2004-01-01

    The goal of this study was to perform 5-alpha-reductase type 2 gene (SRD5A2) analysis in a male pseudohermaphrodite (MPH) patient with normal testosterone (T) production and normal androgen receptor (AR) gene coding sequences. A patient of Chinese origin with ambiguous genitalia at 14 months, a 46,XY karyotype, and normal T secretion under human chorionic gonadotropin (hCG) stimulation underwent a gonadectomy at 20 months. Exons 1-8 of the AR gene and exons 1-5 of the SRD5A2 gene were sequenced from peripheral blood DNA. AR gene coding sequences were normal. SRD5A2 gene analysis revealed 2 consecutive mutations in exon 4, each located in a different allele: 1) a T nucleotide deletion, which predicts a frameshift mutation from codon 219, and 2) a missense mutation at codon 227, where the substitution of guanine (CGA) by adenine (CAA) predicts a glutamine replacement of arginine (R227Q). Testes located in the inguinal canal showed a normal morphology for age. The patient was a compound heterozygote for SRD5A2 mutations, carrying 2 mutations in exon 4. The patient showed an R227Q mutation that has been described in an Asian population and MPH patients, along with a novel frameshift mutation, Tdel219. Testis morphology showed that, during early infancy, the 5-alpha-reductase enzyme deficiency may not have affected interstitial or tubular development.

  6. Severe hypertriglyceridemia in a patient heterozygous for a lipoprotein lipase gene allele with two novel missense variants.

    PubMed

    Kassner, Ursula; Salewsky, Bastian; Wühle-Demuth, Marion; Szijarto, Istvan Andras; Grenkowitz, Thomas; Binner, Priska; März, Winfried; Steinhagen-Thiessen, Elisabeth; Demuth, Ilja

    2015-09-01

    Rare monogenic hyperchylomicronemia is caused by loss-of-function mutations in genes involved in the catabolism of triglyceride-rich lipoproteins, including the lipoprotein lipase gene, LPL. Clinical hallmarks of this condition are eruptive xanthomas, recurrent pancreatitis and abdominal pain. Patients with LPL deficiency and severe or recurrent pancreatitis are eligible for the first gene therapy treatment approved by the European Union. Therefore the precise molecular diagnosis of familial hyperchylomicronemia may affect treatment decisions. We present a 57-year-old male patient with excessive hypertriglyceridemia despite intensive lipid-lowering therapy. Abdominal sonography showed signs of chronic pancreatitis. Direct DNA sequencing and cloning revealed two novel missense variants, c.1302A>T and c.1306G>A, in exon 8 of the LPL gene coexisting on the same allele. The variants result in the amino-acid exchanges p.(Lys434Asn) and p.(Gly436Arg). They are located in the carboxy-terminal domain of lipoprotein lipase that interacts with the glycosylphosphatidylinositol-anchored HDL-binding protein (GPIHBP1) and are likely of functional relevance. No further relevant mutations were found by direct sequencing of the genes for APOA5, APOC2, LMF1 and GPIHBP1. We conclude that heterozygosity for damaging mutations of LPL may be sufficient to produce severe hypertriglyceridemia and that chylomicronemia may be transmitted in a dominant manner, at least in some families.

  7. Severe hypertriglyceridemia in a patient heterozygous for a lipoprotein lipase gene allele with two novel missense variants

    PubMed Central

    Kassner, Ursula; Salewsky, Bastian; Wühle-Demuth, Marion; Szijarto, Istvan Andras; Grenkowitz, Thomas; Binner, Priska; März, Winfried; Steinhagen-Thiessen, Elisabeth; Demuth, Ilja

    2015-01-01

    Rare monogenic hyperchylomicronemia is caused by loss-of-function mutations in genes involved in the catabolism of triglyceride-rich lipoproteins, including the lipoprotein lipase gene, LPL. Clinical hallmarks of this condition are eruptive xanthomas, recurrent pancreatitis and abdominal pain. Patients with LPL deficiency and severe or recurrent pancreatitis are eligible for the first gene therapy treatment approved by the European Union. Therefore the precise molecular diagnosis of familial hyperchylomicronemia may affect treatment decisions. We present a 57-year-old male patient with excessive hypertriglyceridemia despite intensive lipid-lowering therapy. Abdominal sonography showed signs of chronic pancreatitis. Direct DNA sequencing and cloning revealed two novel missense variants, c.1302A>T and c.1306G>A, in exon 8 of the LPL gene coexisting on the same allele. The variants result in the amino-acid exchanges p.(Lys434Asn) and p.(Gly436Arg). They are located in the carboxy-terminal domain of lipoprotein lipase that interacts with the glycosylphosphatidylinositol-anchored HDL-binding protein (GPIHBP1) and are likely of functional relevance. No further relevant mutations were found by direct sequencing of the genes for APOA5, APOC2, LMF1 and GPIHBP1. We conclude that heterozygosity for damaging mutations of LPL may be sufficient to produce severe hypertriglyceridemia and that chylomicronemia may be transmitted in a dominant manner, at least in some families. PMID:25585702

  8. Partial breast irradiation for early breast cancer.

    PubMed

    Hickey, Brigid E; Lehman, Margot; Francis, Daniel P; See, Adrienne M

    2016-07-18

    Breast-conserving therapy for women with breast cancer consists of local excision of the tumour (achieving clear margins) followed by radiotherapy (RT). RT is given to sterilize tumour cells that may remain after surgery to decrease the risk of local tumour recurrence. Most true recurrences occur in the same quadrant as the original tumour. Whole breast radiotherapy (WBRT) may not protect against the development of a new primary cancer developing in other quadrants of the breast. In this Cochrane review, we investigated the delivery of radiation to a limited volume of the breast around the tumour bed (partial breast irradiation (PBI)) sometimes with a shortened treatment duration (accelerated partial breast irradiation (APBI)). To determine whether PBI/APBI is equivalent to or better than conventional or hypo-fractionated WBRT after breast-conserving therapy for early-stage breast cancer. We searched the Cochrane Breast Cancer Group Specialized Register (4 May 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 5), MEDLINE (January 1966 to 4 May 2015), EMBASE (1980 to 4 May 2015), CINAHL (4 May 2015) and Current Contents (4 May 2015). We searched the International Standard Randomised Controlled Trial Number Register (5 May 2015), the World Health Organization's International Clinical Trials Registry Platform (4 May 2015) and ClinicalTrials.gov (17 June 2015). We searched for grey literature: OpenGrey (17 June 2015), reference lists of articles, several conference proceedings and published abstracts, and applied no language restrictions. Randomized controlled trials (RCTs) without confounding, that evaluated conservative surgery plus PBI/APBI versus conservative surgery plus WBRT. Published and unpublished trials were eligible. Two review authors (BH and ML) performed data extraction and used Cochrane's 'Risk of bias' tool, and resolved any disagreements through discussion. We entered data into Review Manager 5 for analysis. We included

  9. The Role of Dipeptidyl Peptidase IV in Lung Metastasis of Breast Cancer Cells

    DTIC Science & Technology

    1999-05-01

    Our studies focused on (1) cloning and sequencing of wild-type endothelial DPP IV (wtDPP IV) and preparation of truncated DPP IV ( tDPP IV); (2...that was identical to hepatic DPP IV. Acid extraction of rat lung yielded a tDPP IV, which was an effective inhibitor of breast cancer cell adhesion to

  10. Multiparametric Breast MRI of Breast Cancer

    PubMed Central

    Rahbar, Habib; Partridge, Savannah C.

    2015-01-01

    Synopsis Breast MRI has increased in popularity over the past two decades due to evidence for its high sensitivity for cancer detection. Current clinical MRI approaches rely on the use of a dynamic contrast enhanced (DCE-MRI) acquisition that facilitates morphologic and semi-quantitative kinetic assessments of breast lesions. The use of more functional and quantitative parameters, such as pharmacokinetic features from high temporal resolution DCE-MRI, apparent diffusion coefficient (ADC) and intravoxel incoherent motion (IVIM) on diffusion weighted MRI, and choline concentrations on MR spectroscopy, hold promise to broaden the utility of MRI and improve its specificity. However, due to wide variations in approach among centers for measuring these parameters and the considerable technical challenges, robust multicenter data supporting their routine use is not yet available, limiting current applications of many of these tools to research purposes. PMID:26613883

  11. Breast Reconstruction with Flap Surgery

    MedlinePlus

    ... vessels requires expertise in surgery through a microscope (microsurgery). An advantage to this type of breast reconstruction ... of your disease Require additional surgery to correct reconstructive problems What breast reconstruction won't do: Make ...

  12. PET scan for breast cancer

    MedlinePlus

    ... radioactive substance (called a tracer) to look for breast cancer. This tracer can help identify areas of cancer ... only after a woman has been diagnosed with breast cancer. It is done to see if the cancer ...

  13. Preventing Breast Cancer: Making Progress

    MedlinePlus

    ... Navigation Bar Home Current Issue Past Issues Preventing Breast Cancer: Making Progress Past Issues / Fall 2006 Table of ... 000 women will have been diagnosed with invasive breast cancer, and nearly 41,000 women will die from ...

  14. General Information about Breast Cancer

    MedlinePlus

    ... Research Breast Cancer Treatment (PDQ®)–Patient Version General Information About Breast Cancer Go to Health Professional Version ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  15. Breast lump removal - series (image)

    MedlinePlus

    ... be a cyst filled with fluid or a solid mass of tissue. A sample of the breast tissue (biopsy) must be made to determine whether malignant (cancerous) cells are present. Almost two-thirds of all breast ...

  16. [Anatomical and artistic breast considerations].

    PubMed

    Moufarrège, R

    2005-10-01

    The author presents the golden ratios of the breast. Out of these ratios, the breast will lack harmony and beauty. Starting there, he gives his advices and rules to follow in order to obtain nice shapes in augmentation mammaplasties.

  17. Breast feeding: overview and breast milk immunology.

    PubMed

    Hanson, L A; Hahn-Zoric, M; Berndes, M; Ashraf, R; Herias, V; Jalil, F; Bhutta, T I; Laeeq, A; Mattsby-Baltzer, I

    1994-10-01

    The transfer of host defence capacity to the human offspring provides a remarkable model of passive transfer of immunity. In fact it may also provide an example of active immunization. The transfer of mucosal protection via breast feeding offers many additional advantages for the mother and infant. Through its contraceptive effects it increases the spacing between births, thus diminshing the infant mortality and the burden on the mother. It also enhances bonding between mother and child, it seems to increase the IQ and school result of the infant and might decrease the risk of certain malignancies and perhaps of juvenile diabetes. A fully breast-fed infant receives as much as 0.5-1 g of secretory immunoglobulin A (SIgA) antibodies daily, the predominant antibody of human milk. This can be compared to the production of some 2.5 g of SIgA per day for a 60 kg adult. These SIgA antibodies have been shown to protect against Vibrio cholerae, ETEC, Campylobacter, Shigella and Giardia. Furthermore, milk is rich in receptor analogues for certain epithelial structures which microbes need for attachment to host tissues as an initial step in infections. Thus the adherence of Haemophilus influenzae and pneumococci for example to retropharyngeal cells is efficiently inhibited by human milk. This may be one explanation for the fact that breast-fed babies have less otitis media than the non-breast-fed. Other milk factors like lysozyme and lactoferin may contribute to the host defence, but this has not yet been well defined. However, human milk also supports the well-being of the infant by being anti-inflammatory.(ABSTRACT TRUNCATED AT 250 WORDS)

  18. How breast cancer presents.

    PubMed Central

    Devitt, J. E.

    1983-01-01

    A study of 501 new breast cancers in patients seen in a consulting surgical practice revealed that 87% were in patients 45 years of age or older. The patients had found 83% of the cancers. The distributions of size and stage were the same for the tumours found by the patients and those found by the referring physicians. Two thirds of the cancers had an associated visible clinical sign, demonstrating the importance of inspection in the examination of the breast. Dimpling, sometimes apparent only on manipulation of the tumour, was present with 264 of the cancers and was often associated with "minimal" lesions. Mammography was done for 63 of the breast cancers but it missed 27. Of the physician-found cancers 15 were in patients who had already had breast cancer, 4 were in patients presenting with symptomatic metastases and 14 were in women presenting with other disorders. Of the 52 cancers found by periodic examination 3 were locally advanced and 21 had axillary metastases, while among the 28 "early" cancers 12 were in women who were senile, mentally defective or psychotic. Only four of the cancers found by the physicians were in women under age 45; two were rapidly fatal, one had an axillary metastasis, and the fourth was in a woman who had had cancer of the opposite breast. The remaining 284 lesions found by periodic or routine examination in women under age 45 were benign. Thus, periodic or routine examination for unsuspected breast cancer in women under age 45 seems unjustified except in those who have already had breast cancer. Images FIG. 1 FIG. 2 PMID:6861046

  19. Association of an α-globin gene cluster duplication and heterozygous β-thalassemia in a patient with a severe thalassemia syndrome.

    PubMed

    Jiang, Hua; Liu, Sha; Zhang, Yong-Ling; Wan, Jun-Hui; Li, Ru; Li, Dong-Zhi

    2015-01-01

    We describe a new case of a β-thalassemia (β-thal) heterozygote with the mutation IVS-II-654 (C>T) presenting with a transfusion-dependent phenotype. Multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (CGH) analyses of the α-globin gene cluster revealed a full duplication of the α-globin genes including the upstream regulatory element. The duplicated allele and the normal allele in trans resulted in a total of six active α-globin genes. The severe clinical phenotype seemed to be related to the considerable excess of the α- and β-globin deficit caused by the presence of the β-thal. α-Globin cluster duplication should be considered in patients heterozygous for β-thal who show a more severe phenotype than β-thal trait.

  20. Rare Compound Heterozygous Frameshift Mutations in ALMS1 Gene Identified Through Exome Sequencing in a Taiwanese Patient With Alström Syndrome.

    PubMed

    Tsai, Meng-Che; Yu, Hui-Wen; Liu, Tsunglin; Chou, Yen-Yin; Chiou, Yuan-Yow; Chen, Peng-Chieh

    2018-01-01

    Alström syndrome (AS) is a rare autosomal recessive disorder that shares clinical features with other ciliopathy-related diseases. Genetic mutation analysis is often required in making differential diagnosis but usually costly in time and effort using conventional Sanger sequencing. Herein we describe a Taiwanese patient presenting cone-rod dystrophy and early-onset obesity that progressed to diabetes mellitus with marked insulin resistance during adolescence. Whole exome sequencing of the patient's genomic DNA identified a novel frameshift mutation in exons 15 (c.10290_10291delTA, p.Lys3431Serfs * 10) and a rare mutation in 16 (c.10823_10824delAG, p.Arg3609Alafs * 6) of ALMS1 gene. The compound heterozygous mutations were predicted to render truncated proteins. This report highlighted the clinical utility of exome sequencing and extended the knowledge of mutation spectrum in AS patients.

  1. Andermann syndrome can be a phenocopy of hereditary motor and sensory neuropathy--report of a discordant sibship with a compound heterozygous mutation of the KCC3 gene.

    PubMed

    Rudnik-Schöneborn, S; Hehr, U; von Kalle, T; Bornemann, A; Winkler, J; Zerres, K

    2009-06-01

    Andermann syndrome is a rare autosomal recessive disorder characterized by agenesis of the corpus callosum (ACC), progressive motor-sensory neuropathy, mental retardation and facial features. We report on two siblings with the clinical picture of a demyelinating hereditary motor and sensory neuropathy (HMSN), where only the presence of ACC in the younger brother pointed to the diagnosis of Andermann syndrome. Mutation analysis of the KCC3 (SLC12A6) gene showed a compound heterozygous mutation; a maternal missense mutation c.1616G>A (p.G539D) and a paternal splice mutation c.1118+1G>A in both siblings. We hypothesize that mutations of the KCC3 gene may result in non-syndromic childhood onset HMSN.

  2. Cosegregation of Robertsonian metacentric chromosomes in the first meiotic division of multiple heterozygous male mice as revealed by FISH analysis of spermatocyte II metaphases.

    PubMed

    Scascitelli, M; Pacchierotti, F; Rizzoni, M; Gustavino, B; Spirito, F

    2003-01-01

    Contrasting results (random segregation or cosegregation of isomorphic chromosomes) have been reported up to now on the segregation pattern of Robertsonian metacentric chromosomes of Mus musculus domesticus in multiple heterozygotes, using different approaches (karyotypical analysis of the progeny or of second meiotic metaphases). In the present contribution data are presented based on FISH (Fluorescence In Situ Hybridisation) analysis with telomeric probes, which allowed us to distinguish metacentric chromosomes from pairs of acrocentric chromosomes with their centromeric regions close to each other. Probes were hybridized to DAPI stained metaphases of spermatocytes II of mice heterozygous for two, three or four Robertsonian metacentrics in an all-acrocentric background, the karyotype of which has been reconstructed starting from laboratory strains. Isomorphic chromosomes tend to cosegregate (metacentrics with metacentrics, acrocentrics with acrocentrics); the values found for cosegregation have a clear even if moderate effect on the reproductive isolation caused by underdominant chromosomal rearrangements. Copyright 2003 S. Karger AG, Basel

  3. Heterozygous SSBP1 start loss mutation co-segregates with hearing loss and the m.1555A>G mtDNA variant in a large multigenerational family.

    PubMed

    Kullar, Peter J; Gomez-Duran, Aurora; Gammage, Payam A; Garone, Caterina; Minczuk, Michal; Golder, Zoe; Wilson, Janet; Montoya, Julio; Häkli, Sanna; Kärppä, Mikko; Horvath, Rita; Majamaa, Kari; Chinnery, Patrick F

    2018-01-01

    The m.1555A>G mtDNA variant causes maternally inherited deafness, but the reasons for the highly variable clinical penetrance are not known. Exome sequencing identified a heterozygous start loss mutation in SSBP1, encoding the single stranded binding protein 1 (SSBP1), segregating with hearing loss in a multi-generational family transmitting m.1555A>G, associated with mtDNA depletion and multiple deletions in skeletal muscle. The SSBP1 mutation reduced steady state SSBP1 levels leading to a perturbation of mtDNA metabolism, likely compounding the intra-mitochondrial translation defect due to m.1555A>G in a tissue-specific manner. This family demonstrates the importance of rare trans-acting genetic nuclear modifiers in the clinical expression of mtDNA disease. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

  4. Biallelic PMS2 Mutation and Heterozygous DICER1 Mutation Presenting as Constitutional Mismatch Repair Deficiency With Corpus Callosum Agenesis: Case Report and Review of Literature.

    PubMed

    Cheyuo, Cletus; Radwan, Walid; Ahn, Janice; Gyure, Kymberly; Qaiser, Rabia; Tomboc, Patrick

    2017-10-01

    Constitutional mismatch repair deficiency syndrome is a cancer predisposition syndrome caused by autosomal recessive biallelic (homozygous) germline mutations in the mismatch repair genes (MLH1, MSH2, MSH6, and PMS2). The clinical spectrum includes neoplastic and non-neoplastic manifestations. We present the case of a 7-year-old boy who presented with T-lymphoblastic lymphoma and glioblastoma, together with non-neoplastic manifestations including corpus callosum agenesis, arachnoid cyst, developmental venous anomaly, and hydrocephalus. Gene mutation analysis revealed pathogenic biallelic mutations of PMS2 and heterozygous DICER1 variant predicted to be pathogenic. This report is the first to allude to a possible interaction of the mismatch repair system with DICER1 to cause corpus callosum agenesis.

  5. Haemolysis in G6PD Heterozygous Females Treated with Primaquine for Plasmodium vivax Malaria: A Nested Cohort in a Trial of Radical Curative Regimens.

    PubMed

    Chu, Cindy S; Bancone, Germana; Moore, Kerryn A; Win, Htun Htun; Thitipanawan, Niramon; Po, Christina; Chowwiwat, Nongnud; Raksapraidee, Rattanaporn; Wilairisak, Pornpimon; Phyo, Aung Pyae; Keereecharoen, Lily; Proux, Stéphane; Charunwatthana, Prakaykaew; Nosten, François; White, Nicholas J

    2017-02-01

    Radical cure of Plasmodium vivax malaria with 8-aminoquinolines (primaquine or tafenoquine) is complicated by haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD heterozygous females, because of individual variation in the pattern of X-chromosome inactivation (Lyonisation) in erythroid cells, may have low G6PD activity in the majority of their erythrocytes, yet are usually reported as G6PD "normal" by current phenotypic screening tests. Their haemolytic risk when treated with 8-aminoquinolines has not been well characterized. In a cohort study nested within a randomised clinical trial that compared different treatment regimens for P. vivax malaria, patients with a normal standard NADPH fluorescent spot test result (≳30%-40% of normal G6PD activity) were randomised to receive 3 d of chloroquine or dihydroartemisinin-piperaquine in combination with primaquine, either the standard high dose of 0.5 mg base/kg/day for 14 d or a higher dose of 1 mg base/kg/d for 7 d. Patterns of haemolysis were compared between G6PD wild-type and G6PD heterozygous female participants. Between 21 February 2012 and 04 July 2014, 241 female participants were enrolled, of whom 34 were heterozygous for the G6PD Mahidol variant. Haemolysis was substantially greater and a larger proportion of participants reached the threshold of clinically significant haemolysis (fractional haematocrit reduction >25%) in G6PD heterozygotes taking the higher (7 d) primaquine dose (9/17 [53%]) compared with G6PD heterozygotes taking the standard high (14 d) dose (2/16 [13%]; p = 0.022). In heterozygotes, the mean fractional haematocrit reductions were correspondingly greater with the higher primaquine dose (7-d regimen): -20.4% (95% CI -26.0% to -14.8%) (nadir on day 5) compared with the standard high (14 d) dose: -13.1% (95% CI -17.6% to -8.6%) (nadir day 6). Two heterozygotes taking the higher (7 d) primaquine dose required blood transfusion. In wild-type participants

  6. Mastocytosis of the female breast.

    PubMed

    Setia, Namrata; Crisi, Giovanna M; Pantanowitz, Liron

    2010-10-01

    A subset of patients with systemic mastocytosis may manifest with extracutaneous involvement. To the best of our knowledge, mastocytosis of the human breast has not been described. This study reports a case with mastocytosis involving the breasts of a 33-year-old woman associated with mammary hypertrophy (breast mastocytosis). The potential for infiltrating mast cells to mimic lobular carcinoma is emphasized and the relationship to breast hypertrophy in this case is discussed.

  7. Breast cancer in Poland syndrome.

    PubMed

    Havlik, R J; Sian, K U; Wagner, J D; Binford, R; Broadie, T A

    1999-07-01

    A 33-year-old African-American woman with a severe manifestation of Poland syndrome developed breast cancer in the ipsilateral breast. She had a severely hypoplastic upper extremity, including symbrachydactyly, and a hypoplastic forearm and upper arm. In addition, she lacked the sternal origin of the pectoralis muscle. She had a very small nipple-areola complex and no axillary hair. This is the first case report of breast cancer developing in the ipsilateral breast of a patient with Poland syndrome.

  8. Cardiac Rehabilitation Program in Improving Cardiorespiratory Fitness in Stage 0-III Breast Cancer Survivors

    ClinicalTrials.gov

    2018-01-04

    Cancer Survivor; Stage 0 Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  9. Virtual Weight Loss Program in Maintaining Weight in African American Breast Cancer Survivors

    ClinicalTrials.gov

    2018-06-13

    Cancer Survivor; Invasive Breast Carcinoma; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  10. Computerized Cognitive Retraining in Improving Cognitive Function in Breast Cancer Survivors

    ClinicalTrials.gov

    2017-12-11

    Cancer Survivor; Stage 0 Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  11. R353Q polymorphism in the factor VII gene and cardiovascular risk in Heterozygous Familial Hypercholesterolemia: a case-control study

    PubMed Central

    2011-01-01

    Background Heterozygous Familial Hypercholesterolemia (FH) is a genetic disorder characterized by a high risk of cardiovascular disease. Certain polymorphisms of the factor VII gene have been associated with the development of coronary artery disease and there is a known association between factor VII levels and polymorphic variants in this gene. To date, no study has evaluated the association between factor VII and coronary artery disease in patients with FH. Results This case-control study comprised 720 patients (546 with FH and 174 controls). We determined the prevalence and allele frequencies of the R353Q polymorphism of factor VII, the plasma levels of factor VII antigen (FVII Ag) and whether they could be predictive factors for cardiovascular risk. 75% (410) of the patients with FH were RR, 23% (127) RQ and 1.6% (9) QQ; in the control group 75.3% (131) were RR, 21.3% (37) RQ and 3.4% (6) QQ (p = 0.32). No statistically significant associations were observed in the distribution of genotypes and allele frequencies between case (FH) and control groups. Nor did we find differences when we evaluated the relationship between the R353Q polymorphism and cardiovascular risk (including coronary disease, ischemic stroke and peripheral arterial disease), either in the univariate analysis or after adjustment for sex, age, arterial hypertension, body mass index, xanthomas, diabetes, smoking, HDLc and LDLc and lipid-lowering treatment. The FVII Ag concentrations behaved in a similar fashion, with no differences for the interaction between controls and those with FH (RR vs. RQ/QQ; p = 0.96). In the subgroup of patients with FH no association was found among cardiovascular disease, genotype and FVII Ag levels (RR vs. RQ/QQ; p = 0.97). Conclusions Our study did not find a direct relationship between cardiovascular risk in patients with Heterozygous Familial Hypercholesterolemia, the R353Q polymorphism of factor VII and FVII Ag levels. PMID:21477332

  12. Effect of the APOC3 Sst I SNP on fasting triglyceride levels in men heterozygous for the LPL P207L deficiency.

    PubMed

    Garenc, Christophe; Couillard, Charles; Laflamme, Nathalie; Cadelis, François; Gagné, Claude; Couture, Patrick; Julien, Pierre; Bergeron, Jean

    2005-10-01

    Lipoprotein lipase (LPL) plays a major role in triglyceride (TG)-rich lipoprotein catabolism. A mutation at codon 207 (P207L) in the exon 5 of the LPL gene has been associated with 50% reduction in postheparin plasma LPL activity and significant increase in plasma TG levels in heterozygous individuals with low HDL. However, heterogeneity in fasting TG concentrations among these carriers suggests that other factors may be involved in the expression of this hypertriglyceridemic state. Indeed, previous studies have shown that the rare S2 allele of the APOC3 Sst I polymorphism was associated with higher concentrations of TG levels in noncarriers of LPL defect. Therefore, we investigated the association of the APOC3 Sst I variant on fasting lipoprotein-lipid levels in a sample of 35 heterozygous men bearing the LPL P207L mutation. Genetic association analyses were performed using the two-genotype groups S1/S1 and S1/S2. The genotype S1/S2 group was characterized by greater plasma cholesterol (plasma-C, P=0.02), plasma-TG (P=0.04), very low-density lipoproteins (VLDL)-C (P=0.004), VLDL-TG (P=0.01), VLDL-apolipoprotein B (apoB) (P=0.001) levels and cholesterol/HDL-C ratio (P=0.008), as well as lower VLDL-TG/VLDL-apoB ratio compared to the S1/S1 genotype group. These results support an exacerbating effect of the APOC3 Sst I single-nucleotide polymorphism on fasting TG levels since a large number of smaller VLDL particles are observed in LPL-deficient men bearing the APOC3 S2 allele.

  13. Variable X-chromosome inactivation and enlargement of pericentral glutamine synthetase zones in the liver of heterozygous females with OTC deficiency.

    PubMed

    Musalkova, Dita; Sticova, Eva; Reboun, Martin; Sokolova, Jitka; Krijt, Jakub; Honzikova, Jitka; Gurka, Jiri; Neroldova, Magdalena; Honzik, Tomas; Zeman, Jiri; Jirsa, Milan; Dvorakova, Lenka; Hrebicek, Martin

    2018-06-01

    Ornithine transcarbamylase (OTC) deficiency is an X-linked disorder that causes recurrent and life-threatening episodes of hyperammonemia. The clinical picture in heterozygous females is highly diverse and derives from the genotype and the degree of inactivation of the mutated X chromosome in hepatocytes. Here, we describe molecular genetic, biochemical, and histopathological findings in the livers explanted from two female patients with late-onset OTC deficiency. Analysis of X-inactivation ratios by DNA methylation-based assays showed remarkable intra-organ variation ranging from 46:54 to 82:18 (average 70:30, n = 37), in favor of the active X chromosome carrying the mutation c.583G>C (p.G195R), in the first patient and from 75:25 to 90:10 (average 82:18, n = 20) in favor of the active X chromosome carrying the splicing mutation c.663+1G>A in the second patient. The X-inactivation ratios in liver samples correlated highly with the proportions of OTC-positive hepatocytes calculated from high-resolution image analyses of the immunohistochemically detected OTC in frozen sections that was performed on total area > 5 cm 2 . X-inactivation ratios in blood in both female patients corresponded to the lower limit of the liver values. Our data indicate that the proportion of about 20-30% of hepatocytes expressing the functional OTC protein is not sufficient to maintain metabolic stability. X-inactivation ratios assessed in liver biopsies taken from heterozygous females with X-linked disorders should not be considered representative of the whole liver.

  14. Exome sequencing reveals two novel compound heterozygous XYLT1 mutations in a Polish patient with Desbuquois dysplasia type 2 and growth hormone deficiency.

    PubMed

    Jamsheer, Aleksander; Olech, Ewelina M; Kozłowski, Kazimierz; Niedziela, Marek; Sowińska-Seidler, Anna; Obara-Moszyńska, Monika; Latos-Bieleńska, Anna; Karczewski, Marek; Zemojtel, Tomasz

    2016-07-01

    Desbuquois dysplasia type 2 (DBQD2) is a rare recessively inherited skeletal genetic disorder characterized by severe prenatal and postnatal growth retardation, generalized joint laxity with dislocation of large joints and facial dysmorphism. The condition was recently described to result from autosomal recessive mutations in XYLT1, encoding the enzyme xylosyltransferase-1. In this paper, we report on a Polish patient with DBQD2 who presented with severe short stature of prenatal onset, joint laxity, psychomotor retardation and multiple radiological abnormalities including short metacarpals, advanced bone age and exaggerated trochanters. Endocrinological examinations revealed that sleep-induced growth hormone (GH) release and GH peak in clonidine- and glucagon-induced provocative tests as well as insulin-like growth factor 1 (IGF-1) and IGF-binding protein-3 levels were all markedly decreased, confirming deficiency of GH secretion. Bone age, unlikely to GH deficiency, was significantly advanced. To establish the diagnosis at a molecular level, we performed whole-exome sequencing and bioinformatic analysis in the index patient, which revealed compound heterozygous XYLT1 mutations: c.595C>T(p.Gln199*) and c.1651C>T(p.Arg551Cys), both of which are novel. Sanger sequencing showed that the former mutation was inherited from the healthy mother, whereas the latter one most probably occurred de novo. Our study describes the first case of DBQD2 resulting from compound heterozygous XYLT1 mutation, expands the mutational spectrum of the disease and provides evidence that the severe growth retardation and microsomia observed in DBQD2 patients may result not only from the skeletal dysplasia itself but also from GH and IGF-1 deficiency.

  15. Heterozygous Null Bone Morphogenetic Protein Receptor Type 2 Mutations Promote SRC Kinase-dependent Caveolar Trafficking Defects and Endothelial Dysfunction in Pulmonary Arterial Hypertension*

    PubMed Central

    Prewitt, Allison R.; Ghose, Sampa; Frump, Andrea L.; Datta, Arumima; Austin, Eric D.; Kenworthy, Anne K.; de Caestecker, Mark P.

    2015-01-01

    Hereditary pulmonary arterial hypertension (HPAH) is a rare, fatal disease of the pulmonary vasculature. The majority of HPAH patients inherit mutations in the bone morphogenetic protein type 2 receptor gene (BMPR2), but how these promote pulmonary vascular disease is unclear. HPAH patients have features of pulmonary endothelial cell (PEC) dysfunction including increased vascular permeability and perivascular inflammation associated with decreased PEC barrier function. Recently, frameshift mutations in the caveolar structural protein gene Caveolin-1 (CAV-1) were identified in two patients with non-BMPR2-associated HPAH. Because caveolae regulate endothelial function and vascular permeability, we hypothesized that defects in caveolar function might be a common mechanism by which BMPR2 mutations promote pulmonary vascular disease. To explore this, we isolated PECs from mice carrying heterozygous null Bmpr2 mutations (Bmpr2+/−) similar to those found in the majority of HPAH patients. We show that Bmpr2+/− PECs have increased numbers and intracellular localization of caveolae and caveolar structural proteins CAV-1 and Cavin-1 and that these defects are reversed after blocking endocytosis with dynasore. SRC kinase is also constitutively activated in Bmpr2+/− PECs, and localization of CAV-1 to the plasma membrane is restored after treating Bmpr2+/− PECs with the SRC kinase inhibitor 3-(4-chlorophenyl)-1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (PP2). Late outgrowth endothelial progenitor cells isolated from HPAH patients show similar increased activation of SRC kinase. Moreover, Bmpr2+/− PECs have impaired endothelial barrier function, and barrier function is restored after treatment with PP2. These data suggest that heterozygous null BMPR2 mutations promote SRC-dependent caveolar trafficking defects in PECs and that this may contribute to pulmonary endothelial barrier dysfunction in HPAH patients. PMID:25411245

  16. R353Q polymorphism in the factor VII gene and cardiovascular risk in Heterozygous Familial Hypercholesterolemia: a case-control study.

    PubMed

    Criado-García, Juan; Fuentes, Francisco; Cruz-Teno, Cristina; García-Rios, Antonio; Jiménez-Morales, Anabel; Delgado-Lista, Javier; Mata, Pedro; Alonso, Rodrigo; López-Miranda, José; Pérez-Jiménez, Francisco

    2011-04-09

    Heterozygous Familial Hypercholesterolemia (FH) is a genetic disorder characterized by a high risk of cardiovascular disease. Certain polymorphisms of the factor VII gene have been associated with the development of coronary artery disease and there is a known association between factor VII levels and polymorphic variants in this gene. To date, no study has evaluated the association between factor VII and coronary artery disease in patients with FH. This case-control study comprised 720 patients (546 with FH and 174 controls). We determined the prevalence and allele frequencies of the R353Q polymorphism of factor VII, the plasma levels of factor VII antigen (FVII Ag) and whether they could be predictive factors for cardiovascular risk. 75% (410) of the patients with FH were RR, 23% (127) RQ and 1.6% (9) QQ; in the control group 75.3% (131) were RR, 21.3% (37) RQ and 3.4% (6) QQ (p = 0.32). No statistically significant associations were observed in the distribution of genotypes and allele frequencies between case (FH) and control groups. Nor did we find differences when we evaluated the relationship between the R353Q polymorphism and cardiovascular risk (including coronary disease, ischemic stroke and peripheral arterial disease), either in the univariate analysis or after adjustment for sex, age, arterial hypertension, body mass index, xanthomas, diabetes, smoking, HDLc and LDLc and lipid-lowering treatment. The FVII Ag concentrations behaved in a similar fashion, with no differences for the interaction between controls and those with FH (RR vs. RQ/QQ; p = 0.96). In the subgroup of patients with FH no association was found among cardiovascular disease, genotype and FVII Ag levels (RR vs. RQ/QQ; p = 0.97). Our study did not find a direct relationship between cardiovascular risk in patients with Heterozygous Familial Hypercholesterolemia, the R353Q polymorphism of factor VII and FVII Ag levels.

  17. A heterozygous microdeletion of 20p12.2-3 encompassing PROKR2 and BMP2 in a patient with congenital hypopituitarism and growth hormone deficiency.

    PubMed

    Parsons, Samuel J H; Wright, Neville B; Burkitt-Wright, Emma; Skae, Mars S; Murray, Phillip G

    2017-08-01

    Congenital growth hormone deficiency is a rare disorder with an incidence of approximately 1 in 4,000 live births. Pituitary development is under the control of a multitude of spatiotemporally regulated signaling molecules and transcription factors. Mutations in the genes encoding these molecules can result in hypopituitarism but for the majority of children with congenital hypopituitarism, the aetiology of their disease remains unknown. The proband is a 5-year-old girl who presented with neonatal hypoglycaemia and prolonged jaundice. No definitive endocrine cause of hypoglycaemia was identified in the neonatal period. She was born of normal size at 42 weeks but demonstrated growth failure with a progressive reduction in height to -3.2 SD by age 4.5 years and failed a growth hormone stimulation test with a peak growth hormone of 4.2 mcg/L. MRI of the pituitary gland demonstrated a hypoplastic anterior lobe and ectopic posterior lobe. Array CGH demonstrated an inherited 0.2 Mb gain at 1q21.1 and a de novo 4.8 Mb heterozygous deletion at 20p12.2-3. The deletion contained 17 protein coding genes including PROKR2 and BMP2, both of which are expressed during embryological development of the pituitary gland. PROKR2 mutations have been associated with hypopituitarism but a heterozygous deletion of this gene with hypopituitarism is a novel observation. In conclusion, congenital hypopituitarism can be present in individuals with a 20p12.3 deletion, observed with incomplete penetrance. Array CGH may be a useful investigation in select cases of early onset growth hormone deficiency, and patients with deletions within this region should be evaluated for pituitary hormone deficiencies. © 2017 Wiley Periodicals, Inc.

  18. Effect of heterozygous deletion of WNK1 on the WNK-OSR1/ SPAK-NCC/NKCC1/NKCC2 signal cascade in the kidney and blood vessels.

    PubMed

    Susa, Koichiro; Kita, Satomi; Iwamoto, Takahiro; Yang, Sung-Sen; Lin, Shih-Hua; Ohta, Akihito; Sohara, Eisei; Rai, Tatemitsu; Sasaki, Sei; Alessi, Dario R; Uchida, Shinichi

    2012-08-01

    We found that a mechanism of hypertension in pseudohypoaldosteronism type II (PHAII) caused by a WNK4 missense mutation (D561A) was activation of the WNK-OSR1/SPAK-NCC signal cascade. However, the pathogenic effect of intronic deletions in WNK1 genes also observed in PHAII patients remains unclear. To understand the pathophysiological roles of WNK1 in vivo, WNK1(+/-)mice have been analyzed, because homozygous WNK1 knockout is embryonic lethal. Although WNK1(+/-) mice have been reported to have hypotension, detailed analyses of the WNK signal cascade in the kidney and other organs of WNK1(+/-) mice have not been performed. We assess the effect of heterozygous deletion of WNK1 on the WNK-OSR1/SPAK-NCC/NKCC1/NKCC2 signal cascade in the kidney and blood vessels. Contrary to the previous report, the blood pressure of WNK1(+/-) mice was not decreased, even under a low-salt diet. Under a WNK4(D561A/+) background, the heterozygous deletion of the WNK1 gene did not reduce the high blood pressure either. We then evaluated the phosphorylation status of OSR1, SPAK, NCC, NKCC1, and NKCC2 in the kidney, but no significant decrease in the phosphorylation was observed in WNK1(+/-) mice or WNK1(+/-)WNK4(D561A/+) mice. In contrast, a significant decrease in NKCC1 phosphorylation in the aorta and a decreased pressure-induced myogenic response in the mesenteric arteries were observed in WNK1(+/-) mice. The contribution of WNK1 to total WNK kinase activity in the kidney may be small, but that WNK1 may play a substantial role in the regulation of blood pressure in the arteries.

  19. A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis.

    PubMed

    Olson, Heather E; Jean-Marçais, Nolwenn; Yang, Edward; Heron, Delphine; Tatton-Brown, Katrina; van der Zwaag, Paul A; Bijlsma, Emilia K; Krock, Bryan L; Backer, E; Kamsteeg, Erik-Jan; Sinnema, Margje; Reijnders, Margot R F; Bearden, David; Begtrup, Amber; Telegrafi, Aida; Lunsing, Roelineke J; Burglen, Lydie; Lesca, Gaetan; Cho, Megan T; Smith, Lacey A; Sheidley, Beth R; Moufawad El Achkar, Christelle; Pearl, Phillip L; Poduri, Annapurna; Skraban, Cara M; Tarpinian, Jennifer; Nesbitt, Addie I; Fransen van de Putte, Dietje E; Ruivenkamp, Claudia A L; Rump, Patrick; Chatron, Nicolas; Sabatier, Isabelle; De Bellescize, Julitta; Guibaud, Laurent; Sweetser, David A; Waxler, Jessica L; Wierenga, Klaas J; Donadieu, Jean; Narayanan, Vinodh; Ramsey, Keri M; Nava, Caroline; Rivière, Jean-Baptiste; Vitobello, Antonio; Tran Mau-Them, Frédéric; Philippe, Christophe; Bruel, Ange-Line; Duffourd, Yannis; Thomas, Laurel; Lelieveld, Stefan H; Schuurs-Hoeijmakers, Janneke; Brunner, Han G; Keren, Boris; Thevenon, Julien; Faivre, Laurence; Thomas, Gary; Thauvin-Robinet, Christel

    2018-05-03

    Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Both proteins harbor cargo(furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase. Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control. Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function. These findings support the causality of this recurrent de novo PACS2 heterozygous missense in DEEs with facial dysmorphim and cerebellar dysgenesis. Copyright © 2018 American Society of Human Genetics. All rights reserved.

  20. Breast Cancer Basics and You

    MedlinePlus

    ... page please turn JavaScript on. Feature: Screening For Breast Cancer Breast Cancer Basics and You Past Issues / Summer 2014 Table ... more than 232,670 new cases of female breast cancer in the United States in 2014. More than ...

  1. Seaweed prevents breast cancer?

    PubMed

    Funahashi, H; Imai, T; Mase, T; Sekiya, M; Yokoi, K; Hayashi, H; Shibata, A; Hayashi, T; Nishikawa, M; Suda, N; Hibi, Y; Mizuno, Y; Tsukamura, K; Hayakawa, A; Tanuma, S

    2001-05-01

    To investigate the chemopreventive effects of seaweed on breast cancer, we have been studying the relationship between iodine and breast cancer. We found earlier that the seaweed, wakame, showed a suppressive effect on the proliferation of DMBA (dimethylbenz(a)anthracene)-induced rat mammary tumors, possibly via apoptosis induction. In the present study, powdered mekabu was placed in distilled water, and left to stand for 24 h at 4 degrees C. The filtered supernatant was used as mekabu solution. It showed an extremely strong suppressive effect on rat mammary carcinogenesis when used in daily drinking water, without toxicity. In vitro, mekabu solution strongly induced apoptosis in 3 kinds of human breast cancer cells. These effects were stronger than those of a chemotherapeutic agent widely used to treat human breast cancer. Furthermore, no apoptosis induction was observed in normal human mammary cells. In Japan, mekabu is widely consumed as a safe, inexpensive food. Our results suggest that mekabu has potential for chemoprevention of human breast cancer.

  2. Drugs in breast milk.

    PubMed

    Hervada, A R; Feit, E; Sagraves, R

    1978-09-01

    The amount of drug excreted into breast milk is dependent upon the lipid solubility of the medication, the mechanism of transport, the degree of ionization, and change in plasma pH. The higher the lipid solubility, the greater the concentration in human milk. The majority of drugs are transported into mammary blood capillaries by passive diffusion. The rest are transported by reverse pinocytosis. Once the drug has entered the epithelial cells of breast tissue, the drug molecules are excreted into the human milk by active transport, passive diffusion, or apocrine secretion. The amount of free (active) drug available for transport depends on the degree of protein binding the plasma pH. Another factor affecting excretion of drugs is the time when breast feeding occurs. In the 1st few days of life, when colostrum is present, water-soluble drugs pass through the breast more easily than afterwards when milk is produced. Then lipid-soluble drugs cross in higher concentrations. The effect on nursing infants is dependent on the amount excreted into the milk, the total amount absorbed by the infant, and the toxicity of the drug. The use of the following drugs in breast feeding mothers is reviewed: anticoagulants, antihypertensives and diuretics, antimicrobials, drugs affecting the central nervous system (alcohol, chloral hydrate, meprobamate, lithium, and aspirin), marijuana, other drugs (antihistamines, atropine, ergot alkaloids, laxatives, nicotine, iodides, propylthiouracil, theophylline), hormones (insulin, thyroxine, and oral contraceptives), and radiopharmaceuticals.

  3. Benign Breast Disease, Mammographic Breast Density, and the Risk of Breast Cancer

    PubMed Central

    2013-01-01

    Background Benign breast disease and high breast density are prevalent, strong risk factors for breast cancer. Women with both risk factors may be at very high risk. Methods We included 42818 women participating in the Breast Cancer Surveillance Consortium who had no prior diagnosis of breast cancer and had undergone at least one benign breast biopsy and mammogram; 1359 women developed incident breast cancer in 6.1 years of follow-up (78.1% invasive, 21.9% ductal carcinoma in situ). We calculated hazard ratios (HRs) using Cox regression analysis. The referent group was women with nonproliferative changes and average density. All P values are two-sided. Results Benign breast disease and breast density were independently associated with breast cancer. The combination of atypical hyperplasia and very high density was uncommon (0.6% of biopsies) but was associated with the highest risk for breast cancer (HR = 5.34; 95% confidence interval [CI] = 3.52 to 8.09, P < .001). Proliferative disease without atypia (25.6% of biopsies) was associated with elevated risk that varied little across levels of density: average (HR = 1.37; 95% CI = 1.11 to 1.69, P = .003), high (HR = 2.02; 95% CI = 1.68 to 2.44, P < .001), or very high (HR = 2.05; 95% CI = 1.54 to 2.72, P < .001). Low breast density (4.5% of biopsies) was associated with low risk (HRs <1) for all benign pathology diagnoses. Conclusions Women with high breast density and proliferative benign breast disease are at very high risk for future breast cancer. Women with low breast density are at low risk, regardless of their benign pathologic diagnosis. PMID:23744877

  4. In the Age of Breast Augmentation, Breast Reconstruction Provides an Opportunity to Augment the Breast.

    PubMed

    Zimmerman, Amanda L; Tugertimur, Bugra; Smith, Paul D; Kumar, Ambuj; Dayicioglu, Deniz

    2017-01-01

    Augmentation mammoplasty remains the most common cosmetic surgery procedure performed. The objective of this article is to evaluate the impact of augmented volume of the reconstructed breast in patients that undergo nipple-sparing mastectomy and patients previously augmented who undergo mastectomy with tissue expander/implant-based reconstruction. Patients undergoing skin-sparing mastectomy, nipple-sparing mastectomy, and mastectomy after previous augmentation followed by tissue expander/implant-based reconstruction between June 2011 and April 2015 by 2 surgeons at the same institution were included. Retrospective chart review of the patients identified using these criteria was performed to record patient characteristics, complications, breast volume, implant volume, and percentage change in volume at the time of reconstruction. Percentage change of breast volume was calculated using the formula (implant breast weight)/(breast weight) for skin-sparing and nipple-sparing mastectomy patients and (final breast implant weight - [breast weight + augmentation breast implant weight])/([breast weight + augmentation breast implant]) for patients undergoing mastectomy following previous augmentation. A total of 293 patients were included in the study with 63 patients who underwent nipple-sparing mastectomy, 166 patients who underwent skin-sparing mastectomy, and 64 patients who underwent previous augmentation with subsequent mastectomy. Mean percentage change in breast volume was 66% in the nipple-sparing mastectomy group, 15% for the right breast and 18% for the left breast in the skin-sparing mastectomy group, and 81% for the right breast and 72% for the left breast in the mastectomy following previous augmentation group. Complication rate for nipple-sparing mastectomy was 27%, mastectomy following previous augmentation was 20.3%, and skin-sparing mastectomy group was 18.7%. Patients who undergo nipple-sparing mastectomy or mastectomy following previous augmentation have

  5. Preoperative Breast Magnetic Resonance Imaging Use by Breast Density and Family History of Breast Cancer.

    PubMed

    Henderson, Louise M; Hubbard, Rebecca A; Zhu, Weiwei; Weiss, Julie; Wernli, Karen J; Goodrich, Martha E; Kerlikowske, Karla; DeMartini, Wendy; Ozanne, Elissa M; Onega, Tracy

    2018-01-15

    Use of preoperative breast magnetic resonance imaging (MRI) among women with a new breast cancer has increased over the past decade. MRI use is more frequent in younger women and those with lobular carcinoma, but associations with breast density and family history of breast cancer are unknown. Data for 3075 women ages >65 years with stage 0-III breast cancer who underwent breast conserving surgery or mastectomy from 2005 to 2010 in the Breast Cancer Surveillance Consortium were linked to administrative claims data to assess associations of preoperative MRI use with mammographic breast density and first-degree family history of breast cancer. Multivariable logistic regression estimated adjusted odds ratios (OR) and 95% confidence intervals (95% CI) for the association of MRI use with breast density and family history, adjusting for woman and tumor characteristics. Overall, preoperative MRI use was 16.4%. The proportion of women receiving breast MRI was similar by breast density (17.6% dense, 16.9% nondense) and family history (17.1% with family history, 16.5% without family history). After adjusting for potential confounders, we found no difference in preoperative MRI use by breast density (OR = 0.95 for dense vs. nondense, 95% CI: 0.73-1.22) or family history (OR = 0.99 for family history vs. none, 95% CI: 0.73-1.32). Among women aged >65 years with breast cancer, having dense breasts or a first-degree relative with breast cancer was not associated with greater preoperative MRI use. This utilization is in keeping with lack of evidence that MRI has higher yield of malignancy in these subgroups.

  6. Benign breast disease, mammographic breast density, and the risk of breast cancer.

    PubMed

    Tice, Jeffrey A; O'Meara, Ellen S; Weaver, Donald L; Vachon, Celine; Ballard-Barbash, Rachel; Kerlikowske, Karla

    2013-07-17

    Benign breast disease and high breast density are prevalent, strong risk factors for breast cancer. Women with both risk factors may be at very high risk. We included 42818 women participating in the Breast Cancer Surveillance Consortium who had no prior diagnosis of breast cancer and had undergone at least one benign breast biopsy and mammogram; 1359 women developed incident breast cancer in 6.1 years of follow-up (78.1% invasive, 21.9% ductal carcinoma in situ). We calculated hazard ratios (HRs) using Cox regression analysis. The referent group was women with nonproliferative changes and average density. All P values are two-sided. Benign breast disease and breast density were independently associated with breast cancer. The combination of atypical hyperplasia and very high density was uncommon (0.6% of biopsies) but was associated with the highest risk for breast cancer (HR = 5.34; 95% confidence interval [CI] = 3.52 to 8.09, P < .001). Proliferative disease without atypia (25.6% of biopsies) was associated with elevated risk that varied little across levels of density: average (HR = 1.37; 95% CI = 1.11 to 1.69, P = .003), high (HR = 2.02; 95% CI = 1.68 to 2.44, P < .001), or very high (HR = 2.05; 95% CI = 1.54 to 2.72, P < .001). Low breast density (4.5% of biopsies) was associated with low risk (HRs <1) for all benign pathology diagnoses. Women with high breast density and proliferative benign breast disease are at very high risk for future breast cancer. Women with low breast density are at low risk, regardless of their benign pathologic diagnosis.

  7. Nodular Fasciitis of the Breast Previously Misdiagnosed as Breast Carcinoma

    PubMed Central

    Ozben, Volkan; Aydogan, Fatih; Karaca, Fatih Can; Ilvan, Sennur; Uras, Cihan

    2009-01-01

    Summary Background Nodular fasciitis of the breast is a rare benign pathology that can mimic breast cancer clinically, radiologically, and histopathologically. Case Report An 18-year-old female patient had first visited a physician in a different center with the complaint of a lump in her left breast. Breast examination had revealed a palpable mass located in the left upper outer quadrant. Ultrasonography had demonstrated a hypoechoic lesion. Excisional biopsy of the lump had been performed and histopathologic examination misdiagnosed this lump as a mesenchymal tumor. The patient was then referred to our clinic for further investigations. Pathologic revision was performed and the diagnosis of nodular fasciitis of the breast was established. Conclusion Awareness of this rare clinical entity, nodular fasciitis, in the breast eliminates the misdiagnosis of breast cancer. PMID:20877676

  8. Reductive Augmentation of the Breast.

    PubMed

    Chasan, Paul E

    2018-06-01

    Although breast reduction surgery plays an invaluable role in the correction of macromastia, it almost always results in a breast lacking in upper pole fullness and/or roundness. We present a technique of breast reduction combined with augmentation termed "reductive augmentation" to solve this problem. The technique is also extremely useful for correcting breast asymmetry, as well as revising significant pseudoptosis in the patient who has previously undergone breast augmentation with or without mastopexy. An evolution of techniques has been used to create a breast with more upper pole fullness and anterior projection in those patients desiring a more round, higher-profile appearance. Reductive augmentation is a one-stage procedure in which a breast augmentation is immediately followed by a modified superomedial pedicle breast reduction. Often, the excision of breast tissue is greater than would normally be performed with breast reduction alone. Thirty-five patients underwent reductive augmentation, of which 12 were primary surgeries and 23 were revisions. There was an average tissue removal of 255 and 227 g, respectively, per breast for the primary and revision groups. Six of the reductive augmentations were performed for gross asymmetry. Fourteen patients had a previous mastopexy, and 3 patients had a previous breast reduction. The average follow-up was 26 months. Reductive augmentation is an effective one-stage method for achieving a more round-appearing breast with upper pole fullness both in primary breast reduction candidates and in revisionary breast surgery. This technique can also be applied to those patients with significant asymmetry. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

  9. Hypohidrotic Ectodermal Dysplasia: Breastfeeding Complications Due to Impaired Breast Development.

    PubMed

    Wahlbuhl-Becker, Mandy; Faschingbauer, Florian; Beckmann, Matthias W; Schneider, Holm

    2017-04-01

    Background X-linked hypohidrotic ectodermal dysplasia (XLHED), the most common form of ectodermal dysplasia, is caused by mutations in the gene EDA. While only affected men develop the full-blown clinical picture, females who are heterozygous for an EDA mutation often also show symptoms such as hypodontia, hypotrichosis and hypohidrosis. These women may also suffer from malformations of the mammary gland which represent not just a cosmetic problem but can limit their breastfeeding capability. This paper summarizes the findings of the first systematic study on the impact of hypohidrotic ectodermal dysplasia on breastfeeding. Patients Thirty-eight adult female members of the German-Swiss-Austrian ectodermal dysplasia patient support group participated in a structured interview; most of them also agreed to a photodocumentation of their mammary region. Thirty-one women carried mutations in EDA (Group A) and seven were affected by other forms of hypohidrotic ectodermal dysplasia (Group B). Results 39 % of the women of Group A reported that their breasts were of different size or entirely absent on one side. In Group B, 86 % of the women reported differently sized or even absent breasts; two of these women lacked both breasts entirely. Most women described their nipples as exceptionally flat. 10 % of the women of Group A had more than two nipples. The high percentage of deviations from the norm was confirmed in the photodocumentation. Both groups had few or no sebaceous glands of Montgomery in the areolar region. Around 80 % of interviewed women had children and had attempted to breastfeed their first child. 67 % of the mothers in Group A had had difficulty in breastfeeding their infants and generally attributed this difficulty to their flat nipples. All of the mothers in Group B reported difficulties in breastfeeding; 60 % had not been able to breastfeed their first child. Conclusion Mothers with hypohidrotic ectodermal dysplasia very often have difficulty

  10. Brucellar breast abscess.

    PubMed

    Erdem, G; Karakas, H M; Yetkin, F; Alkan, A; Firat, A K; Kahraman, B

    2006-08-01

    Brucellosis is an endemic disease seen in many countries. It may affect different organ systems. Brucellar breast abscess is a rare entity. We report the radiological findings of breast abscess due to brucella. A 63-year-old female was investigated with mammography, ultrasonography, magnetic resonance imaging (MRI), and magnetic resonance spectroscopy (MRS). A mass measuring 25 x 20 x 15 mm was detected in the left breast on mammography and ultrasonography. The mass was homogenously hyperintense on T1- and T2-weighted MRI images. On contrast-enhanced T1-weighted images, peripheral capsular enhancement was found. MR spectroscopic analysis of the mass revealed elevated lipid and acetate peaks. The diagnosis was provided by fine needle aspiration biopsy and specimen culture. The lesion had diminished in size after 12 months' treatment with combined tetracycline and rifampicine.

  11. Breast tissue engineering.

    PubMed

    Patrick, Charles W

    2004-01-01

    Tissue engineering has the potential to redefine rehabilitation for the breast cancer patient by providing a translatable strategy that restores the postmastectomy breast mound while concomitantly obviating limitations realized with contemporary reconstructive surgery procedures. The engineering design goal is to provide a sufficient volume of viable fat tissue based on a patient's own cells such that deficits in breast volume can be abrogated. To be sure, adipose tissue engineering is in its infancy, but tremendous strides have been made. Numerous studies attest to the feasibility of adipose tissue engineering. The field is now poised to challenge barriers to clinical translation that are germane to most tissue engineering applications, namely scale-up, large animal model development, and vascularization. The innovative and rapid progress of adipose engineering to date, as well as opportunities for its future growth, is presented.

  12. Reproduction and Breast Cancer Risk

    PubMed Central

    Hanf, Volker; Hanf, Dorothea

    2014-01-01

    Summary Reproduction is doubtlessly one of the main biological meanings of life. It is therefore not surprising that various aspects of reproduction impact on breast cancer risk. Various developmental levels may become targets of breast tumorigenesis. This review follows the chronologic sequence of events in the life of a female at risk, starting with the intrauterine development. Furthermore, the influence of both contraceptive measures and fertility treatment on breast cancer development is dealt with, as well as various pregnancy-associated factors, events, and perinatal outcomes. Finally, the contribution of breast feeding to a reduced breast cancer risk is discussed. PMID:25759622

  13. Breast manifestations of systemic diseases

    PubMed Central

    Dilaveri, Christina A; Mac Bride, Maire Brid; Sandhu, Nicole P; Neal, Lonzetta; Ghosh, Karthik; Wahner-Roedler, Dietlind L

    2012-01-01

    Although much emphasis has been placed on the primary presentations of breast cancer, little focus has been placed on how systemic illnesses may affect the breast. In this article, we discuss systemic illnesses that can manifest in the breast. We summarize the clinical features, imaging, histopathology, and treatment recommendations for endocrine, vascular, systemic inflammatory, infectious, and hematologic diseases, as well as for the extramammary malignancies that can present in the breast. Despite the rarity of these manifestations of systemic disease, knowledge of these conditions is critical to the appropriate evaluation and treatment of patients presenting with breast symptoms. PMID:22371658

  14. Congenital anomalies of the breast.

    PubMed

    Caouette-Laberge, Louise; Borsuk, Daniel

    2013-02-01

    Poland syndrome is a combination of chest wall deformity and absent or hypoplastic pectoralis muscle and breast associated with shortening and brachysyndactyly of the upper limb. Clinical presentation varies widely; therefore, reconstructive procedures have to be adapted to the deformity, ranging from chest wall stabilization or augmentation, dynamic muscle transfer, nipple and areola repositioning, and breast augmentation using prosthesis or autologous tissue transfer. Other congenital breast anomalies include supernumerary nipple and areola (polythelia) and breast (polymastia), which can generally be found on the embryonic mammary ridge. Absence of the nipple, areola (athelia), or the breast tissue (amastia) is less frequent.

  15. Congenital Anomalies of the Breast

    PubMed Central

    Caouette-Laberge, Louise; Borsuk, Daniel

    2013-01-01

    Poland syndrome is a combination of chest wall deformity and absent or hypoplastic pectoralis muscle and breast associated with shortening and brachysyndactyly of the upper limb. Clinical presentation varies widely; therefore, reconstructive procedures have to be adapted to the deformity, ranging from chest wall stabilization or augmentation, dynamic muscle transfer, nipple and areola repositioning, and breast augmentation using prosthesis or autologous tissue transfer. Other congenital breast anomalies include supernumerary nipple and areola (polythelia) and breast (polymastia), which can generally be found on the embryonic mammary ridge. Absence of the nipple, areola (athelia), or the breast tissue (amastia) is less frequent. PMID:24872738

  16. Ultrasound in Detecting Taxane-Induced Neuropathy in Patients With Breast Cancer

    ClinicalTrials.gov

    2018-04-26

    Peripheral Neuropathy; Stage 0 Breast Cancer; Stage I Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage III Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer

  17. Coronal Activity in the R CrA T Association

    NASA Technical Reports Server (NTRS)

    Patten, Brian M.; Oliversen, Ronald J. (Technical Monitor)

    2005-01-01

    Brian Patten is the Principal Investigator of the NASA ROSS-ADP project Coronal Activity in the R CrA T Association. For this project we have extracted net counts and variability information for all of the X-ray sources found in 23 archival ROSAT PSPC and HRI images in the region of the R CrA T association. These data have been merged with an extensive database of optical and near-infrared photometry, optical spectroscopy, and parallax data. These data have been used to (1) identify new association members and clarify the membership status of a number of previously suspected members of the association, and (2) derive, for the first time, an accurate coronal luminosity function for the T Tauri members of this T association and make direct comparisons between the coronal luminosity functions for other T associations and those of large clusters. We have used our survey data to assess (a) the importance of the star-formation environment in initial coronal activity levels, (b) the effects of PMS evolution on dynamo activity as a function of mass and age, and (c) the level of contamination by field post-T Tauri stars on association membership surveys.

  18. Association between Microrna 146a and Microrna 196a2 Genes Polymorphism and Breast Cancer Risk in North Indian Women

    PubMed

    Bodal, Vijay Kumar; Sangwan, Shruti; Bal, Manjit Singh; Kaur, Mohanvir; Sharma, Sidarth; Kaur, Bhavleen

    2017-09-27

    Background: Micro RNAs (miRNAs) are small, noncoding RNA molecules. They can function as either oncogenes or tumor suppressor genes. Single nucleotide polymorphisms (SNP) present in the pre-miRNA region could affect the processing of miRNA and thus alter mature miRNA expression. The studies done so far had shown conflicting results regarding association of two common polymorphisms i.e.hsa-miR-146 rs2910164 and hsa-miR-196a2 rs11614913 with breast cancer. OBJECTIVE: In the study, we examined the hsa-miR-146 rs2910164 and hsa-miR-196a2 rs11614913 SNP association with breast cancer patients in north Indian women. Materials and Methods: This study included 100 breast cancer patients and 100 controls and was done over a period of two years. Genotypes of the hsa-miR-146 (rs2910164 G>C) and hsa-miR-196a2 (rs11614913 C>T) were identified by polymerase chain reaction – restriction length polymorphism (PCR-RFLP) technique in peripheral blood DNA samples. Statistical analysis: We assessed the strength of association of miRNA polymorphisms with breast cancer using Odds ratio (OR) along with 95% confidence intervals. Results: Heterozygous genotypes of hsa-miR-196a2 rs11614913 and combined hsa-miR-146 rs2910164 & hsa-miR-196a2 polymorphism were associated with significantly increased risk of breast cancer (OR-1.7, 95% CI–1.00-3.18) and (OR-1.9, 95% CI-0.85-4.46) respectively. Conclusion: Our study suggests that rs2910164 GC and rs11614913 CT genotypes may contribute to breast cancer susceptibility in north Indian women. Creative Commons Attribution License

  19. Fulvestrant and/or Anastrozole in Treating Postmenopausal Patients With Stage II-III Breast Cancer Undergoing Surgery

    ClinicalTrials.gov

    2018-06-08

    Estrogen Receptor-positive Breast Cancer; HER2-negative Breast Cancer; Invasive Ductal Breast Carcinoma; Invasive Lobular Breast Carcinoma; Recurrent Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  20. Mindfulness Meditation or Survivorship Education in Improving Behavioral Symptoms in Younger Stage 0-III Breast Cancer Survivors (Pathways to Wellness)

    ClinicalTrials.gov

    2018-02-15

    Cancer Survivor; Early-Stage Breast Carcinoma; Stage 0 Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  1. Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer

    ClinicalTrials.gov

    2018-06-08

    Ductal Breast Carcinoma; Invasive Breast Carcinoma; Lobular Breast Carcinoma; Medullary Breast Carcinoma; Stage II Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Tubular Breast Carcinoma

  2. Adipokines in human breast milk.

    PubMed

    Kratzsch, Juergen; Bae, Yoon Ju; Kiess, Wieland

    2018-01-01

    The review describes the molecular characteristics of so far detected breast milk adipokines and ranks their breast milk level compared to the respective levels in maternal and infant blood. Moreover, analytical knowledge for measurements of breast milk adipokines will be delineated. Next, we summarized data about two main potential influencing factors on adipokine concentration in breast milk, maternal weight and pasteurization of milk. Finally, associations between adipokines in breast milk and weight gain in infants as well as the putative mechanisms for effects of breast milk adipokines on food intake and weight gain in later life will debated. Our findings suggest that a source of adipokines in human breast milk cannot be uniformly defined. In dependence on the ratio between serum and breast milk levels the major quantity of these proteins may be derived from peripheral tissues, from the breast tissue itself or from both. Thus, leptin and in part adiponectin levels in breast milk are dependent on a plenty of influencing factors with an important relevance of maternal anthropometric characteristics There is some evidence that leptin, adiponectin and ghrelin levels in breast milk may be associated with growth gain of infants and even with increased risk for being overweight during infancy or childhood. We hypothesize that a dysregulation in adipokine homeostasis in early life could promote obesity and metabolic disturbance in later life. Copyright © 2018 Elsevier Ltd. All rights reserved.

  3. Persistent breast pain among women with histories of breast conserving surgery for breast cancer compared to women without histories of breast surgery or cancer

    PubMed Central

    Edmond, Sara N.; Shelby, Rebecca A.; Keefe, Francis J.; Fisher, Hannah M.; Schmidt, John; Soo, Mary Scott; Skinner, Celette Sugg; Ahrendt, Gretchen M.; Manculich, Jessica; Sumkin, Jules H.; Zuley, Margarita L.; Bovbjerg, Dana H.

    2016-01-01

    Objectives This study compared persistent breast pain among women who received breast-conserving surgery for breast cancer and women without a history of breast cancer. Methods Breast cancer survivors (n=200) were recruited at their first post-surgical surveillance mammogram (6-15 months post-surgery). Women without a breast cancer history (n=150) were recruited at the time of a routine screening mammogram. All women completed measures of breast pain, pain interference with daily activities and intimacy, worry about breast pain, anxiety symptoms, and depression symptoms. Demographic and medical information were also collected. Results Persistent breast pain (duration ≥ 6 months) was reported by 46.5% of breast cancer survivors and 12.7% of women without a breast cancer history (p<0.05). Breast cancer survivors also had significantly higher rates of clinically significant persistent breast pain (pain intensity score ≥3/10), as well as higher average breast pain intensity and unpleasantness scores. Breast cancer survivors with persistent breast pain had significantly higher levels of depressive symptoms, as well as pain worry and interference, compared to survivors without persistent breast pain or women without a breast cancer history. Anxiety symptoms were significantly higher in breast cancer survivors with persistent breast pain compared to women without a breast cancer history. Discussion Results indicate that persistent breast pain negatively impacts women with a history of breast conserving cancer surgery compared to women without that history. Strategies to ameliorate persistent breast pain and to improve adjustment among women with persistent breast pain should be explored for incorporation into standard care for breast cancer survivors. PMID:27922843

  4. Simultaneous Vascular Targeting and Tumor Targeting of Cerebral Breast Cancer Metastases Using a T Cell Receptor Mimic Antibody

    DTIC Science & Technology

    2015-05-01

    ORGANIZATION : Texas Tech University Health Sciences Center Lubbock, TX 79430 REPORT DATE: May 2015 TYPE OF REPORT: Annual...PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER Texas Tech University Health Sciences Center 3601...now available to treat the primary tumor and metastatic disease in peripheral organs . Unfortunately, current therapeutic options for brain metastases

  5. Hemolytic Potential of Tafenoquine in Female Volunteers Heterozygous for Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency (G6PD Mahidol Variant) versus G6PD-Normal Volunteers.

    PubMed

    Rueangweerayut, Ronnatrai; Bancone, Germana; Harrell, Emma J; Beelen, Andrew P; Kongpatanakul, Supornchai; Möhrle, Jörg J; Rousell, Vicki; Mohamed, Khadeeja; Qureshi, Ammar; Narayan, Sushma; Yubon, Nushara; Miller, Ann; Nosten, François H; Luzzatto, Lucio; Duparc, Stephan; Kleim, Jörg-Peter; Green, Justin A

    2017-09-01

    Tafenoquine is an 8-aminoquinoline under investigation for the prevention of relapse in Plasmodium vivax malaria. This open-label, dose-escalation study assessed quantitatively the hemolytic risk with tafenoquine in female healthy volunteers heterozygous for the Mahidol 487A glucose-6-phosphate dehydrogenase (G6PD)-deficient variant versus G6PD-normal females, and with reference to primaquine. Six G6PD-heterozygous subjects (G6PD enzyme activity 40-60% of normal) and six G6PD-normal subjects per treatment group received single-dose tafenoquine (100, 200, or 300 mg) or primaquine (15 mg × 14 days). All participants had pretreatment hemoglobin levels ≥ 12.0 g/dL. Tafenoquine dose escalation stopped when hemoglobin decreased by ≥ 2.5 g/dL (or hematocrit decline ≥ 7.5%) versus pretreatment values in ≥ 3/6 subjects. A dose-response was evident in G6PD-heterozygous subjects ( N = 15) receiving tafenoquine for the maximum decrease in hemoglobin versus pretreatment values. Hemoglobin declines were similar for tafenoquine 300 mg (-2.65 to -2.95 g/dL [ N = 3]) and primaquine (-1.25 to -3.0 g/dL [ N = 5]). Two further cohorts of G6PD-heterozygous subjects with G6PD enzyme levels 61-80% ( N = 2) and > 80% ( N = 5) of the site median normal received tafenoquine 200 mg; hemolysis was less pronounced at higher G6PD enzyme activities. Tafenoquine hemolytic potential was dose dependent, and hemolysis was greater in G6PD-heterozygous females with lower G6PD enzyme activity levels. Single-dose tafenoquine 300 mg did not appear to increase the severity of hemolysis versus primaquine 15 mg × 14 days.

  6. Hemolytic Potential of Tafenoquine in Female Volunteers Heterozygous for Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency (G6PD Mahidol Variant) versus G6PD-Normal Volunteers

    PubMed Central

    Rueangweerayut, Ronnatrai; Bancone, Germana; Harrell, Emma J.; Beelen, Andrew P.; Kongpatanakul, Supornchai; Möhrle, Jörg J.; Rousell, Vicki; Mohamed, Khadeeja; Qureshi, Ammar; Narayan, Sushma; Yubon, Nushara; Miller, Ann; Nosten, François H.; Luzzatto, Lucio; Duparc, Stephan; Kleim, Jörg-Peter; Green, Justin A.

    2017-01-01

    Abstract. Tafenoquine is an 8-aminoquinoline under investigation for the prevention of relapse in Plasmodium vivax malaria. This open-label, dose-escalation study assessed quantitatively the hemolytic risk with tafenoquine in female healthy volunteers heterozygous for the Mahidol487A glucose-6-phosphate dehydrogenase (G6PD)-deficient variant versus G6PD-normal females, and with reference to primaquine. Six G6PD-heterozygous subjects (G6PD enzyme activity 40–60% of normal) and six G6PD-normal subjects per treatment group received single-dose tafenoquine (100, 200, or 300 mg) or primaquine (15 mg × 14 days). All participants had pretreatment hemoglobin levels ≥ 12.0 g/dL. Tafenoquine dose escalation stopped when hemoglobin decreased by ≥ 2.5 g/dL (or hematocrit decline ≥ 7.5%) versus pretreatment values in ≥ 3/6 subjects. A dose–response was evident in G6PD-heterozygous subjects (N = 15) receiving tafenoquine for the maximum decrease in hemoglobin versus pretreatment values. Hemoglobin declines were similar for tafenoquine 300 mg (−2.65 to −2.95 g/dL [N = 3]) and primaquine (−1.25 to −3.0 g/dL [N = 5]). Two further cohorts of G6PD-heterozygous subjects with G6PD enzyme levels 61–80% (N = 2) and > 80% (N = 5) of the site median normal received tafenoquine 200 mg; hemolysis was less pronounced at higher G6PD enzyme activities. Tafenoquine hemolytic potential was dose dependent, and hemolysis was greater in G6PD-heterozygous females with lower G6PD enzyme activity levels. Single-dose tafenoquine 300 mg did not appear to increase the severity of hemolysis versus primaquine 15 mg × 14 days. PMID:28749773

  7. Identify and validate a quantitative trait locus underlying stearic acid on chromosome 14 in a soybean landrace using recombinant inbred lines and resident heterozygous lines

    USDA-ARS?s Scientific Manuscript database

    Stearic acid (ST) is one of the saturated fatty acids (FAs) in soybean oil and great efforts have been made to elevate ST content through plant breeding. Improving ST content will be helpful to reduce the health risk of coronary heart diseases and breast, colon and prostate cancer. In this study, re...

  8. Types of Breast Pumps

    MedlinePlus

    ... nipple (the areola). b. Pump: creates the gentle vacuum that expresses milk. The pump may be attached to the breast-shield or ... out of a larger tube to create a vacuum that expresses milk and collects it in an attached container. Another type of manual pump, called a bicycle horn pump, consists of a ...

  9. Living Beyond Breast Cancer

    MedlinePlus

    ... What is the ACA? Sex and Intimacy Birth Control and Breast Cancer Maintaining Sexual Life If You Feel Pain During Sex Sexual Side Effects Body Image and Sexuality Improving Sexual Health With Medical Approaches Improving Sexual Health With Self Care Talking With ...

  10. Breast Cancer Research Program

    DTIC Science & Technology

    2010-09-01

    a novel curcumin analog that specifically targets tumor blood vessels. Ligand-transformed alpha - fetoprotein peptide (AFPep) – Dr. James Bennett and...showed that inflammatory cytokines (e.g., TNF- alpha ) enhanced nanoparticle uptake by endothelial cells. When animals inoculated with 4T1 breast

  11. Human Breast Cancer Histoid

    PubMed Central

    Kaur, Pavinder; Ward, Brenda; Saha, Baisakhi; Young, Lillian; Groshen, Susan; Techy, Geza; Lu, Yani; Atkinson, Roscoe; Taylor, Clive R.; Ingram, Marylou

    2011-01-01

    Progress in our understanding of heterotypic cellular interaction in the tumor microenvironment, which is recognized to play major roles in cancer progression, has been hampered due to unavailability of an appropriate in vitro co-culture model. The aim of this study was to generate an in vitro 3-dimensional human breast cancer model, which consists of cancer cells and fibroblasts. Breast cancer cells (UACC-893) and fibroblasts at various densities were co-cultured in a rotating suspension culture system to establish co-culture parameters. Subsequently, UACC-893, BT.20, or MDA.MB.453 were co-cultured with fibroblasts for 9 days. Co-cultures resulted in the generation of breast cancer histoid (BCH) with cancer cells showing the invasion of fibroblast spheroids, which were visualized by immunohistochemical (IHC) staining of sections (4 µm thick) of BCH. A reproducible quantitative expression of C-erbB.2 was detected in UACC-893 cancer cells in BCH sections by IHC staining and the Automated Cellular Imaging System. BCH sections also consistently exhibited qualitative expression of pancytokeratins, p53, Ki-67, or E-cadherin in cancer cells and that of vimentin or GSTPi in fibroblasts, fibronectin in the basement membrane and collagen IV in the extracellular matrix. The expression of the protein analytes and cellular architecture of BCH were markedly similar to those of breast cancer tissue. PMID:22034518

  12. Family History of Breast Cancer, Breast Density, and Breast Cancer Risk in a U.S. Breast Cancer Screening Population.

    PubMed

    Ahern, Thomas P; Sprague, Brian L; Bissell, Michael C S; Miglioretti, Diana L; Buist, Diana S M; Braithwaite, Dejana; Kerlikowske, Karla

    2017-06-01

    Background: The utility of incorporating detailed family history into breast cancer risk prediction hinges on its independent contribution to breast cancer risk. We evaluated associations between detailed family history and breast cancer risk while accounting for breast density. Methods: We followed 222,019 participants ages 35 to 74 in the Breast Cancer Surveillance Consortium, of whom 2,456 developed invasive breast cancer. We calculated standardized breast cancer risks within joint strata of breast density and simple (1 st -degree female relative) or detailed (first-degree, second-degree, or first- and second-degree female relative) breast cancer family history. We fit log-binomial models to estimate age-specific breast cancer associations for simple and detailed family history, accounting for breast density. Results: Simple first-degree family history was associated with increased breast cancer risk compared with no first-degree history [Risk ratio (RR), 1.5; 95% confidence interval (CI), 1.0-2.1 at age 40; RR, 1.5; 95% CI, 1.3-1.7 at age 50; RR, 1.4; 95% CI, 1.2-1.6 at age 60; RR, 1.3; 95% CI, 1.1-1.5 at age 70). Breast cancer associations with detailed family history were strongest for women with first- and second-degree family history compared with no history (RR, 1.9; 95% CI, 1.1-3.2 at age 40); this association weakened in higher age groups (RR, 1.2; 95% CI, 0.88-1.5 at age 70). Associations did not change substantially when adjusted for breast density. Conclusions: Even with adjustment for breast density, a history of breast cancer in both first- and second-degree relatives is more strongly associated with breast cancer than simple first-degree family history. Impact: Future efforts to improve breast cancer risk prediction models should evaluate detailed family history as a risk factor. Cancer Epidemiol Biomarkers Prev; 26(6); 938-44. ©2017 AACR . ©2017 American Association for Cancer Research.

  13. Progestins and breast cancer.

    PubMed

    Pasqualini, Jorge R

    2007-10-01

    Progestins exert their progestational activity by binding to the progesterone receptor (form A, the most active and form B, the less active) and may also interact with other steroid receptors (androgen, glucocorticoid, mineralocorticoid, estrogen). They can have important effects in other tissues besides the endometrium, including the breast, liver, bone and brain. The biological responses of progestins cover a very large domain: lipids, carbohydrates, proteins, water and electrolyte regulation, hemostasis, fibrinolysis, and cardiovascular and immunological systems. At present, more than 200 progestin compounds have been synthesized, but the biological response could be different from one to another depending on their structure, metabolism, receptor affinity, experimental conditions, target tissue or cell line, as well as the biological response considered. There is substantial evidence that mammary cancer tissue contains all the enzymes responsible for the local biosynthesis of estradiol (E(2)) from circulating precursors. Two principal pathways are implicated in the final steps of E(2) formation in breast cancer tissue: the 'aromatase pathway', which transforms androgens into estrogens, and the 'sulfatase pathway', which converts estrone sulfate (E(1)S) into estrone (E(1)) via estrone sulfatase. The final step is the conversion of weak E(1) to the potent biologically active E(2) via reductive 17beta-hydroxysteroid dehydrogenase type 1 activity. It is also well established that steroid sulfotransferases, which convert estrogens into their sulfates, are present in breast cancer tissues. It has been demonstrated that various progestins (e.g. nomegestrol acetate, medrogestone, promegestone) as well as tibolone and their metabolites can block the enzymes involved in E(2) bioformation (sulfatase, 17beta-hydroxysteroid dehydrogenase) in breast cancer cells. These substances can also stimulate the sulfotransferase activity which converts estrogens into the biologically

  14. Whole-exome sequencing identifies novel compound heterozygous mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa.

    PubMed

    Méndez-Vidal, Cristina; González-Del Pozo, María; Vela-Boza, Alicia; Santoyo-López, Javier; López-Domingo, Francisco J; Vázquez-Marouschek, Carmen; Dopazo, Joaquin; Borrego, Salud; Antiñolo, Guillermo

    2013-01-01

    Retinitis pigmentosa (RP) is an inherited retinal dystrophy characterized by extreme genetic and clinical heterogeneity. Thus, the diagnosis is not always easily performed due to phenotypic and genetic overlap. Current clinical practices have focused on the systematic evaluation of a set of known genes for each phenotype, but this approach may fail in patients with inaccurate diagnosis or infrequent genetic cause. In the present study, we investigated the genetic cause of autosomal recessive RP (arRP) in a Spanish family in which the causal mutation has not yet been identified with primer extension technology and resequencing. We designed a whole-exome sequencing (WES)-based approach using NimbleGen SeqCap EZ Exome V3 sample preparation kit and the SOLiD 5500×l next-generation sequencing platform. We sequenced the exomes of both unaffected parents and two affected siblings. Exome analysis resulted in the identification of 43,204 variants in the index patient. All variants passing filter criteria were validated with Sanger sequencing to confirm familial segregation and absence in the control population. In silico prediction tools were used to determine mutational impact on protein function and the structure of the identified variants. Novel Usher syndrome type 2A (USH2A) compound heterozygous mutations, c.4325T>C (p.F1442S) and c.15188T>G (p.L5063R), located in exons 20 and 70, respectively, were identified as probable causative mutations for RP in this family. Family segregation of the variants showed the presence of both mutations in all affected members and in two siblings who were apparently asymptomatic at the time of family ascertainment. Clinical reassessment confirmed the diagnosis of RP in these patients. Using WES, we identified two heterozygous novel mutations in USH2A as the most likely disease-causing variants in a Spanish family diagnosed with arRP in which the cause of the disease had not yet been identified with commonly used techniques. Our data

  15. Whole-exome sequencing identifies novel compound heterozygous mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa

    PubMed Central

    Méndez-Vidal, Cristina; González-del Pozo, María; Vela-Boza, Alicia; Santoyo-López, Javier; López-Domingo, Francisco J.; Vázquez-Marouschek, Carmen; Dopazo, Joaquin; Borrego, Salud

    2013-01-01

    Purpose Retinitis pigmentosa (RP) is an inherited retinal dystrophy characterized by extreme genetic and clinical heterogeneity. Thus, the diagnosis is not always easily performed due to phenotypic and genetic overlap. Current clinical practices have focused on the systematic evaluation of a set of known genes for each phenotype, but this approach may fail in patients with inaccurate diagnosis or infrequent genetic cause. In the present study, we investigated the genetic cause of autosomal recessive RP (arRP) in a Spanish family in which the causal mutation has not yet been identified with primer extension technology and resequencing. Methods We designed a whole-exome sequencing (WES)-based approach using NimbleGen SeqCap EZ Exome V3 sample preparation kit and the SOLiD 5500×l next-generation sequencing platform. We sequenced the exomes of both unaffected parents and two affected siblings. Exome analysis resulted in the identification of 43,204 variants in the index patient. All variants passing filter criteria were validated with Sanger sequencing to confirm familial segregation and absence in the control population. In silico prediction tools were used to determine mutational impact on protein function and the structure of the identified variants. Results Novel Usher syndrome type 2A (USH2A) compound heterozygous mutations, c.4325T>C (p.F1442S) and c.15188T>G (p.L5063R), located in exons 20 and 70, respectively, were identified as probable causative mutations for RP in this family. Family segregation of the variants showed the presence of both mutations in all affected members and in two siblings who were apparently asymptomatic at the time of family ascertainment. Clinical reassessment confirmed the diagnosis of RP in these patients. Conclusions Using WES, we identified two heterozygous novel mutations in USH2A as the most likely disease-causing variants in a Spanish family diagnosed with arRP in which the cause of the disease had not yet been identified with

  16. Pregnancy-associated osteoporosis with a heterozygous deactivating LDL receptor-related protein 5 (LRP5) mutation and a homozygous methylenetetrahydrofolate reductase (MTHFR) polymorphism.

    PubMed

    Cook, Fiona J; Mumm, Steven; Whyte, Michael P; Wenkert, Deborah

    2014-04-01

    Pregnancy-associated osteoporosis (PAO) is a rare, idiopathic disorder that usually presents with vertebral compression fractures (VCFs) within 6 months of a first pregnancy and delivery. Spontaneous improvement is typical. There is no known genetic basis for PAO. A 26-year-old primagravida with a neonatal history of unilateral blindness attributable to hyperplastic primary vitreous sustained postpartum VCFs consistent with PAO. Her low bone mineral density (BMD) seemed to respond to vitamin D and calcium therapy, with no fractures after her next successful pregnancy. Investigation of subsequent fetal losses revealed homozygosity for the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism associated both with fetal loss and with osteoporosis (OP). Because her neonatal unilateral blindness and OP were suggestive of loss-of-function mutation(s) in the gene that encodes LDL receptor-related protein 5 (LRP5), LRP5 exon and splice site sequencing was also performed. This revealed a unique heterozygous 12-bp deletion in exon 21 (c.4454_4465del, p.1485_1488del SSSS) in the patient, her mother and sons, but not her father or brother. Her mother had a normal BMD, no history of fractures, PAO, ophthalmopathy, or fetal loss. Her two sons had no ophthalmopathy and no skeletal issues. Her osteoporotic father (with a family history of blindness) and brother had low BMDs first documented at ages ∼40 and 32 years, respectively. Serum biochemical and bone turnover studies were unremarkable in all subjects. We postulate that our patient's heterozygous LRP5 mutation together with her homozygous MTHFR polymorphism likely predisposed her to low peak BMD. However, OP did not cosegregate in her family with the LRP5 mutation, the homozygous MTHFR polymorphism, or even the combination of the two, implicating additional genetic or nongenetic factors in her PAO. Nevertheless, exploration for potential genetic contributions to PAO may explain part of the pathogenesis of this

  17. Facts for Life: Benign Breast Changes

    MedlinePlus

    ... breast. Your doctor may use the term “fibrocystic change” to describe a range of benign breast conditions. ... a doctor if you notice any of these changes: • Lump, hard knot or thickening inside the breast ...

  18. Silicone Gel-Filled Breast Implants

    MedlinePlus

    ... and Medical Procedures Implants and Prosthetics Breast Implants Silicone Gel-Filled Breast Implants Share Tweet Linkedin Pin ... sharing options Linkedin Pin it Email Print Description: Silicone gel-filled breast implants have a silicone outer ...

  19. Computer Simulation of Breast Cancer Screening

    DTIC Science & Technology

    1999-07-01

    techniques for evaluating the screening efficacy of mammography. Breast cancer growth rates, incidence rates, multiracial population demographics, death ... rates , breast cancer prognosis factors, breast density considerations, detection versus diameter probabilities, and other pertinent data have been

  20. Breast-Feeding Twins: Making Feedings Manageable

    MedlinePlus

    ... breast-feed more than one baby? Here's help breast-feeding twins or other multiples, from getting positioned and ensuring an adequate milk supply to combining breast-feeding and formula-feeding. By Mayo Clinic Staff If ...

  1. Benign Breast Disease: Toward Molecular Prediction of Breast Cancer Risk

    DTIC Science & Technology

    2007-06-01

    progress on these aims. Our current cohort comprises 9,376 women , 758 (8%) of whom have been diagnosed with breast cancer since the time of their benign... women . Our focus in 2007-2008 will be on the Wayne State cohort and exploring additional molecular markers. 15. SUBJECT TERMS benign breast disease...Excellence: 1) the establishment of a large tissue repository from a retrospective cohort of women with benign breast disease (BBD) (1967-1991); 2

  2. Benign Breast Disease: Toward Molecular Prediction of Breast Cancer Risk

    DTIC Science & Technology

    2008-06-01

    of benign histology in predicting risk of future breast cancer, examining in detail the role of proliferative disease, atypia , papillomas, radial...who had proliferative disease with atypia , especially those of younger age. • We identified a marked increased risk of breast cancer in women with...imparts an increased risk of developing a subsequent carcinoma similar to other forms of proliferative breast disease without atypia . Atypical

  3. The Role of Oncoplastic Breast Surgery in Breast Cancer Treatment

    PubMed Central

    Emiroğlu, Mustafa; Sert, İsmail; İnal, Abdullah

    2015-01-01

    The aim of this study is to discuss indications, advantages, disadvantages, oncologic and aesthetic results of Oncoplastic Surgery (OBS). Pubmed and Medline database were searched for articles published between 1998 and 2014 for keywords: oncoplastic breast surgery, therapeutic mammoplasty, oncoplastic breast reduction, synchrenous reconstructions. Role of OBS in breast cancer surgery, its aspects to be considered, its value and results have been interpreted. This technique has advantages by providing more extensive tumourectomy, yielding better aesthetic results compared with breast conserving surgery, allowing oncoplastic reduction in breast cancer patients with macromastia, with higher patient satisfaction and quality of life and by being inexpensive due to single session practice. As for its disadvantages are: re-excision is more difficult, risk for mastectomy is higher, it is depent on the Surgeron’s experience, it has a risk for delay in adjuvant therapies and its requirement for additional imaging studies during management. Main indications are patients with small tumour/breast volume, macromastia, multifocality, procedures which can disrupt breast cosmesis such as surgeries for upper inner breas tquadrient tumours. Contraindications are positive margin problems after wide excision, diffuse malign microcalsifications, inflammatory breast cancer, history of radiotherapy and patients’ preferences. Despite low evidence level, Oncoplastic Breast Surgery seems to be both reliable and acceptable in terms of oncologic and aesthetic aspects. Oncoplastic Breast Surgery increase the application rate of breast conserving surgery by obviating practical limitations and improve the results of breast conserving surgery. Correct patient and technique choice in OBS is vital for optimization of post surgical PMID:28331682

  4. Breast metastasis from cutaneous malignant melanoma mimicking a breast cancer.

    PubMed

    Maniglio, Marina; Capalbo, Emanuela; Viganò, Sara; Trecate, Giovanna; Scaperrotta, Gianfranco Paride; Panizza, Pietro

    2015-06-25

    Breast metastases are very uncommon, either from solid tumors or malignant melanoma. We present the case of a 42-year-old woman with a history of cutaneous melanoma of the shoulder excised 21 years ago. She presented with a palpable lump in the upper outer quadrant of the right breast. Ultrasound demonstrated a solid mass within a cystic lesion. A core biopsy was taken and first histology reported a poorly differentiated primary breast cancer suspected to be triple negative. MRI detected a satellite lesion in the same breast, a focus of suspected enhancement in the other breast, and the extramammary finding of an enhancing pulmonary lesion. Staging computed tomography detected widespread metastases to the lungs, brain, subcutaneous left shoulder, liver, pancreas, and hepatorenal recess. A core biopsy was taken from the left breast lesion and the previous slides were reviewed; histopathology and immunohistochemistry were in keeping with metastasis from melanoma. The possibility of a metastatic lesion to the breast should be taken into account in any patient presenting with a breast lump and a previous history of melanoma. Breast involvement cannot be considered an isolated finding, as it might be the first manifestation of widespread disease.

  5. Validation of the breast evaluation questionnaire for breast hypertrophy and breast reduction.

    PubMed

    Lewin, Richard; Elander, Anna; Lundberg, Jonas; Hansson, Emma; Thorarinsson, Andri; Claudelin, Malin; Bladh, Helena; Lidén, Mattias

    2018-06-13

    There is a lack of published, validated questionnaires for evaluating psychosocial morbidity in patients with breast hypertrophy undergoing breast reduction surgery. To validate the breast evaluation questionnaire (BEQ), originally developed for the assessment of breast augmentation patients, for the assessment of psychosocial morbidity in patients with breast hypertrophy undergoing breast reduction surgery. Validation study Subjects: Women with macromastia Methods: The validation of the BEQ, adapted to breast reduction, was performed in several steps. Content validity, reliability, construct validity and responsiveness were assessed. The original version was adjusted according to the results for content validity and resulted in item reduction and a modified BEQ (mBEQ) that was then assessed for reliability, construct validity and responsiveness. Internal and external validation was performed for the modified BEQ. Convergent validity was tested against Breast-Q (reduction) and discriminate validity was tested against the SF-36. Known-groups validation revealed significant differences between the normal population and patients undergoing breast reduction surgery. The BEQ showed good reliability by test-re-test analysis and high responsiveness. The modified BEQ may be reliable, valid and responsive instrument for assessing women who undergo breast reduction.

  6. Hematolymphoid lesions of the breast.

    PubMed

    Hoffmann, Jenny; Ohgami, Robert S

    2017-09-01

    Hematolymphoid malignancies of the breast are most commonly neoplasms of mature B-lymphocytes, and may arise as a primary disease or by secondary involvement of a systemic disease. Primary breast lymphomas (PBL) account for 0.04-0.5% of breast malignancies, less than 1% of all non-Hodgkin's lymphomas (NHL), and less than 5% of extranodal lymphomas (Lakhani et al., 2012; Swerdlow et al., 2008; Joks et al., 2011; Barişta et al., 2000; Giardini et al., 1992; Brogi and Harris, 1999; Topalovski et al., 1999). 1-7 Secondary breast lymphomas (SBL) are also rare, with an estimated annual incidence of 0.07% (Domchek et al., 2002; Talwalkar et al., 2008). 8,9 Recognition of breast lesions as hematolymphoid is critical to distinguish them from other entities that can occur in the breast. Copyright © 2017. Published by Elsevier Inc.

  7. Breast ptosis: causes and cure.

    PubMed

    Rinker, Brian; Veneracion, Melissa; Walsh, Catherine P

    2010-05-01

    Breast ptosis is one of the most common conditions treated by plastic surgeons, but the causes are not clearly defined. A review was conducted of 132 consecutive patients presenting for breast augmentation or mastopexy. Information was obtained by chart review and telephone interview. Standardized photographs were examined to determine degree of ptosis by the Regnault classification. Of patients who had at least one pregnancy, 85% reported adverse changes in breast shape following pregnancy, 35% reported a reduction in breast size, and 30% reported an increase in size. Upon logistic regression, age, history of significant (>50 lbs) weight loss, higher body mass index, larger bra cup size, number of pregnancies, and smoking history were found to be significant risk factors for breast ptosis (P < 0.05). History of breast-feeding, weight gain during pregnancy, and lack of participation in regular upper body exercise were not found to be significant risk factors for ptosis.

  8. Breast metastases from colorectal carcinoma.

    PubMed

    Mihai, Radu; Christie-Brown, Jonathan; Bristol, James

    2004-04-01

    A case history is presented of a 53-year-old woman with an incidental finding of a breast lump, identified after having had chemotherapy for lung metastases from a rectal carcinoma. Clinical examination, ultrasound, mammography, fine needle aspiration and core biopsies could not prove definitively whether the breast lump represented a metastasis from colorectal carcinoma. Following local excision, the final diagnosis of metastatic colorectal carcinoma to the breast was based on the absence of any site of origin within the breast (i.e. no surrounding DCIS) and on the expression of cytokeratin CK7 and CK20 on immunohistochemistry. Postoperative chemotherapy was initiated. Four months later, although without local recurrence in the breast, the patient developed cutaneous metastatic deposits and active treatment was stopped. A review of other cases of breast metastases from extramammary sources is presented. Possible mechanisms for this rare and unusual phenomenon are discussed.

  9. Digital Mammography and Digital Breast Tomosynthesis.

    PubMed

    Moseley, Tanya W

    2016-06-01

    Breast imaging technology has advanced significantly from the 1930s until the present. American women have a 1 in 8 chance of developing breast cancer. Mammography has been proven in multiple clinical trials to reduce breast cancer mortality. Although a mainstay of breast imaging and improved from film-screen mammography, digital mammography is not a perfect examination. Overlapping obscuring breast tissue limits mammographic interpretation. Breast digital tomosynthesis reduces and/or eliminates overlapping obscuring breast tissue. Although there are some disadvantages with digital breast tomosynthesis, this relatively lost-cost technology may be used effectively in the screening and diagnostic settings.

  10. Unusual cutaneous features associated with a heterozygous gain-of-function mutation in IFIH1: overlap between Aicardi–Goutières and Singleton–Merten syndromes

    PubMed Central

    Bursztejn, A.-C.; Briggs, T.A.; del Toro Duany, Y.; Anderson, B.H.; O’Sullivan, J.; Williams, S.G.; Bodemer, C.; Fraitag, S.; Gebhard, F.; Leheup, B.; Lemelle, I.; Oojageer, A.; Raffo, E.; Schmitt, E.; Rice, G.I.; Hur, S.; Crow, Y.J.

    2016-01-01

    Summary Cutaneous lesions described as chilblain lupus occur in the context of familial chilblain lupus or Aicardi–Goutières syndrome. To date, seven genes related to Aicardi–Goutières syndrome have been described. The most recently described encodes the cytosolic double-stranded RNA receptor IFIH1 (also known as MDA5), a key component of the antiviral type I interferon-mediated innate immune response. Enhanced type I interferon signalling secondary to gain-of-function mutations in IFIH1 can result in a range of neuroinflammatory phenotypes including classical Aicardi–Goutières syndrome. It is of note that none of the patients with a neurological phenotype so far described with mutations in this gene was reported to demonstrate cutaneous involvement. We present a family segregating a heterozygous pathogenic mutation in IFIH1 showing dermatological involvement as a prominent feature, variably associated with neurological disturbance and premature tooth loss. All three affected individuals exhibited increased expression of interferon-stimulated genes in whole blood, and the mutant protein resulted in enhanced interferon signalling in vitro, both in the basal state and following ligand stimulation. Our results further extend the phenotypic spectrum associated with mutations in IFIH1, indicating that the disease can be confined predominantly to the skin, while also highlighting phenotypic overlap with both Aicardi–Goutières syndrome and Singleton–Merten syndrome. PMID:26284909

  11. Impact of the A2V Mutation on the Heterozygous and Homozygous Aβ1-40 Dimer Structures from Atomistic Simulations.

    PubMed

    Nguyen, Phuong H; Sterpone, Fabio; Campanera, Josep M; Nasica-Labouze, Jessica; Derreumaux, Philippe

    2016-06-15

    The A2V mutation was reported to protect from Alzheimer's disease in its heterozygous form and cause an early Alzheimer's disease type dementia in its homozygous form. Experiments showed that the aggregation rate follows the order A2V > WT (wild-type) > A2V-WT. To understand the impact of this mutation, we carried out replica exchange molecular dynamics simulations of Aβ1-40 WT-A2V and A2V-A2V dimers and compared to the WT dimer. Our atomistic simulations reveal that the mean secondary structure remains constant, but there are substantial differences in the intramolecular and intermolecular conformations upon single and double A2V mutation. Upon single mutation, the intrinsic disorder is reduced, the intermolecular potential energies are reduced, the population of intramolecular three-stranded β-sheets is increased, and the number of all α dimer topologies is decreased. Taken together, these results offer an explanation for the reduced aggregation rate of the Aβ1-40 A2V-WT peptides and the protective effect of A2V in heterozygotes.

  12. Embryonal rhabdomyosarcoma in a patient with a heterozygous frameshift variant in the DICER1 gene and additional manifestations of the DICER1 syndrome.

    PubMed

    Fremerey, Julia; Balzer, Stefan; Brozou, Triantafyllia; Schaper, Joerg; Borkhardt, Arndt; Kuhlen, Michaela

    2017-07-01

    Germline mutations in the DICER1 gene are associated with an inherited cancer predisposition syndrome also known as the DICER1-syndrome, which is implicated in a broad range of tumors including pleuropulmonary blastoma, ovarian Sertoli-Leydig cell tumors, ciliary body medulloepithelioma (CBME), pituitary blastoma, embryonal rhabdomyosarcoma (eRMS), anaplastic renal sarcoma as well as ocular, sinonasal tumors ovarian sex-cord tumors, thyroid neoplasia and cystic nephroma. This study describes a novel, heterozygous frameshift DICER1 mutation in a patient, who is affected by different tumors of the DICER1-syndrome, including eRMS, CBME and suspected pleuropulmonary blastoma type I. By whole-exome sequencing of germline material using peripheral blood-derived DNA, we identified a single base pair duplication within the DICER1 gene (c.3405 dupA) that leads to a frameshift and results in a premature stop in exon 21 (p.Gly1136Arg). The metachronous occurrence of two unrelated tumor entities (eRMS and CBME) in a very young child within a short timeframe should have raised the suspicion of an underlying cancer susceptibility syndrome and should be prompt tested for DICER1.

  13. High density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis

    PubMed Central

    Goyette, Philippe; Boucher, Gabrielle; Mallon, Dermot; Ellinghaus, Eva; Jostins, Luke; Huang, Hailiang; Ripke, Stephan; Gusareva, Elena S; Annese, Vito; Hauser, Stephen L; Oksenberg, Jorge R; Thomsen, Ingo; Leslie, Stephen; Daly, Mark J; Van Steen, Kristel; Duerr, Richard H; Barrett, Jeffrey C; McGovern, Dermot PB; Schumm, L Philip; Traherne, James A; Carrington, Mary N; Kosmoliaptsis, Vasilis; Karlsen, Tom H; Franke, Andre; Rioux, John D

    2014-01-01

    Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn’s disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical HLA molecules1. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but lacked the statistical power to define the architecture of association and causal alleles2,3. To address this, we performed high-density SNP typing of the MHC in >32,000 patients with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn’s disease and ulcerative colitis. Significant differences were observed between these diseases, including a predominant role of class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response to the colonic environment in the pathogenesis of IBD. PMID:25559196

  14. Impaired Insulin Signaling is Associated with Hepatic Mitochondrial Dysfunction in IR+/−-IRS-1+/− Double Heterozygous (IR-IRS1dh) Mice

    PubMed Central

    Franko, Andras; Kunze, Alexander; Böse, Marlen; von Kleist-Retzow, Jürgen-Christoph; Paulsson, Mats; Hartmann, Ursula; Wiesner, Rudolf J.

    2017-01-01

    Mitochondria play a pivotal role in energy metabolism, but whether insulin signaling per se could regulate mitochondrial function has not been identified yet. To investigate whether mitochondrial function is regulated by insulin signaling, we analyzed muscle and liver of insulin receptor (IR)+/−-insulin receptor substrate-1 (IRS-1)+/− double heterozygous (IR-IRS1dh) mice, a well described model for insulin resistance. IR-IRS1dh mice were studied at the age of 6 and 12 months and glucose metabolism was determined by glucose and insulin tolerance tests. Mitochondrial enzyme activities, oxygen consumption, and membrane potential were assessed using spectrophotometric, respirometric, and proton motive force analysis, respectively. IR-IRS1dh mice showed elevated serum insulin levels. Hepatic mitochondrial oxygen consumption was reduced in IR-IRS1dh animals at 12 months of age. Furthermore, 6-month-old IR-IRS1dh mice demonstrated enhanced mitochondrial respiration in skeletal muscle, but a tendency of impaired glucose tolerance. On the other hand, 12-month-old IR-IRS1dh mice showed improved glucose tolerance, but normal muscle mitochondrial function. Our data revealed that deficiency in IR/IRS-1 resulted in normal or even elevated skeletal muscle, but impaired hepatic mitochondrial function, suggesting a direct cross-talk between insulin signaling and mitochondria in the liver. PMID:28556799

  15. Population genetic structure and disease in montane boreal toads: More heterozygous individuals are more likely to be infected with amphibian chytrid

    USGS Publications Warehouse

    Addis, Brett; Lowe, Winsor; Hossack, Blake R.; Allendorf, Fred

    2015-01-01

    Amphibians are more threatened than any other vertebrate group, with 41 % of species classified as threatened. The causes of most declines are not well understood, though many declines have been linked to disease. Additionally, amphibians are physiologically constrained to moist habitats and considered poor dispersers; thus, they may suffer genetic consequences of population isolation. To understand threats to the persistence of boreal toads (Bufo boreas) in Glacier National Park, USA, we genotyped 551 individuals at 11 microsatellite loci and used Bayesian clustering methods to describe population genetic structure and identify barriers to gene flow. We found evidence of two primary genetic groups that differed substantially in elevation and two secondary groups within the high elevation group. There was also evidence of further substructure within the southern high elevation group, suggesting mountain ridges are barriers to gene flow at local scales. Overall, genetic variation was high, but allelic richness declined with increasing elevation, reflecting greater isolation or smaller effective population sizes of high altitude populations. We tested for Batrachochytrium dendrobatidis (Bd), the fungal pathogen which causes chytridiomycosis, and we found that 35 of 199 toads were positive for Bd. Unexpectedly, more heterozygous individuals were more likely to be infected. This suggests that dispersal facilitates the spread of disease because heterozygosity may be highest where dispersal and gene flow are greatest.

  16. Characterization of a Case of Pigmentary Retinopathy in Sanfilippo Syndrome Type IIIA Associated with Compound Heterozygous Mutations in the SGSH Gene.

    PubMed

    Wilkin, Justin; Kerr, Natalie C; Byrd, Kathryn W; Ward, Jewell C; Iannaccone, Alessandro

    2016-06-01

    To report longitudinal phenotypic findings in a patient with Sanfilippo syndrome type IIIA, harboring SGSH mutations, one of which is novel. Heparan-N-sulfatidase enzyme function testing in skin fibroblasts and white blood cells and SGSH gene sequencing were obtained. Clinical office examinations, examinations under anesthesia, electroretinogram, spectral domain optical coherence tomography (SD-OCT), and fundus photography were performed over a 5-year period. Fundus examination revealed a progressive breadcrumb-like pigmentary retinopathy with perifoveal pigmentary involvement. SD-OCT showed loss of normal neuroretinal lamination and cystic macular changes responsive to treatment with carbonic anhydrase inhibitors. Electroretinography exhibited complex characteristics indicative of a generalized retinal rod > cone dysfunction with significant ON > OFF postreceptoral response compromise. Sequencing revealed compound heterozygous mutations in the SGSH gene, the novel c.88G > C (p.A30P) change and a second, previously reported one (c.734G > A, p.R245H). We have identified ocular features of a patient with Sanfilippo syndrome type IIIA harboring a novel SGHS mutation that were not previously known to occur in this disease - namely, a progressive retinopathy with distinctive features, cystic macular changes responsive to carbonic anhydrase inhibitors, and complex electroretinographic abnormalities consistent with postreceptoral dysfunction. SD-OCT imaging revealed retinal lamination changes consistent with previously reported histologic studies. Both the SD-OCT and the electroretinogram changes appear attributable to intraretinal deposition of heparan sulfate.

  17. Tropomyosin 2 heterozygous knockout in mice using CRISPR-Cas9 system displays the inhibition of injury-induced epithelial-mesenchymal transition, and lens opacity

    PubMed Central

    Shibata, Teppei; Shibata, Shinsuke; Ishigaki, Yasuhito; Kiyokawa, Etsuko; Ikawa, Masahito; Singh, Dhirendra P.; Sasaki, Hiroshi; Kubo, Eri

    2018-01-01

    The process of epithelial–mesenchymal transition (EMT) of lens epithelial cells (LECs) after cataract surgery contributes to tissue fibrosis, wound healing and lens regeneration via a mechanism not yet fully understood. Here, we show that tropomyosin 2 (Tpm2) plays a critical role in wound healing and lens aging. Posterior capsular opacification (PCO) after lens extraction surgery was accompanied by elevated expression of Tpm2. Tpm2 heterozygous knockout mice, generated via the clustered regularly interspaced short palindromic repeat/ Cas9 (CRISPR/Cas9) system showed promoted progression of cataract with age. Further, injury-induced EMT of the mouse lens epithelium, as evaluated histologically and by the expression patterns of Tpm1 and Tpm2, was attenuated in the absence of Tpm2. In conclusion, Tpm2 may be important in maintaining lens physiology and morphology. However, Tpm2 is involved in the progression of EMT during the wound healing process of mouse LECs, suggesting that inhibition of Tpm2 may suppress PCO. PMID:29510160

  18. Production of a mouse strain with impaired glucose tolerance by systemic heterozygous knockout of the glucokinase gene and its feasibility as a prediabetes model

    PubMed Central

    SAITO, Mikako; KANEDA, Asako; SUGIYAMA, Tae; IIDA, Ryousuke; OTOKUNI, Keiko; KABURAGI, Misako; MATSUOKA, Hideaki

    2015-01-01

    Exon II of glucokinase (Gk) was deleted to produce a systemic heterozygous Gk knockout (Gk+/−) mouse. The relative expression levels of Gk in the heart, lung, liver, stomach, and pancreas in Gk+/− mice ranged from 0.41–0.68 versus that in wild (Gk+/+) mice. On the other hand, its expression levels in the brain, adipose tissue, and muscle ranged from 0.95–1.03, and its expression levels in the spleen and kidney were nearly zero. Gk knockout caused no remarkable off-target effect on the expression of 7 diabetes causing genes (Shp, Hnf1a, Hnf1b, Irs1, Irs2, Kir6.2, and Pdx1) in 10 organs. The glucose tolerance test was conducted to determine the blood glucose concentrations just after fasting for 24 h (FBG) and at 2 h after high-glucose application (GTT2h). The FBG-GTT2h plots obtained with the wild strain fed the control diet (CD), Gk+/− strain fed the CD, and Gk+/− strain fed the HFD were distributed in separate areas in the FBG-GTT2h diagram. The respective areas could be defined as the normal state, prediabetes state, and diabetes state, respectively. Based on the results, the criteria for prediabetes could be defined for the Gk+/− strain developed in this study. PMID:25765873

  19. [Frequency of intron 1 inversion of factor VIII gene in Chinese hemophilia A patients with case report of a female patient with heterozygous intron 1 inversion].

    PubMed

    Yan, Zhen-yu; Liang, Yan; Yan, Mei; Fan, Lian-kai; Xiao, Bai; Hua, Bao-lai; Liu, Jing-zhong; Zhao, Yong-qiang

    2008-10-21

    To investigate the frequency of intron 1 inversion (inv1) in FVIII gene in Chinese hemophilia A (HA) patients and to investigate the mechanism of pathogenesis. Peripheral blood samples were collected from 158 unrelated HA patients, aged 20 (1 - 73), including one female HA patient, aged 5, and several family members of a patient positive in inv1. One-stage method was used to assay the FVIII activity (FVIII:C). Long distance PCR and multiple PCR in duplex reactions were used to screen for the intron 22 inversion (inv22) and inv1 of the FVIII coding gene (F8). The F8 coding sequence was amplified with PCR and sequenced with an automatic sequencer. Two unrelated patients (pedigrees) were detected as inv1 positive with a positive rate of 1.26%. A rare female HA patient with inv1 was also discovered in a positive family (3 HA cases were found in this family and regarded as one case in calculating the total detection rate). The full length of FVIII was sequenced, and no other mutation was detected. There frequency of FVIII inv1 is low in Chinese HA patients compared with other populations. Female HA patients are heterozygous for FVIII inv1 and that may be resulted from nonrandom inactivation of X chromosome.

  20. Contact zone between chromosomal races of Mus musculus domesticus. 2. Fertility and segregation in laboratory-reared and wild mice heterozygous for multiple robertsonian rearrangements.

    PubMed

    Castiglia, R; Capanna, E

    2000-08-01

    Litter size, anaphase I nondisjunction and X-Y dissociation at metaphase I were studied in homozygous and heterozygous house mice from a central Italian chromosomal hybrid zone between the CD (2n=22) race and the standard race (2n=40). We also observed the segregation of the two chromosomal forms (Robertsonian and non-Robertsonian) in male and female multiple heterozygotes from the karyotype of their offspring and chromosomal arm counts of metaphase II. Litter size was significantly reduced in the F1 hybrids, but there was no difference in litter size between male and female F1s. Fertility in wild mice decreased with increasing numbers of structural heterozygosities (0-5). Some metacentrics appear to be under meiotic drive but there was no rule as to which of the two forms was favoured in backcrosses. An original observation of a negative correlation between the length of metacentrics and transmission rate was described in hybrids. Slight cosegregation of chromosomes with a similar morphology was present in the progeny of males and females. These observations are discussed in relation to the stability of this hybrid zone through time.

  1. Hereditary Xerocytosis due to Mutations in PIEZO1 Gene Associated with Heterozygous Pyruvate Kinase Deficiency and Beta-Thalassemia Trait in Two Unrelated Families.

    PubMed

    Fermo, Elisa; Vercellati, Cristina; Marcello, Anna Paola; Zaninoni, Anna; van Wijk, Richard; Mirra, Nadia; Curcio, Cristina; Cortelezzi, Agostino; Zanella, Alberto; Barcellini, Wilma; Bianchi, Paola

    2017-01-01

    Hereditary xerocytosis (HX) is a rare disorder caused by defects of RBC permeability, associated with haemolytic anaemia of variable degree and iron overload. It is sometimes misdiagnosed as hereditary spherocytosis or other congenital haemolytic anaemia. Splenectomy is contraindicated due to increased risk of thromboembolic complications. We report the clinical, haematological, and molecular characteristics of four patients from two unrelated Italian families affected by HX, associated with beta-thalassemia trait and heterozygous pyruvate kinase deficiency, respectively. Two patients had been splenectomised and displayed thrombotic episodes. All patients had iron overload in the absence of transfusion, two of them requiring iron chelation. The diagnosis of HX was confirmed by LoRRca Osmoscan analysis showing a left-shifted curve. PIEZO1 gene sequencing revealed the presence of mutation p.E2496ELE, showing that this is one of the most frequent mutations in this disease. The concomitant defects did not aggravate the clinical phenotype; however, in one patient, the initial diagnosis of pyruvate kinase deficiency delayed the correct diagnosis of HX for many years and resulted in splenectomy followed by thrombotic complications. The study underlines the importance of a precise diagnosis in HX, particularly in view of splenectomy, and the need of a molecular confirmation of suspected RBC enzymopathy.

  2. Hereditary Xerocytosis due to Mutations in PIEZO1 Gene Associated with Heterozygous Pyruvate Kinase Deficiency and Beta-Thalassemia Trait in Two Unrelated Families

    PubMed Central

    Vercellati, Cristina; Marcello, Anna Paola; Zaninoni, Anna; van Wijk, Richard; Mirra, Nadia; Curcio, Cristina; Cortelezzi, Agostino; Zanella, Alberto; Barcellini, Wilma; Bianchi, Paola

    2017-01-01

    Hereditary xerocytosis (HX) is a rare disorder caused by defects of RBC permeability, associated with haemolytic anaemia of variable degree and iron overload. It is sometimes misdiagnosed as hereditary spherocytosis or other congenital haemolytic anaemia. Splenectomy is contraindicated due to increased risk of thromboembolic complications. We report the clinical, haematological, and molecular characteristics of four patients from two unrelated Italian families affected by HX, associated with beta-thalassemia trait and heterozygous pyruvate kinase deficiency, respectively. Two patients had been splenectomised and displayed thrombotic episodes. All patients had iron overload in the absence of transfusion, two of them requiring iron chelation. The diagnosis of HX was confirmed by LoRRca Osmoscan analysis showing a left-shifted curve. PIEZO1 gene sequencing revealed the presence of mutation p.E2496ELE, showing that this is one of the most frequent mutations in this disease. The concomitant defects did not aggravate the clinical phenotype; however, in one patient, the initial diagnosis of pyruvate kinase deficiency delayed the correct diagnosis of HX for many years and resulted in splenectomy followed by thrombotic complications. The study underlines the importance of a precise diagnosis in HX, particularly in view of splenectomy, and the need of a molecular confirmation of suspected RBC enzymopathy. PMID:28367341

  3. Heterozygous congenital Factor VII deficiency with the 9729del4 mutation, associated with severe spontaneous intracranial bleeding in an adolescent male.

    PubMed

    Cramer, Thomas J; Anderson, Kristin; Navaz, Karanjia; Brown, Justin M; Mosnier, Laurent O; von Drygalski, Annette

    2016-03-01

    In congenital Factor (F) VII deficiency bleeding phenotype and intrinsic FVII activity levels don't always correlate. Patients with FVII activity levels <30% appear to have a higher bleeding propensity, but bleeding can also occur at higher FVII activity levels. Reasons for bleeding at higher FVII activity levels are unknown, and it remains challenging to manage such patients clinically. A 19year old male with spontaneous intracranial hemorrhage and FVII activity levels of 44%, requiring emergent surgical intervention and a strategy for FVII replacement. Genotyping showed the rare heterozygous FVII 9729del4 mutation. Bleed evacuation was complicated by epidural abscess requiring craniectomy, bone graft procedures, and prolonged administration of recombinant human (rh) activated FVII (FVIIa). The patient recovered without neurological deficits, and remains on prophylactic low dose treatment with rhFVIIa in relation to risky athletic activities. For clinicians, it is important to recognize that effects of rhFVIIa within these pathways are independent of its contribution to blood clot formation and cannot be assessed by clotting assays. Reduced FVII levels should therefore not be dismissed, as even a mild reduction may result in spontaneous bleeding. Treatment of mild FVII deficiency requires a careful case-by-case approach, based on the clinical scenario. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Heterozygous p.Asp50Asn mutation in the GJB2 gene in two Cameroonian patients with keratitis-ichthyosis-deafness (KID) syndrome.

    PubMed

    Wonkam, Ambroise; Noubiap, Jean Jacques N; Bosch, Jason; Dandara, Collet; Toure, Geneviève Bengono

    2013-08-07

    Keratitis-Ichthyosis-Deafness (KID) syndrome (OMIM 148210) is a congenital ectodermal defect that consists of an atypical ichthyosiform erythroderma associated with congenital sensorineural deafness. KID appears to be genetically heterogeneous and most cases are caused by GJB2 mutations. Mutations in African patients have been rarely described. We report on two unrelated Cameroonian individuals affected with sporadic KID, presenting with the classic phenotypic triad. The two patients were heterozygous for the most frequent p.Asp50Asn mutation. This first report in patients from sub-Saharan African origin supports the hypothesis that the occurrence of KID due to p.Asp50Asn mutation in GJB2 seems not to be population specific. Our finding has implication in medical genetic practice, specifically in the molecular diagnosis of KID in Africans. These cases also reveal and emphasize the urgent need to develop appropriate policies to care for patients with rare/orphan diseases in Sub-Saharan Africa, as many of these cases become more and more recognizable.

  5. Heterozygous p.Asp50Asn mutation in the GJB2 gene in two Cameroonian patients with keratitis-ichthyosis-deafness (KID) syndrome

    PubMed Central

    2013-01-01

    Background Keratitis-Ichthyosis-Deafness (KID) syndrome (OMIM 148210) is a congenital ectodermal defect that consists of an atypical ichthyosiform erythroderma associated with congenital sensorineural deafness. KID appears to be genetically heterogeneous and most cases are caused by GJB2 mutations. Mutations in African patients have been rarely described. Case presentation We report on two unrelated Cameroonian individuals affected with sporadic KID, presenting with the classic phenotypic triad. The two patients were heterozygous for the most frequent p.Asp50Asn mutation. This first report in patients from sub-Saharan African origin supports the hypothesis that the occurrence of KID due to p.Asp50Asn mutation in GJB2 seems not to be population specific. Conclusions Our finding has implication in medical genetic practice, specifically in the molecular diagnosis of KID in Africans. These cases also reveal and emphasize the urgent need to develop appropriate policies to care for patients with rare/orphan diseases in Sub-Saharan Africa, as many of these cases become more and more recognizable. PMID:23924173

  6. Novel compound heterozygous DPH1 mutations in a patient with the unique clinical features of airway obstruction and external genital abnormalities.

    PubMed

    Nakajima, Junya; Oana, Shingo; Sakaguchi, Tomohiro; Nakashima, Mitsuko; Numabe, Hironao; Kawashima, Hisashi; Matsumoto, Naomichi; Miyake, Noriko

    2018-04-01

    The diphthamide biosynthesis 1 (DPH1) gene encodes one of the essential components of the enzyme catalyzing the first step of diphthamide formation on eukaryotic elongation factor 2 (EEF2). Diphthamide is the posttranslationally modified histidine residue on EEF2 that promotes protein chain elongation in the ribosome. DPH1 defects result in a failure of protein synthesis involving EEF2, leading to growth defects, embryonic lethality, and cell death. In humans, DPH1 mutations cause developmental delay with a short stature, dysmorphic features, and sparse hair, and are inherited in an autosomal recessive manner (MIM#616901). To date, only two homozygous missense mutations in DPH1 (c.17T>A, p.Met6Lys and c.701T>C, p.Leu234Pro) have been reported. We used WES to identify novel compound heterozygous mutations in DPH1 (c.289delG, p.Glu97Lysfs*8 and c.491T>C, p.Leu164Pro) in a patient from a nonconsanguineous family presenting with intellectual disability, a short stature, craniofacial abnormalities, and external genital abnormalities. The clinical phenotype of all patients with DPH1 mutations, including the current patient, revealed core features, although the external genital anomaly was newly recognized in our case.

  7. Impaired Insulin Signaling is Associated with Hepatic Mitochondrial Dysfunction in IR+/--IRS-1+/- Double Heterozygous (IR-IRS1dh) Mice.

    PubMed

    Franko, Andras; Kunze, Alexander; Böse, Marlen; von Kleist-Retzow, Jürgen-Christoph; Paulsson, Mats; Hartmann, Ursula; Wiesner, Rudolf J

    2017-05-30

    Mitochondria play a pivotal role in energy metabolism, but whether insulin signaling per se could regulate mitochondrial function has not been identified yet. To investigate whether mitochondrial function is regulated by insulin signaling, we analyzed muscle and liver of insulin receptor (IR) +/- -insulin receptor substrate-1 (IRS-1) +/- double heterozygous (IR-IRS1dh) mice, a well described model for insulin resistance. IR-IRS1dh mice were studied at the age of 6 and 12 months and glucose metabolism was determined by glucose and insulin tolerance tests. Mitochondrial enzyme activities, oxygen consumption, and membrane potential were assessed using spectrophotometric, respirometric, and proton motive force analysis, respectively. IR-IRS1dh mice showed elevated serum insulin levels. Hepatic mitochondrial oxygen consumption was reduced in IR-IRS1dh animals at 12 months of age. Furthermore, 6-month-old IR-IRS1dh mice demonstrated enhanced mitochondrial respiration in skeletal muscle, but a tendency of impaired glucose tolerance. On the other hand, 12-month-old IR-IRS1dh mice showed improved glucose tolerance, but normal muscle mitochondrial function. Our data revealed that deficiency in IR/IRS-1 resulted in normal or even elevated skeletal muscle, but impaired hepatic mitochondrial function, suggesting a direct cross-talk between insulin signaling and mitochondria in the liver.

  8. Mice heterozygous for an inactivated allele of the schizophrenia associated Brd1 gene display selective cognitive deficits with translational relevance to schizophrenia.

    PubMed

    Qvist, Per; Rajkumar, Anto P; Redrobe, John P; Nyegaard, Mette; Christensen, Jane H; Mors, Ole; Wegener, Gregers; Didriksen, Michael; Børglum, Anders D

    2017-05-01

    Schizophrenia is a debilitating brain disorder characterized by disturbances of emotion, perception and cognition. Cognitive impairments predict functional outcome in schizophrenia and are detectable even in the prodromal stage of the disorder. However, our understanding of the underlying neurobiology is limited and procognitive treatments remain elusive. We recently demonstrated that mice heterozygous for an inactivated allele of the schizophrenia-associated Brd1 gene (Brd1 +/ - mice) display behaviors reminiscent of schizophrenia, including impaired social cognition and long-term memory. Here, we further characterize performance of these mice by following the preclinical guidelines recommended by the 'Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS)' and 'Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS)' initiatives to maximize translational value. Brd1 +/- mice exhibit relational encoding deficits, compromised working and long term memory, as well as impaired executive cognitive functioning with cognitive behaviors relying on medial prefrontal cortex being particularly affected. Akin to patients with schizophrenia, the cognitive deficits displayed by Brd1 +/ - mice are not global, but selective. Our results underline the value of Brd1 +/ - mice as a promising tool for studying the neurobiology of cognitive deficits in schizophrenia. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Identification of a Heterozygous SPG11 Mutation by Clinical Exome Sequencing in a Patient With Hereditary Spastic Paraplegia: A Case Report.

    PubMed

    Oh, Ja-Young; Do, Hyun Jung; Lee, Seungok; Jang, Ja-Hyun; Cho, Eun-Hae; Jang, Dae-Hyun

    2016-12-01

    Next-generation sequencing, such as whole-genome sequencing, whole-exome sequencing, and targeted panel sequencing have been applied for diagnosis of many genetic diseases, and are in the process of replacing the traditional methods of genetic analysis. Clinical exome sequencing (CES), which provides not only sequence variation data but also clinical interpretation, aids in reaching a final conclusion with regards to genetic diagnosis. Sequencing of genes with clinical relevance rather than whole exome sequencing might be more suitable for the diagnosis of known hereditary disease with genetic heterogeneity. Here, we present the clinical usefulness of CES for the diagnosis of hereditary spastic paraplegia (HSP). We report a case of patient who was strongly suspected of having HSP based on her clinical manifestations. HSP is one of the diseases with high genetic heterogeneity, the 72 different loci and 59 discovered genes identified so far. Therefore, traditional approach for diagnosis of HSP with genetic analysis is very challenging and time-consuming. CES with TruSight One Sequencing Panel, which enriches about 4,800 genes with clinical relevance, revealed compound heterozygous mutations in SPG11 . One workflow and one procedure can provide the results of genetic analysis, and CES with enrichment of clinically relevant genes is a cost-effective and time-saving diagnostic tool for diseases with genetic heterogeneity, including HSP.

  10. Paclitaxel Albumin-Stabilized Nanoparticle Formulation in Treating Older Patients With Locally Advanced or Metastatic Breast Cancer

    ClinicalTrials.gov

    2018-03-05

    Male Breast Cancer; Recurrent Breast Cancer; Stage IV Breast Cancer; Estrogen Receptor-negative Breast Cancer; Estrogen Receptor-positive Breast Cancer; HER2-negative Breast Cancer; HER2-positive Breast Cancer; Progesterone Receptor-negative Breast Cancer; Progesterone Receptor-positive Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Triple-negative Breast Cancer

  11. Biomarkers in Tissue Samples From Patients With Newly Diagnosed Breast Cancer Treated With Zoledronic Acid

    ClinicalTrials.gov

    2018-06-01

    Estrogen Receptor-positive Breast Cancer; Invasive Ductal Breast Carcinoma; Progesterone Receptor-positive Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer

  12. Caloric Restriction in Treating Patients With Stage 0-I Breast Cancer Undergoing Surgery and Radiation Therapy

    ClinicalTrials.gov

    2017-09-25

    Ductal Breast Carcinoma in Situ; Invasive Ductal Breast Carcinoma; Invasive Lobular Breast Carcinoma; Lobular Breast Carcinoma in Situ; Recurrent Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer

  13. Soy Isoflavones Supplementation in Treating Women at High Risk For or With Breast Cancer

    ClinicalTrials.gov

    2018-03-30

    BRCA1 Mutation Carrier; BRCA2 Mutation Carrier; Ductal Breast Carcinoma in Situ; Lobular Breast Carcinoma in Situ; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer

  14. Neo-adjuvant Therapy With Anastrozole Plus Pazopanib in Stage II and III ER+ Breast Cancer

    ClinicalTrials.gov

    2017-03-29

    Estrogen Receptor-positive Breast Cancer; Human Epidermal Growth Factor 2 Negative Carcinoma of Breast; Male Breast Cancer; Recurrent Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer

  15. Vascular and Cognitive Assessments in Patients With Breast Cancer Undergoing Chemotherapy After Surgery

    ClinicalTrials.gov

    2017-05-25

    Cognitive/Functional Effects; Recurrent Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  16. Rosuvastatin in Treating Women With Cardiovascular Complications Who Are Undergoing Chemotherapy For Breast Cancer

    ClinicalTrials.gov

    2017-05-25

    Cardiovascular Complications; Recurrent Breast Cancer; Stage I Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer

  17. Effects of age at first pregnancy and breast-feeding on the development of postmenopausal osteoporosis.

    PubMed

    Schnatz, Peter F; Barker, Kathaleen G; Marakovits, Kimberly A; O'Sullivan, David M

    2010-01-01

    Although pregnancy and breast-feeding require adequate calcium mobilization, it is not known if these affect the acquisition of a healthy peak bone mass (PBM) and, hence, postmenopausal osteoporosis (OPS). The objective of this study was to analyze previous pregnancies and/or breast-feeding and their association with OPS. After obtaining institutional review board approval, postmenopausal women (>49 y) presenting for a dual-energy x-ray absorptiometry bone density scan were invited to participate. Risk factors for OPS, including previous fractures, pregnancy information, and dual-energy x-ray absorptiometry results, were collected. OPS was defined as a T score of -2.5 or lower. Data were obtained from 619 women. Of these, 49.8% were smokers, 27.2% used a bisphosphonate, 64.1% used hormone therapy, and 5.5% had used steroids. Based on PBM, ages at first pregnancy were dichotomized to younger than 27 years and 27 years or older. Women with a history of breast-feeding had a lower prevalence of OPS (7.6%) versus women who had never breast-fed (18.7%; P < 0.001). Women with a first pregnancy when they were 27 years or older and a history of breast-feeding had the lowest prevalence of OPS (4.6%) versus women with a first pregnancy when they were younger than 27 years and no history of breast-feeding (16.3%; P = 0.001). Breast-feeding seems to significantly decrease the incidence of postmenopausal OPS. Women whose first pregnancy occurs after PBM (≥27 y of age) and who have a history of breast-feeding had the lowest prevalence of OPS. Thus, an association between OPS and both breast-feeding and age of pregnancy seems to be present.

  18. Selenium and breast-feeding.

    PubMed

    Dorea, Jose G

    2002-11-01

    The objective of the present review is to discuss Se nutrition during breast-feeding, encompassing environmental and maternal constitutional factors affecting breast-milk-Se metabolism and secretion. A literature search of Medline and Webofscience was used to retrieve and select papers dealing with Se and breast milk. Although Se in natural foods occurs only in organic form, breast milk responds to organic and inorganic Se in supplements. Inorganic Se (selenite, selenate), which is largely used in maternal supplements, is not detectable in breast milk. The mammary-gland regulating mechanism controls the synthesis and secretion of seleno-compounds throughout lactation, with a high total Se level in colostrum that decreases as lactation progresses. Se appears in breast milk as a component of specific seleno-proteins and seleno-amino-acids in milk proteins that are well tolerated by breast-fed infants even in high amounts. Se in breast milk occurs as glutathione peroxidase (4-32 % total Se) > selenocystamine > selenocystine > selenomethionine. The wide range of breast-milk Se concentrations depends on Se consumed in natural foods, which reflects the Se content of the soils where they are grown. Se prophylaxis, either through soil Se fertilization or maternal supplements, is effective in raising breast-milk Se concentration. In spite of wide variation, the median Se concentration from studies worldwide are 26, 18, 15, and 17 microg/l in colostrum (0-5 d), transitional milk (6-21 d), mature milk (1-3 months) and late lactation (>5 months) respectively. Se recommendations for infants are presently not achieved in 30 % of the reported breast-milk Se concentrations; nevertheless Se status is greater in breast-fed than in formula-fed infants.

  19. Breast Cancer Research at NASA

    NASA Technical Reports Server (NTRS)

    1998-01-01

    Dr. Robert Richmond extracts breast cell tissue from one of two liquid nitrogen dewars. NASA's Marshall Space Flight Center (MSFC) is sponsoring research with Bioreactors, rotating wall vessels designed to grow tissue samples in space, to understand how breast cancer works. This ground-based work studies the growth and assembly of human mammary epithelial cells (HMEC) from breast cancer susceptible tissue. Radiation can make the cells cancerous, thus allowing better comparisons of healthy vs. tunourous tissues.

  20. Breast Cancer Research at NASA

    NASA Technical Reports Server (NTRS)

    1998-01-01

    Dr. Harry Mahtani analyzes the gas content of nutrient media from Bioreactor used in research on human breast cancer. NASA's Marshall Space Flight Center (MSFC) is sponsoring research with Bioreactors, rotating wall vessels designed to grow tissue samples in space, to understand how breast cancer works. This ground-based work studies the growth and assembly of human mammary epithelial cells (HMEC) from breast cancer susceptible tissue. Radiation can make the cells cancerous, thus allowing better comparisons of healthy vs. tunourous tissues.