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1

Seamless Correction of the Sickle Cell Disease Mutation of the HBB Gene in Human Induced  

E-print Network

Seamless Correction of the Sickle Cell Disease Mutation of the HBB Gene in Human Induced ABSTRACT: Sickle cell disease (SCD) is the most common human genetic disease which is caused by a single effector nucleases; induced pluripotent stem cells; piggyBac transposon; sickle cell disease; gene therapy

Zhao, Huimin

2

Non-thalassemic phenotype associated with the -83 (G > A) mutation of the ?-globin gene promoter (HBB: c.-133G > A).  

PubMed

The -83 (G > A) mutation of the ?-globin gene promoter (HBB: c.-133G > A) was first reported in an adult male patient with mild thalassemic indices, suggesting that this may be a mild ?(+)-thalassemia (?(+)-thal) allele. In this report, we present data from several patients who are simple heterozygotes for the -83 mutation, or compound heterozygotes for -83 and Hb S (HBB: c.20A > T) or ?-thal. These cases illustrate that the -83 sequence variant is not associated with a thalassemic phenotype. This has important implications for carrier screening and genetic counseling, particularly since the -83 mutation is relatively common in African and Hispanic populations. PMID:25405919

Waye, John S; Eng, Barry; Hanna, Meredith; Hohenadel, Betty-Ann; Nakamura, Lisa N; Walker, Lynda

2014-01-01

3

Identification of a Novel Mutation in the ?-Globin Gene 3' Untranslated Region (HBB: c.*+118A?>?G) in Spain.  

PubMed

Abstract The 3' untranslated region (3'UTR) region is well known to be associated with mRNA stability because of its associations with 3' end processing, polyadenylation and mRNA capping. Mutations located in this area cause a ?-thalassemia (?-thal) phenotype compatible with ?(+)-thal. Two brothers, 49- and 41-years-old, were diagnosed with ?-thal intermedia (?-TI) at 2 years of age. The ?-globin gene from the promoter region to the 3'UTR was sequenced and both brothers were diagnosed to be compound heterozygotes for the 3'UTR +1592 (A?>?G) (HBB: c.*+118A?>?G) and codon 39 (C?>?T) (HBB: c.118C?>?T) mutations. Their mother was a carrier of the nonsense codon 39 mutation and her hematological data suggested ?-thal trait; their father was a carrier of the 3'UTR +1592 mutation, though he did not have hematological parameters associated with ?-thal. The adenine at position +1592 or +118 bases downstream of the termination codon is highly conserved among primates and placental mammals, as it is located between the polyadenylation A signal (PAS) and the polyadenylation A cleavage (PAC) sites. Given its location, it is likely that this mutation would interfere with mRNA maturation; however, the clinical data of the heterozygous carriers show virtually no significant alterations. Therefore, we suggest that the impact on cleavage-stimulation factor (CstF) recognition of the mRNA sequence would be minimal and not significantly alter polyadenylation. Although the mechanism is not known, and because the carrier has no ?-thal minor, the mRNA is stable enough that the synthesis of the ?-globin chain is unaffected. PMID:25572186

Herrera, Maria Ascensión; De La Fuente-Gonzalo, Félix; González, Fernando Ataúlfo; Nieto, Jorge M; Dominguez, Alejandra Blum; Villegas, Ana; Ropero, Paloma

2015-01-01

4

Lateral flow dipstick test for genotyping of 15 beta-globin gene (HBB) mutations with naked-eye detection.  

PubMed

For definitive diagnosis of thalassemia carriers and patients, as well as for prenatal diagnosis, genotype analysis is of fundamental importance. We report a dry-reagent, lateral flow dipstick test that enables visual genotyping (detection by naked eye) of 15 mutations common in Mediterranean populations in the beta-globin gene (HBB). The method comprises 3 simple steps: (i) PCR amplification of a single 1896 bp segment of the beta globin gene flanking all 15 mutations; (ii) a multiplex (10-plex and/or 30-plex) primer extension reaction of the unpurified amplification product using allele-specific primers. Biotin is incorporated in the extended product; (iii) a dry-reagent multi-allele (10-plex) dipstick assay for visual detection of the primer extension reaction products within minutes. The total time required for PCR, primer extension reaction and the dipstick assay is ~2 h. The method was evaluated by genotyping 45 DNA samples of known genotypes and 54 blind samples. The results were fully concordant with reference methods. The method is simple, rapid, and cost-effective. Detection by the dipstick assay does not require specialized instrumentation or highly qualified personnel. The proposed method could be a particularly useful tool in laboratories with limited resources and a basis for point-of-care diagnostics especially in combination with PCR amplification from whole blood. PMID:22541824

Papanikos, Frantzeskos; Iliadi, Alexandra; Petropoulou, Margarita; Ioannou, Penelope C; Christopoulos, Theodore K; Kanavakis, Emmanuel; Traeger-Synodinos, Jan

2012-05-21

5

Hb Knossos: HBB:c.82G>T Associated with HBB:c.315+1G>A Beta Zero Mutation Causes Thalassemia Intermedia.  

PubMed

?-thalassemia is the most common single gene disorder worldwide and in Iran. In the present study we report for the first time a rare variant of hemoglobin HBB:c.82G>T; Codon 27 GCC?TCC (Ala?Ser), Hb Knossos, using sequencing and reverse dot blot hybridization, in members of a family from North Iran. The family has a 16 years-old compound heterozygous thalassemia intermedia male child presenting this variant together with HBB:c.315+1G>A (IVSII-I) mutation. The father, heterozygous for Hb Knossos, showed borderline hematological indices. To our knowledge, this is the first report of Hb Knossos in trans with the ?(O) IVSII-I allele leading to thalassemia intermedia. Our data also highlight the necessity of deep molecular characterization of subjects presenting normal HbA2 level associated with abnormal or borderline red cell indices. PMID:25332589

Nasouhipur, Hengameh; Banihashemi, Ali; Youssefi Kamangar, Reza; Akhavan-Niaki, Haleh

2014-09-01

6

A novel ?-globin gene mutation HBB.c.22 G>C produces a hemoglobin variant (Hb Vellore) mimicking HbS in HPLC.  

PubMed

Hemoglobinopathies are highly prevalent in Indian population. DNA analysis to detect causative mutations is required for identifying rare hemoglobin variants or when hematological results are discordant with the clinical phenotype. In this report, we describe a novel hemoglobin variant caused by a mutation in beta-globin gene, Codon 7 GAG?CAG (Glu?Gln) that elutes in the position of sickle haemoglobin (HbS) in cation exchange high performance liquid chromatography. This report highlights possible diagnostic pitfalls in interpreting data solely based on haemoglobin analysis and usefulness of mutation screening in definitive diagnosis of hemoglobinopathies. PMID:22471768

Edison, E S; Sathya, M; Rajkumar, S V; Nair, S C; Srivastava, A; Shaji, R V

2012-10-01

7

Impact of single nucleotide polymorphisms in HBB gene causing haemoglobinopathies: in silico analysis.  

PubMed

Single nucleotide polymorphisms (SNPs) are being intensively studied to understand the biological basis of complex traits and diseases. Deleterious mutations of the human beta-globin gene (HBB) are responsible for beta-thalassaemia and other haemoglobinopathies, which are the most common genetic diseases of blood. Single amino acid substitutions in the globin chain are the commonest forms of haemoglobinopathy. Although many haemoglobinopathies present similar structural abnormal points, their functions sometimes are different. Here, using computational methods, we analysed the genetic variations that can alter the expression and function of the HBB gene. We applied an evolutionary perspective to screen the SNPs using a sequence homology-based SIFT tool, which suggested that 210 (90%) non-synonymous (ns)SNPs were found to be deleterious. The structure-based approach PolyPhen server suggested that 134 (57%) nsSNPS may disrupt protein function and structure. The PupaSuite tool predicted the phenotypic effect of SNPs on the structure and function of the affected protein. Structure analysis was carried out with the major mutation that occurred in the native protein coded by the HBB gene in HbC, HbD, HbE and HbS. The amino acid residues in the native and mutant modelled protein were further analysed for solvent accessibility, and secondary structure to check the stability of the proteins. The functional analysis presented here may be a good model for further research. PMID:19429541

George Priya Doss, C; Rao, Sethumadhavan

2009-04-01

8

Normal Hb A2 ?-thalassemia trait: frameshift mutation (HBB: c.187_251dup) in cis with the Hb A2' ?-globin gene missense mutation (HBD: c.49G>C).  

PubMed

We report the case of a father and daughter who are heterozygous for a duplication of 65 bp within exon 2 of the ?-globin gene, resulting in an altered and truncated ?-globin chain that is predicted to be non functional. The ?-globin gene mutation is in cis with the common Hb A2?' missense mutation of the ?-globin gene (HBD: c.49G>C), resulting in ?-thalassemia (?-thal) trait with normal levels of Hb A2. This is the second report of this ?(0)-thal mutation, and both families were associated with the Hb A2?' variant and normal levels of Hb A2. Laboratories should be aware of the rare occurrence of ?-thal trait with normal levels of Hb A2. PMID:23398055

Waye, John S; Eng, Barry; Hellens, Laurie; Hohenadel, Betty-Ann; Nakamura, Lisa M; Walker, Lynda

2013-01-01

9

Molecular diagnostics of the HBB gene in an Omani cohort using bench-top DNA Ion Torrent PGM technology.  

PubMed

Hemoglobinopathies, such as sickle cell disease (SCD) and beta-thalassemia major (TM), are severe diseases and the most common autosomal recessive condition worldwide and in particular in Oman. Early screening and diagnosis of carriers are the key for primary prevention. Once a country-wide population screening program is mandated by law, a sequencing technology that can rapidly confirm or identify disease-causing mutations for a large number of patients in a short period of time will be necessary. While Sanger sequencing is the standard protocol for molecular diagnosis, next generation sequencing starts to become available to reference laboratories. Using the Ion Torrent PGM sequencer, we have analyzed a cohort of 297 unrelated Omani cases and reliably identified mutations in the beta-globin (HBB) gene. Our model study has shown that Ion Torrent PGM can rapidly sequence such a small gene in a large number of samples using a barcoded uni-directional or bi-directional sequence methodology, reducing cost, workload and providing accurate diagnosis. Based on our results we believe that the Ion Torrent PGM sequencing platform, able to analyze hundreds of patients simultaneously for a single disease gene can be a valid molecular screening alternative to ABI sequencing in the diagnosis of hemoglobinopathies and other genetic disorders in the near future. PMID:24880717

Hassan, S M; Vossen, R H A M; Chessa, R; den Dunnen, J T; Bakker, E; Giordano, P C; Harteveld, C L

2014-09-01

10

A New Hemoglobin Variant: Hb Meylan [?73(E17)Asp???Phe; HBB: c.220G>T; c.221A>T] with a Double Base Mutation at the Same Codon.  

PubMed

Abstract We report a new ?-globin chain variant: Hb Meylan [?73(E17)Asp???Phe; HBB: c.220G>T; c.221A>T]. The new variant results from a double nucleotide mutation at the same codon. The possible molecular mechanisms are discussed. PMID:25476778

Renoux, Céline; Feray, Cécile; Joly, Philippe; Zanella-Cleon, Isabelle; Garcia, Caroline; Lacan, Philippe; Couprie, Nicole; Francina, Alain

2015-01-01

11

Seamless gene correction of ?-thalassemia mutations in patient-specific iPSCs using CRISPR/Cas9 and piggyBac.  

PubMed

?-thalassemia, one of the most common genetic diseases worldwide, is caused by mutations in the human hemoglobin beta (HBB) gene. Creation of human induced pluripotent stem cells (iPSCs) from ?-thalassemia patients could offer an approach to cure this disease. Correction of the disease-causing mutations in iPSCs could restore normal function and provide a rich source of cells for transplantation. In this study, we used the latest gene-editing tool, CRISPR/Cas9 technology, combined with the piggyBac transposon to efficiently correct the HBB mutations in patient-derived iPSCs without leaving any residual footprint. No off-target effects were detected in the corrected iPSCs, and the cells retain full pluripotency and exhibit normal karyotypes. When differentiated into erythroblasts using a monolayer culture, gene-corrected iPSCs restored expression of HBB compared to the parental iPSCs line. Our study provides an effective approach to correct HBB mutations without leaving any genetic footprint in patient-derived iPSCs, thereby demonstrating a critical step toward the future application of stem cell-based gene therapy to monogenic diseases. PMID:25096406

Xie, Fei; Ye, Lin; Chang, Judy C; Beyer, Ashley I; Wang, Jiaming; Muench, Marcus O; Kan, Yuet Wai

2014-09-01

12

Hb Feilding [?12(A9)Thr???Pro; HBB: c.37A>C]: A Novel Unstable ?-Globin Chain Variant.  

PubMed

Abstract We report here a patient heterozygous for a previously unreported ? chain variant. A 72-year-old Caucasian female was found to have an abnormal hemoglobin (Hb) as an incidental finding following Hb A1C analysis. There was no family history of anemia or hemoglobinopathy. Her full blood count revealed a mild normochromic anemia with Hb 11.1 g/dL (range 11.5-15.0), mean corpuscular volume (MCV) 93.0 fL (range 80.0-100.0) and mean corpuscular Hb (MCH) 30.0 pg (range 27.0-32.0). Isopropanol stability tests and a variant Hb on high performance liquid chromatography (HPLC) comprizing 37.0% of the total Hb suggested an unstable Hb variant. Sanger sequencing of the ?-globin gene revealed a single base substitution, HBB: c.37A>C, causing the missense mutation ?12(A9)Thr???Pro in exon 1 of the HBB gene. This mutation changes the threonine residue at position 12(A9) to a proline in the ?-globin chain. We propose that this variant be called Hb Feilding after the town where the proband lived. Three dimensional modeling suggested that the disruption of the Hb structure was due to the introduction of a proline at helix A9 which caused distortion of the helical structure and resulted in reduced solubility. PMID:25572184

Ghallyan, Nikhil; Donald, Tarn; Broad, David; Johnson, Steve; Browett, Peter; Van de Water, Neil

2015-01-01

13

A novel 26 bp deletion [HBB: c.20_45del26bp] in exon 1 of the ?-globin gene causing ?-thalassemia major.  

PubMed

Molecular characterization of ?-thalassemia (?-thal) is essential in prevention and in understanding the biology of the disease. Deletion mutations are relatively uncommon in ?-thal. In this report, we describe a novel 26 bp deletion from codon 6 to codon 14 in the ?-globin in a consanguineous family from Tamil Nadu, India. This novel mutation causes a shift in the normal reading frame of the ?-globin coding sequence, and consequently, a premature chain termination of translation due to the creation of a stop codon at the position of codon 21. The identification of this novel deletional mutation adds to the repertoire of ?-thal mutations in India. PMID:22233277

Edison, Eunice S; Venkatesan, Rajkumar S; Govindanattar, Sankari Devi; George, Biju; Shaji, Ramachandran V

2012-01-01

14

Characterization of Hb Calvino (HBB: c.406G?>?A): a new silent ?-globin gene variant found in coexistence with ?-thalassemia in a family of African origin.  

PubMed

We report a new silent ?-globin gene variant found in a family from Angola living in the north eastern Italian city of Ferrara. The probands, two young sisters, presented with hematological parameters compatible with a ?-thalassemia (?-thal) minor but with normal Hb A2 levels and normal hemoglobin (Hb) separation on high performance liquid chromatography (HPLC). Molecular analyses revealed a homozygosity for the common -?(3.7) (rightward) deletion and heterozygosity for a novel transition (GCT?>?ACT) at codon 135 of the ?-globin gene, leading to an Ala???Thr single amino acid substitution that was inherited from the healthy father. PMID:25222042

Marsella, Maria; Salvagno, Gianluca; Dolcini, Bernadetta; Ferlini, Alessandra; Ravani, Anna; Harteveld, Cornelis L; Giordano, Piero C; Borgna-Pignatti, Caterina

2014-01-01

15

Rare Hemoglobin Variants: Hb G-Szuhu (HBB: c.243C>G), Hb G-Coushatta (HBB: c.68A>C) and Hb Mizuho (HBB: c.206T>C) in Sri Lankan Families.  

PubMed

Abstract In this short communication, we describe the clinical presentation of unusual hemoglobin (Hb), variants in three Sri Lankan cases under study for ?-thalassemia intermedia (?-TI). We believe this is the first report on their occurrence in Sri Lanka as well as from the Indian subcontinent. During a molecular study performed on ?-TI patients, we identified three unusual Hb variants as Hb G-Szuhu (HBB: c.243C>G), Hb G-Coushatta (HBB: c.68A>C) and Hb Mizuho (HBB: c.206T>C) in three unrelated families. Hb G-Szuhu and Hb G-Coushatta were found in combination with the common ?-thalassemia (?-thal) mutation, IVS-I-5 (G>C). Both probands had mild anemia with greatly reduced red cell indices and had non palpable livers and spleens, however, by ultrasound, both were observed to be enlarged. The final Hb variant, Hb Mizuho, was identified as a heterozygous mutation found in both proband and his mother. Both family members had severe anemia and were regularly transfused and had increased red cell parameters. PMID:25572187

Perera, P Shiromi; Silva, Ishari; Hapugoda, Menaka; Wickramarathne, Merita N; Wijesiriwardena, Indira; Efremov, Dimitar G; Fisher, Christopher A; Weatherall, David J; Premawardhena, Anuja

2015-01-01

16

The Human Gene Mutation Database: 2008 update  

Microsoft Academic Search

The Human Gene Mutation Database (HGMD®) is a comprehensive core collection of germline mutations in nuclear genes that underlie or are associated with human inherited\\u000a disease. Here, we summarize the history of the database and its current resources. By December 2008, the database contained\\u000a over 85,000 different lesions detected in 3,253 different genes, with new entries currently accumulating at a

Peter D Stenson; Matthew Mort; Edward V Ball; Katy Howells; Andrew D Phillips; Nick ST Thomas; David N Cooper

2009-01-01

17

Epilepsy and fragile X gene mutations  

Microsoft Academic Search

We used two strategies to investigate a possible link between predisposition for epilepsy and mutations in the fragile X mental retardation-1 gene. The first entailed performing electroencephalography on 14 patients with an amplification in the fragile X mental retardation-1 gene, and the second involved molecular genetic analysis of the fragile X mental retardation-1 gene in 16 children with benign childhood

Gerhard Kluger; Ingolf Böhm; Michael C. Laub; Claus Waldenmaier

1996-01-01

18

Genes and Mutations in Hearing Impairment  

Microsoft Academic Search

The programmed expression of proteins is required for hearing. This chapter describes the structure of chromosomes and genes and delineates how the processes of DNA transcription and RNA translation are required to form functional proteins. In cases of genetic hearing loss, mutations have occurred in either transcription or translation of the genes that encode for proteins crucial for the proper

Karen B. Avraham; Tama Hasson

19

Novel mutations in the human HPRT gene.  

PubMed

Inherited mutation of a purine salvage enzyme, hypoxanthine guanine phosphoribosyltransferase (HPRT), gives rise to Lesch-Nyhan Syndrome (LNS) or HPRT-related gout. Here, we report five novel independent mutations in the coding region of the HPRT gene from five unrelated male patients manifesting different clinical phenotypes associated with LNS: exon 2: c.133A > G, p.45R > G; c.35A > C, p.12D > A; c.88delG; exon 7: c.530A > T, p.177D > V; and c.318 + 1G > C: IVS3 + 1G > C splice site mutation. PMID:21780909

Nguyen, Khue Vu; Naviaux, Robert K; Paik, Kacie K; Nyhan, William L

2011-06-01

20

[Gene mutations in familial amyotrophic lateral sclerosis].  

PubMed

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle weakness that reflects degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem, and spinal cord. Most ALS cases are sporadic, but about 5%-10% are familial. The majority of familial ALS (FALS) cases follow an autosomal dominant inheritance pattern, and include the following mutations: ALS1, Cu/Zn superoxide dismutase (SOD1); ALS3; ALS4, senataxin; ALS6, fused in sarcoma (FUS); ALS7; ALS8, vesicle-associated membrane protein; ALS9, angiogenin; ALS10, TAR DNA-binding protein (TARDBP); and ALS11/FIG4. Some of these gene mutations are rarely seen in sporadic ALS cases. ALS2/alsin and ALS5 show an autosomal recessive inheritance pattern. Recently, mutations in the gene encoding optineurin, earlier reported to be a causative gene for primary open-angle glaucoma, have also been found in patients with ALS. It has also been demonstrated that a mutation in the D-amino acid oxidase gene is associated with classic adult-onset FALS. However, these genetic defects occur in only about 20%-30% FLAS cases, while most genes causing FALS remain unknown. PMID:21301041

Oda, Masaya; Izumi, Yuishin; Kaji, Ryuji

2011-02-01

21

CARD15 gene mutations in sarcoidosis.  

PubMed

Sarcoidosis, Blau syndrome and Crohn's disease are complex disorders, characterised by granulomatous inflammation affecting a variety of organs. Mutations of the CARD15 gene, on chromosome 16, have been shown to contribute significantly to Crohn's disease and to cause Blau syndrome. These factors prompted the current authors to study CARD15 mutations in sarcoidosis. A total of 138 families were genotyped, including 302 patients with sarcoidosis and 127 patients without a family history of sarcoidosis (together with their parents), for four main coding CARD15 polymorphisms associated with increased risk of Crohn's disease. Furthermore, the gene segment that harbours Blau syndrome mutations was sequenced in 39 selected patients from 39 families with affected siblings identical for one or two parental chromosomes 16s and in eight patients from multi-case families. None of the reported Blau syndrome mutations and no new sequence alterations were found. There was an increased frequency of transmission of the rare allele of the polymorphic sites 802C>T (SNP5) and 2722G>C (SNP12) in at least one of the two study groups. In conclusion, CARD15 mutations, which are important in Crohn's disease and Blau syndrome, play no major role in sarcoidosis in this study population. However, these mutations could be of limited importance, especially in patients without a family history of sarcoidosis. PMID:14621080

Schürmann, M; Valentonyte, R; Hampe, J; Müller-Quernheim, J; Schwinger, E; Schreiber, S

2003-11-01

22

Mutations of the GREAT gene cause cryptorchidism.  

PubMed

In humans, failure of testicular descent (cryptorchidism) is one of the most frequent congenital malformations, affecting 1-3% of newborn boys. The clinical consequences of this abnormality are infertility in adulthood and a significantly increased risk of testicular malignancy. Recently, we described a mouse transgene insertional mutation, crsp, causing high intraabdominal cryptorchidism in homozygous males. A candidate gene Great (G-protein-coupled receptor affecting testis descent), was identified within the transgene integration site. Great encodes a seven-transmembrane receptor with a close similarity to the glycoprotein hormone receptors. The Great gene is highly expressed in the gubernaculum, the ligament that controls testicular movement during development, and therefore may be responsible for mediating hormonal signals that affect testicular descent. Here we show that genetic targeting of the Great gene in mice causes infertile bilateral intraabdominal cryptorchidism. The mutant gubernaculae fail to differentiate, indicating that the Great gene controls their development. Mutation screening of the human GREAT gene was performed using DHPLC analysis of the genomic DNA from 60 cryptorchid patients. Nucleotide variations in GREAT cDNA were found in both the patient and the control populations. A unique missense mutation (T222P) in the ectodomain of the GREAT receptor was identified in one of the patients. This mutant receptor fails to respond to ligand stimulation, implicating the GREAT gene in the etiology in some cases of cryptorchidism in humans. PMID:12217959

Gorlov, Ivan P; Kamat, Aparna; Bogatcheva, Natalia V; Jones, Eric; Lamb, Dolores J; Truong, Anne; Bishop, Colin E; McElreavey, Ken; Agoulnik, Alexander I

2002-09-15

23

?-Globin gene mutations in Isfahan Province, Iran.  

PubMed

?-Thalassemia (?-thal) encompasses a spectrum of mutations including deletion and point mutations on the ?-globin chains that is characterized by a reduction or complete absence of ?-globin genes. Most of the ?-thal cases are deletions involving one (?(+)) or both (?(0)) ?-globin genes, although point mutations (?(T)? or ??(T)) are found as well. In this study, 314 individuals with low hematological values, normal Hb A2 who were not affected with ?-thal or iron deficiency, were investigated for the presence of ?-thal mutations. The most common deletion was -?(3.7) (rightward) with a frequency of 70.7%, followed by ?(-5 nt) (-TGAGG) (8.7%), -?(4.2) (leftward) (4.7%), the polyadenylation signal (polyA2) site (AATAAA?>?AATGAA) (4.2%), -(?)(20.5) (3.8%), Hb Constant Spring [Hb CS, ?142, Stop?Gln; HBA2: c.427T?>?C] (2.9%), polyA1 (AATAAA?>?AATAAG) and ?(codon 19) (GCG?>?GC-, ?2) (16%), and -?-(MED) (0.9%). The results of this study may be valuable for designing a plan for carrier screening, premarital genetic counseling, prenatal diagnosis (PND) and reducing excessive health care costs to an affordable level in Isfahan Province, Iran. PMID:24826792

Karamzade, Arezo; Mirzapour, Hadi; Hoseinzade, Majid; Asadi, Sara; Gholamrezapour, Tahere; Tavakoli, Parvaneh; Salehi, Mansoor; Selebi, Mansoor

2014-01-01

24

The Androgen Receptor Gene Mutations Database.  

PubMed Central

The current version of the androgen receptor (AR) gene mutations database is described. The total number of reported mutations has risen from 272 to 309 in the past year. We have expanded the database: (i) by giving each entry an accession number; (ii) by adding information on the length of polymorphic polyglutamine (polyGln) and polyglycine (polyGly) tracts in exon 1; (iii) by adding information on large gene deletions; (iv) by providing a direct link with a completely searchable database (courtesy EMBL-European Bioinformatics Institute). The addition of the exon 1 polymorphisms is discussed in light of their possible relevance as markers for predisposition to prostate or breast cancer. The database is also available on the internet (http://www.mcgill. ca/androgendb/ ), from EMBL-European Bioinformatics Institute (ftp. ebi.ac.uk/pub/databases/androgen ), or as a Macintosh FilemakerPro or Word file (MC33@musica.mcgill.ca). PMID:9399843

Gottlieb, B; Lehvaslaiho, H; Beitel, L K; Lumbroso, R; Pinsky, L; Trifiro, M

1998-01-01

25

Mutations of the GREAT gene cause cryptorchidism  

Microsoft Academic Search

In humans, failure of testicular descent (cryptorchidism) is one of the most frequent congenital malformations, affecting 1-3% of newborn boys. The clinical consequences of this abnormality are infertility in adulthood and a significantly increased risk of testicular malignancy. Recently, we described a mouse transgene insertional mutation, crsp, causing high intraabdominal cryptorchidism in homozygous males. A candidate gene Great (G-protein-coupled receptor

Ivan P. Gorlov; Aparna Kamat; Natalia V. Bogatcheva; Eric Jones; Dolores J. Lamb; Anne Truong; Colin E. Bishop; Ken McElreavey; Alexander I. Agoulnik

2002-01-01

26

A Recurring FBN1 Gene Mutation in Neonatal Marfan Syndrome  

Microsoft Academic Search

Background: Marfan syndrome is an autosomal domi- nant disorder of connective tissue caused by mutations in the fibrillin 1 gene (FBN1). FBN1 mutations have been associated with a broad spectrum of phenotypes. Neo- natal Marfan syndrome has unique clinical manifesta- tions and mutations. Objective: To determine if there is a discernible geno- typic-phenotypic correlation associated with the unique mutation in

Amanda M. Jacobs; Ivanka Toudjarska; Andrew Racine; Petros Tsipouras; Michael W. Kilpatrick; Alan Shanske

2002-01-01

27

Different Gene Mutations May Determine Severity, Type of Autism  

MedlinePLUS

... features on this page, please enable JavaScript. Different Gene Mutations May Determine Severity, Type of Autism Finding ... 22, 2014 Related MedlinePlus Pages Autism Spectrum Disorder Genes and Gene Therapy MONDAY, Dec. 22, 2014 (HealthDay ...

28

Gene Mutations Linked to Colon Cancer in Black Patients  

MedlinePLUS

... sharing features on this page, please enable JavaScript. Gene Mutations Linked to Colon Cancer in Black Patients ... Related MedlinePlus Pages African American Health Colorectal Cancer Genes and Gene Therapy TUESDAY, Jan. 13, 2015 (HealthDay ...

29

Researchers Find Gene Mutation That May Protect Against Heart Disease  

MedlinePLUS

... on this page, please enable JavaScript. Researchers Find Gene Mutation That May Protect Against Heart Disease Rare ... Preidt Wednesday, November 12, 2014 Related MedlinePlus Pages Genes and Gene Therapy Heart Diseases WEDNESDAY, Nov. 12, ...

30

Childhood Peanut Allergy May Be Linked to Skin Gene Mutation  

MedlinePLUS

... on this page, please enable JavaScript. Childhood Peanut Allergy May Be Linked to Skin Gene Mutation Study ... Friday, October 24, 2014 Related MedlinePlus Pages Food Allergy Genes and Gene Therapy Skin Conditions FRIDAY, Oct. ...

31

NOTCH3 gene mutations in subjects clinically suspected of CADASIL  

Microsoft Academic Search

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease due to mutations involving loss or gain of a cysteine residue in the NOTCH3 gene. A cluster of mutations around exons 3 and 4 was originally reported. Identification of pathogenic mutation is important for diagnostic confirmation of the disease, however genetic counselling and testing of

Lorena Mosca; Raffaella Marazzi; Alfonso Ciccone; Ignazio Santilli; Anna Bersano; Valeria Sansone; Enrico Grosso; Giorgia Mandrile; Daniela Francesca Giachino; Laura Adobbati; Elisabetta Corengia; Elio Agostoni; Anna Fiumani; Salvatore Gallone; Elio Scarpini; Mario Guidotti; Roberto Sterzi; Clara Ajmone; Alessandro Marocchi; Silvana Penco

2011-01-01

32

Smad2 and Smad4 gene mutations in hepatocellular carcinoma  

Microsoft Academic Search

TGF-? is a negative regulator of liver growth. Smad family of genes, as mediators of TGF-? pathway, are candidate tumor suppressor genes in hepatocellular carcinoma (HCC). We studied 35 HCC and non-tumour liver tissues for possible mutations in Smad2 and Smad4 genes. Three tumours displayed somatic mutations; two in Smad4 (Asp332Gly and Cys401Arg) and one in Smad2 (Gln407Arg) genes. All

M C Yakicier; M B Irmak; A Romano; M Kew; M Ozturk

1999-01-01

33

Mutations and Disease Mutations in the HFE gene are associated with the hemochromatosis  

E-print Network

1 Mutations and Disease Mutations in the HFE gene are associated with the hemochromatosis disease. A laboratory working on the hemochromatosis disease wants to elucidate the biochemical and structural basis and their locations in the HFE gene (using dbSNP). 3. Learn more about hemochromatosis and its genetic testing (using

Levin, Judith G.

34

New ABCC6 gene mutations in German pseudoxanthoma elasticum patients  

Microsoft Academic Search

Pseudoxanthoma elasticum (PXE; OMIM 177850 and 264800) is a rare heritable disorder of the connective tissue affecting the extracellular matrix of the skin, eyes, gastrointestinal system, and cardiovascular system. It has recently been found that mutations in the ABCC6 gene encoding the multidrug resistance-associated protein (MRP) 6 cause PXE. This study examined novel mutations in the ABCC6 gene in our

Doris Hendig; Veronika Schulz; Jutta Eichgrün; Christiane Szliska; Christian Götting; Knut Kleesiek

2005-01-01

35

Mutational analysis of the lambda S gene  

E-print Network

BR322) AmpR lacPO StsgB R+Rz (in pBR322) Amp lacPO Sam7 R+Rz+ (in pBR322) AmpR TetR glori I3 AmpR TetR ~ori 13 AmpR glori 13 lacPO g'R+Rz+ (from pZ150) AmpR ~ori 13 lacPO S+R+Rz+ (from pZ150) lab. stock lab. stock J. Messing (40) (20... should be very low. In fact, only I of the sequenced S 25 TABLE 2. Possible S gene mutations. a aagb aa codon possible codon changes change in aa 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29...

Neal, Gregory Scott

2012-06-07

36

21 CFR 866.5900 - Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation detection system.  

Code of Federal Regulations, 2011 CFR

...transmembrane conductance regulator (CFTR) gene mutation detection system. 866.5900...transmembrane conductance regulator (CFTR) gene mutation detection system. (a) Identification . The CFTR gene mutation detection system is a...

2011-04-01

37

21 CFR 866.5900 - Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation detection system.  

...transmembrane conductance regulator (CFTR) gene mutation detection system. 866.5900...transmembrane conductance regulator (CFTR) gene mutation detection system. (a) Identification. The CFTR gene mutation detection system is a...

2014-04-01

38

21 CFR 866.5900 - Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation detection system.  

Code of Federal Regulations, 2013 CFR

...transmembrane conductance regulator (CFTR) gene mutation detection system. 866.5900...transmembrane conductance regulator (CFTR) gene mutation detection system. (a) Identification . The CFTR gene mutation detection system is a...

2013-04-01

39

21 CFR 866.5900 - Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation detection system.  

Code of Federal Regulations, 2012 CFR

...transmembrane conductance regulator (CFTR) gene mutation detection system. 866.5900...transmembrane conductance regulator (CFTR) gene mutation detection system. (a) Identification . The CFTR gene mutation detection system is a...

2012-04-01

40

Gene Expression in the Star Mutation of Petunia x Hybrida  

Technology Transfer Automated Retrieval System (TEKTRAN)

Differences in structural gene expression are responsible for a wide range of responses from human cancer to patterned flowers. Gene silencing is one of the ways in which gene expression is controlled. We have developed a model system to study anthocyanin gene silencing using a mutation in Petunia ...

41

Clustering of mutations in the carbamyl phosphate synthetase I gene  

SciTech Connect

The carbamyl phosphate synthetase I (CPSI) gene encodes the 165 kDa protein catalyzing the first step of the urea cycle, and its deficiency leads to life-threatening hyperammonemia in the newborn period. In our study of the molecular changes underlying CPSID we have found three silent mutations, two single base deletion mutants, four missense mutations that are present in both controls and patients, and two missense mutations present only in CPSID patients. These mutations are clustered in two exonic regions. Region one is located between the ATP-bicarbonate binding domains near the 3{prime} end of the message and is 220 bases in size (4% of total message). It contains 7 of the 11 mutations. Region two spanning 350 bases (7% of total message) contains the 4 remaining mutations and includes an ATP-bicarbonate binding domain. These mutations do not occur at CpG dinucleotides and sequence analysis revealed no hairpin loops or other structures. While analysis for intrageneic homologies revealed several small direct and inverted repeats involving the mutated sequences, the corresponding regions did not contain sequences consistent with the mutations found. Although the underlying cause of these mutation clusters is unclear, their presence suggests a configuration either in the primary sequence or a secondary/tertiary structure leading to a degradation in sequence fidelity. Additionally, the location of 11 of the 12 mutations in the CPSI gene within 11% of the message length allows us to narrow our initial mutation searches in CPSID patients.

Summar, M.L.; Hall, L. [Vanderbilt Univ. Medical Center, Nashville, TN (United States)

1994-09-01

42

Mutations of the BRAF gene in human cancer  

Microsoft Academic Search

Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS-RAF-MEK-ERK-MAP kinase pathway mediates cellular responses to growth

Helen Davies; Graham R. Bignell; Charles Cox; Philip Stephens; Sarah Edkins; Sheila Clegg; Jon Teague; Hayley Woffendin; Mathew J. Garnett; William Bottomley; Neil Davis; Ed Dicks; Rebecca Ewing; Yvonne Floyd; Kristian Gray; Sarah Hall; Rachel Hawes; Jaime Hughes; Vivian Kosmidou; Andrew Menzies; Catherine Mould; Adrian Parker; Claire Stevens; Stephen Watt; Steven Hooper; Rebecca Wilson; Hiran Jayatilake; Barry A. Gusterson; Colin Cooper; Janet Shipley; Darren Hargrave; Katherine Pritchard-Jones; Norman Maitland; Georgia Chenevix-Trench; Gregory J. Riggins; Darell D. Bigner; Giuseppe Palmieri; Antonio Cossu; Adrienne Flanagan; Andrew Nicholson; Judy W. C. Ho; Suet Y. Leung; Siu T. Yuen; Barbara L. Weber; Hilliard F. Seigler; Timothy L. Darrow; Hugh Paterson; Richard Marais; Christopher J. Marshall; Richard Wooster; Michael R. Stratton; P. Andrew Futreal

2002-01-01

43

CFTR gene mutations in isolated chronic obstructive pulmonary disease  

SciTech Connect

In order to identify a possible hereditary predisposition to the development of chronic obstructive pulmonary disease (COPD), we have looked for the presence of cystic fibrosis transmembrane regulator (CFTR) gene DNA sequence modifications in 28 unrelated patients with no signs of cystic fibrosis. The known mutations in Italian CF patients, as well as the most frequent worldwide CF mutations, were investigated. In addition, a denaturing gradient gel electrophoresis analysis of about half of the coding sequence of the gene in 56 chromosomes from the patients and in 102 chromosomes from control individuals affected by other pulmonary diseases and from normal controls was performed. Nine different CFTR gene mutations and polymorphisms were found in seven patients, a highly significant increase over controls. Two of the patients were compound heterozygotes. Two frequent CF mutations were detected: deletion F508 and R117H; two rare CF mutations: R1066C and 3667ins4; and five CF sequence variants: R75Q (which was also described as a disease-causing mutation in male sterility cases due to the absence of the vasa deferentia), G576A, 2736 A{r_arrow}G, L997F, and 3271+18C{r_arrow}T. Seven (78%) of the mutations are localized in transmembrane domains. Six (86%) of the patients with defined mutations and polymorphisms had bronchiectasis. These results indicate that CFTR gene mutations and sequence alterations may be involved in the etiopathogenesis of some cases of COPD.

Pignatti, P.F.; Bombien, C.; Marigo, C. [and others

1994-09-01

44

KMD: Korean Mutation Database for genes related to diseases.  

PubMed

The number of known disease-causing mutations has increased dramatically. However, there have been few organized mutation databases developed that are available to the public or not-for-profit entities. Thus, clinicians and diagnostic laboratories had to spend time searching many publications and databases to determine whether a mutation has been previously reported. To assist in genetic diagnoses, the systematic collection and curation of mutations are necessary. The Korean Mutation Database (KMD; http://kmd.cdc.go.kr) is a country-specific database of human gene mutations that was established in September 2009. The KMD is a database consolidating mutations of genes related to diseases in Korea; it now contains more than 1,600 mutations from 245 genes. We collected mutation data from diagnostic laboratories and published journals over recent decades in Korea. KMD has been open to the public for searches and registration of mutation data without charge. Our aim is to provide organized information for clinicians and researchers who are interested in genetic diseases. It will be useful not only for researchers in Korea but also for researchers in countries with similar ethnic backgrounds. Ultimately, KMD will be an essential base to improve researches in genetic diseases, developments of diagnostics, and therapeutic optimization. PMID:22323337

Park, Mi-Hyun; Koo, Soo Kyung; Lee, Jin-Sung; Yoo, Han-Wook; Kim, Jong-Won; Cheong, Hae Il; Park, Hyun-Young

2012-04-01

45

Ferredoxin Gene Mutation in Iranian Trichomonas vaginalis Isolates  

PubMed Central

Background Trichomonas vaginalis causes trichomoniasis and metronidazole is its chosen drug for treatment. Ferredoxin has role in electron transport and carbohydrate metabolism and the conversion of an inactive form of metronidazole (CO) to its active form (CPR). Ferredoxin gene mutations reduce gene expression and increase its resistance to metronidazole. In this study, the frequency of ferredoxin gene mutations in clinical isolates of T.vaginalis in Tehran has been studied. Methods Forty six clinical T. vaginalis isolates of vaginal secretions and urine sediment were collected from Tehran Province since 2011 till 2012. DNA was extracted and ferredoxin gene was amplified by PCR technique. The ferredoxin gene PCR products were sequenced to determine gene mutations. Results In four isolates (8.69%) point mutation at nucleotide position -239 (the translation start codon) of the ferredoxin gene were detected in which adenosine were converted to thymine. Conclusion Mutation at nucleotide -239 ferredoxin gene reduces translational regulatory protein's binding affinity which concludes reduction of ferredoxin expression. For this reduction, decrease in activity and decrease in metronidazole drug delivery into the cells occur. Mutations in these four isolates may lead to resistance of them to metronidazole. PMID:24454433

HEIDARI, Soudabeh; BANDEHPOUR, Mojgan; SEYYED-TABAEI, Seyyed-Javad; VALADKHANI, Zarintaj; HAGHIGHI, Ali; ABADI, AliReza; KAZEMI, Bahram

2013-01-01

46

Androgen receptor gene mutation, rearrangement, polymorphism.  

PubMed

Genetic aberrations of the androgen receptor (AR) caused by mutations, rearrangements, and polymorphisms result in a mutant receptor that has varied functions compared to wild type AR. To date, over 1,000 mutations have been reported in the AR with most of these being associated with androgen insensitivity syndrome (AIS). While mutations of AR associated with prostate cancer occur less often in early stage localized disease, mutations in castration-resistant prostate cancer (CRPC) patients treated with anti-androgens occur more frequently with 10-30% of these patients having some form of mutation in the AR. Resistance to anti-androgen therapy usually results from gain-of-function mutations in the LBD such as is seen with bicalutamide and more recently with enzalutamide (MDV3100). Thus, it is crucial to investigate these new AR mutations arising from drug resistance to anti-androgens and other small molecule pharmacological agents. PMID:25045626

Eisermann, Kurtis; Wang, Dan; Jing, Yifeng; Pascal, Laura E; Wang, Zhou

2013-09-01

47

Androgen receptor gene mutation, rearrangement, polymorphism  

PubMed Central

Genetic aberrations of the androgen receptor (AR) caused by mutations, rearrangements, and polymorphisms result in a mutant receptor that has varied functions compared to wild type AR. To date, over 1,000 mutations have been reported in the AR with most of these being associated with androgen insensitivity syndrome (AIS). While mutations of AR associated with prostate cancer occur less often in early stage localized disease, mutations in castration-resistant prostate cancer (CRPC) patients treated with anti-androgens occur more frequently with 10–30% of these patients having some form of mutation in the AR. Resistance to anti-androgen therapy usually results from gain-of-function mutations in the LBD such as is seen with bicalutamide and more recently with enzalutamide (MDV3100). Thus, it is crucial to investigate these new AR mutations arising from drug resistance to anti-androgens and other small molecule pharmacological agents. PMID:25045626

Eisermann, Kurtis; Wang, Dan; Jing, Yifeng; Pascal, Laura E.; Wang, Zhou

2014-01-01

48

Aneuploidy versus gene mutation as cause of cancer  

Microsoft Academic Search

The mutagenic ranges of aneuploidy, an abnormal number of chromosomes, and gene mutation are analyzed for their abilities to cause the dominan t phe- notypes of cancer. In the cell, activating gene mut a- tions are buffered because virtually all gene products are kinetically linked into biochemical assembly lines and thus functionally controlled by upstream and downstream enzymes working at

Peter Duesberg; Reinhard Stindl; Ruhong Li; Ruediger Hehlmann; David Rasnick

2001-01-01

49

Preservation of Duplicate Genes by Complementary, Degenerative Mutations  

Microsoft Academic Search

The origin of organismal complexity is generally thought to be tightly coupled to the evolution of new gene functions arising subsequent to gene duplication. Under the classical model for the evolution of duplicate genes, one member of the duplicated pair usually degenerates within a few million years by accumulating deleterious mutations, while the other duplicate retains the original function. This

Allan Force; Michael Lynch; F. Bryan Pickett; Angel Amores; Yi-lin Yan; John Postlethwait

1999-01-01

50

Four novel mutations of the coproporphyrinogen III oxidase gene.  

PubMed

Here we report the characterization of four novel mutations and a previously described one of the coproporphyrinogen III oxidase (CPO) gene in five Italian patients affected by Hereditary Coproporphyria (HCP). Three of the novel genetic variants are missense mutations (p.Gly242Cys; p.Leu398Pro; p.Ser245Phe) and one is a frameshift mutation (p.Gly188TrpfsX45). PMID:19267996

Aurizi, C; Lupia Palmieri, G; Barbieri, L; Macrì, A; Sorge, F; Usai, G; Biolcati, G

2009-01-01

51

Diverse growth hormone receptor gene mutations in Laron syndrome.  

PubMed Central

To better understand the molecular genetic basis and genetic epidemiology of Laron syndrome (growth-hormone insensitivity syndrome), we analyzed the growth-hormone receptor (GHR) genes of seven unrelated affected individuals from the United States, South America, Europe, and Africa. We amplified all nine GHR gene exons and splice junctions from these individuals by PCR and screened the products for mutations by using denaturing gradient gel electrophoresis (DGGE). We identified a single GHR gene fragment with abnormal DGGE results for each affected individual, sequenced this fragment, and, in each case, identified a mutation likely to cause Laron syndrome, including two nonsense mutations (R43X and R217X), two splice-junction mutations, (189-1 G to T and 71 + 1 G to A), and two frameshift mutations (46 del TT and 230 del TA or AT). Only one of these mutations, R43X, has been previously reported. Using haplotype analysis, we determined that this mutation, which involves a CpG dinucleotide hot spot, likely arose as a separate event in this case, relative to the two prior reports of R43X. Aside from R43X, the mutations we identified are unique to patients from particular geographic regions. Ten GHR gene mutations have now been described in this disorder. We conclude that Laron syndrome is caused by diverse GHR gene mutations, including deletions, RNA processing defects, translational stop codons, and missense codons. All the identified mutations involve the extracellular domain of the receptor, and most are unique to particular families or geographic areas. Images Figure 1 Figure 2 PMID:8488849

Berg, M A; Argente, J; Chernausek, S; Gracia, R; Guevara-Aguirre, J; Hopp, M; Pérez-Jurado, L; Rosenbloom, A; Toledo, S P; Francke, U

1993-01-01

52

Diverse growth hormone receptor gene mutations in Laron syndrome  

SciTech Connect

To better understand the molecular genetic basis and genetic epidemiology of Laron syndrome (growth-hormone insensitivity syndrome), the authors analysed the growth-hormone receptor (GHR) genes of seven unrelated affected individuals from the United States, South America, Europe, and Africa. They amplified all nine GHR gene exons and splice junctions from these individuals by PCR and screened the products for mutations by using denaturing gradient gel electrophoresis (DGGE). They identified a single GHR gene fragment with abnormal DGGE results for each affected individual, sequenced this fragment, and, in each case, identified a mutation likely to cause Laron syndrome, including two nonsense mutations (R43X and R217X), two splice-junction mutations, (189-1 G to T and 71+1 G to A), and two frameshift mutations (46 del TT and 230 del TA or AT). Only one of these mutations, R43X, has been previously reported. Using haplotype analysis, they determined that this mutation, which involves a CpG dinucleotide hot spot, likely arose as a separate event in this case, relative to the two prior reports of R43X. Aside from R43X, the mutations identified are unique to patients from particular geographic regions. Ten GHR gene mutations have now been described in this disorder. The authors conclude that Laron syndrome is caused by diverse GHR gene mutations, including deletions, RNA processing defects, translational stop codons, and missense codons. All the identified mutations involve the extracellular domain of the receptor, and most are unique to particular families or geographic areas. 35 refs., 3 figs., 1 tab.

Berg, M.A.; Francke, U. (Stanford Univ. School of Medicine, CA (United States)); Gracia, R.; Rosenbloom, A.; Toledo, S.P.A. (Univ. Autonoma, Madrid (Spain)); Chernausek, S. (Children's Hospital Medical Center, Cincinnati, OH (United States)); Guevara-Aguirre, J. (Institute of Endocrinology, Metabolism, and Reproduction, Quito (Ecuador)); Hopp, M. (Univ. of Witwatersrand, Johannesburg (South Africa)); Rosenbloom, A.; Argente, J. (Univ. of Florida, Gainesville (United States)); Toledo, S.P.A. (Univ. of Sao Paulo (Brazil))

1993-05-01

53

Bioinformatic Analysis of GJB2 Gene Missense Mutations.  

PubMed

Gap junction beta 2 (GJB2) gene is the most commonly mutated connexin gene in patients with autosomal recessive and dominant hearing loss. According to Ensembl (release 74) database, 1347 sequence variations are reported in the GJB2 gene and about 13.5 % of them are categorized as missense SNPs or nonsynonymous variant. Because of the high incidence of GJB2 mutations in hearing loss patients, revealing the molecular effect of GJB2 mutations on protein structure may also provide clear point of view regarding the molecular etiology of deafness. Hence, the aim of this study is to analyze structural and functional consequences of all known GJB2 missense variations to the Cx26 protein by applying multiple bioinformatics methods. Two-hundred and eleven nonsynonymous variants were collected from Ensembl release 74, Leiden Open Variation Database (LOVD) and The Human Gene Mutation Database (HGMD). A number of bioinformatic tools were utilized for predicting the effect of GJB2 missense mutations at the sequence, structural, and functional levels. Some of the mutations were found to locate highly conserved regions and have structural and functional properties. Moreover, GJB2 mutations were also found to affect Cx26 protein at the molecular level via loss or gain of disorder, catalytic site, and post-translational modifications, including methylation, glycosylation, and ubiquitination. Findings, presented here, demonstrated the application of bioinformatic algorithms to predict the effects of mutations causing hearing impairment. I expect, this type of analysis will serve as a start point for future experimental evaluation of the GJB2 gene mutations and it will also be helpful in evaluating other deafness-related gene mutations. PMID:25388846

Yilmaz, Akin

2014-11-12

54

Single Cell Analysis of Mutations in the APC Gene  

Microsoft Academic Search

Introduction: Mutation analysis of inherited monogenic diseases is an important aspect of preimplantation genetic diagnosis. Familial adenomatous polyposis of the colon is an autosomal dominant inherited disorder caused by mutations in the tumor suppressor gene adenomatous polyposis coli (APC). A characteristic of this severe disease is the development of thousands of polyps in the colon which untreated evolve into malignant

Veronika Mayer; Ulrike Schoen; Elke Holinski-Feder; Udo Koehler; Stefan Thalhammer

2009-01-01

55

EGF receptor gene mutations are common in lung cancers from  

Microsoft Academic Search

Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. In-frame deletions occur in exon 19, whereas point mutations occur frequently in codon 858 (exon 21). We found from sequencing the EGFR TK domain that 7 of 10 gefitinib-sensitive tumors had

William Pao; Vincent Miller; Maureen Zakowski; Jennifer Doherty; Katerina Politi; Inderpal Sarkaria; Bhuvanesh Singh; Robert Heelan; Valerie Rusch; Lucinda Fulton; Elaine Mardis; Doris Kupfer; Richard Wilson; Mark Kris; Harold Varmus

2004-01-01

56

A mutation spectra database for bacterial and mammalian genes.  

PubMed

Each mutation spectrum in this database is a dataset of changes in DNA base sequence in mutations induced in a gene by a particular mutagen (including spontaneous processes) under defined conditions. There are 240 datasets with 24 500 mutants in nine bacterial genes, two phage genes, five mammalian genes and one yeast gene. The database is available on the Web at http://info.med.yale.edu/mutbase/ . The data tables can be viewed on the Web and downloaded in text form for local use. The data are also available in dBASE III, a format which can be utilized by essentially any desktop computer database program or spreadsheet, and makes feasible analyses of a large number of mutants. Researchers are invited to submit additional data. A data entry program, MUTSIN, diagrams each mutation on the computer screen as the data are entered and alerts the user to any discrepancies between the entry and the gene sequence. PMID:9016534

Hutchinson, F; Donnellan, J E

1997-01-01

57

?-Globin Mutations in Egyptian Patients With ?-Thalassemia.  

PubMed

?-thalassemia is a common hereditary disorder, particularly in Middle Eastern countries. More than 200 mutations in the ? globin gene have been reported; most are point mutations in functionally important regions (HBB; OMIM #141900)). The spectrum of mutations varies significantly between different geographical regions; only a few common mutations of ?-globin cause ?-thalassemia in each population. The aim of this study was to determine the spectrum of mutations that cause ?-thalassemia in the North Coast of Egypt and to investigate their correlation with the phenotypic severity of ?-thalassemia. We carried out our study with a total of 47 Egyptian patients (25 male and 22 female) confirmed to have ?-thalassemia. Evaluation of ?-thalassemia mutations revealed the presence of 10 ?-globin mutations. The most frequently encountered mutations were intronic: IVS 1.6 [T>C] (27.66%) and IVS 1.110 [G>A] (22.35%), followed by IVS 2.848 [C>A], IVS 1.1 (G>A), and IVS 2.745 [C>G]. We observed the exonic and promoter mutations less frequently. A homozygous mutation was found in 24 patients (51%) and compound heterozygous mutations were found in 13 patients (28%). However, in 9 patients (19%), we identified only 1 mutation. In 1 patient (2%), we detected no mutation. The detection rate of the method that we used in our population was 88% (83 of the tested 94 alleles). The results we obtained did not reveal any correlation between genotype and phenotype among patients with ?-thalassemia. PMID:25617386

Elmezayen, Ammar D; Kotb, Samia M; Sadek, Nadia A; Abdalla, Ebtesam M

2015-01-01

58

Galactosialidosis: review and analysis of CTSA gene mutations  

PubMed Central

Background Mutations in the CTSA gene, that encodes the protective protein/cathepsin A or PPCA, lead to the secondary deficiency of ?-galactosidase (GLB1) and neuraminidase 1 (NEU1), causing the lysosomal storage disorder galactosialidosis (GS). Few clinical cases of GS have been reported in the literature, the majority of them belonging to the juvenile/adult group of patients. Methods The correct nomenclature of mutations for this gene is discussed through the analysis of the three PPCA/CTSA isoforms available in the GenBank database. Phenotype-genotype correlation has been assessed by computational analysis and review of previously reported single amino acid substitutions. Results We report the clinical and mutational analyses of four cases with the rare infantile form of GS. We identified three novel nucleotide changes, two of them resulting in the missense mutations, c.347A>G (p.His116Arg), c.775T>C (p.Cys259Arg), and the third, c.1216C>T, resulting in the p.Gln406* stop codon, a type of mutation identified for the first time in GS. An Italian founder effect of the c.114delG mutation can be suggested according to the origin of the only three patients carrying this mutation reported here and in the literature. Conclusions In early reports mutations nomenclature was selected according to all CTSA isoforms (three different isoforms), thus generating a lot of confusion. In order to assist physicians in the interpretation of detected mutations, we mark the correct nomenclature for CTSA mutations. The complexity of pathology caused by the multifunctions of CTSA, and the very low numbers of mutations (only 23 overall) in relation to the length of the CTSA gene are discussed. In addition, the in silico functional predictions of all reported missense mutations allowed us to closely predict the early infantile, late infantile and juvenile phenotypes, also disclosing different degrees of severity in the juvenile phenotype. PMID:23915561

2013-01-01

59

The androgen receptor gene mutations database: 2012 update.  

PubMed

The current version of the androgen receptor gene (AR) mutations database is described. A major change to the database is that the nomenclature and numbering scheme now conforms to all Human Genome Variation Society norms. The total number of reported mutations has risen from 605 to 1,029 since 2004. The database now contains a number of mutations that are associated with prostate cancer (CaP) treatment regimens, while the number of AR mutations found in CaP tissues has more than doubled from 76 to 159. In addition, in a number of androgen insensitivity syndrome (AIS) and CaP cases, multiple mutations have been found within the same tissue samples. For the first time, we report on a disconnect within the AIS phenotype-genotype relationship among our own patient database, in that over 40% of our patients with a classic complete AIS or partial AIS phenotypes did not appear to have a mutation in their AR gene. The implications of this phenomenon on future locus-specific mutation database (LSDB) development are discussed, together with the concept that mutations can be associated with both loss- and gain-of-function, and the effect of multiple AR mutations within individuals. The database is available on the internet (http://androgendb.mcgill.ca), and a web-based LSDB with the variants using the Leiden Open Variation Database platform is available at http://www.lovd.nl/AR. PMID:22334387

Gottlieb, Bruce; Beitel, Lenore K; Nadarajah, Abbesha; Paliouras, Miltiadis; Trifiro, Mark

2012-05-01

60

Noninvasive detection of filaggrin gene mutations using Raman spectroscopy  

PubMed Central

Knowledge of the existence of filaggrin (FLG) gene mutations might be helpful for a subclassification of patients with atopic dermatitis (AD) which can be used to introduce individualized treatments. In this work the filaggrin content in the skin is assessed using Raman spectroscopy and the results are compared to FLG genotyping of Mexican-mestizo patients. Results showed that the 2282del4 and R501X mutations present in the European population but absent in people of Asian or African descent are also present in the Mexican-mestizo population. The results also showed that patients with filaggrin gene mutations presented lower filaggrin concentrations measured using the vector correlation of their skin Raman spectra and a fixed spectrum of pure human recombinant filaggrin, these results indicate that Raman spectroscopy may be used as a noninvasive tool to detect FLG gene mutations. PMID:22162825

González, Francisco J.; Valdes-Rodríguez, Rodrigo; Ramírez-Elías, Miguel G.; Castillo-Martínez, Claudio; Saavedra-Alanis, Victor M.; Moncada, Benjamín

2011-01-01

61

A novel aspartoacylase (ASPA) gene mutation in Canavan disease.  

PubMed

Canavan disease is a severe autosomal recessive leukodystrophy characterized by macrocephaly, ataxia, severe motor and mental retardation, dysmyelination, and progressive spongial atrophy of the brain. The human aspartoacylase (ASPA) gene, which catalyzes the deacetylation of N-acetyl-L-aspartate, is mutated in Canavan disease. In the presented family sequencing analysis for the aspartoacylase gene was performed on the blood samples of the parents as the affected child had died due to Canavan disease. After the mutation was detected, prenatal diagnosis was also performed and heterozygous Y88X mutation was detected in the fetus. In this report, we present a novel mutation Y88X within the aspartoacylase gene in a consanguineous family with an affected child diagnosed as Canavan disease. PMID:22468686

Durmaz, Asude Alpman; Akin, Haluk; Onay, Huseyin; Vahabi, Ali; Ozkinay, Ferda

2012-08-01

62

Suppression of gene 49 mutations of bacteriophage T4 by a second mutation in gene X: structure of pseudorevertant DNA.  

PubMed Central

Mutations in gene 49 of bacteriophage T4 were suppressed by a second mutation in gene X. Mapping studies located gene X between genes 41 and 42. Complementation results indicated that mutations in FdsA gene (a suppressor of gene 49 mutants) were in gene X. The intracellular pseudorevertant DNA was examined for unusual properties which could explain its successful encapsidation. After the in vivo inactivation of a temperature-sensitive gene 32 (DNA unwinding) protein, the intracellular pseudorevertant DNA was converted into DNA pieces of approximately genome size. A similar conversion was observed after in vitro digestion of pseudorevertant DNA with single-strand-specific S1 endonuclease. Appreciable quantities of oligomeric intermediates were not produced during this conversion process. These data indicate that pseudorevertant DNA contains sizable single-stranded gaps and has a conformation similar to that of wild-type DNA. The results further suggest that the suppression of gene 49 mutant abnormal DNA phenotype and the encapsidation defect by a second mutation in gene X is associated with the formation of sizable single-stranded gaps. These studies raise the possibility that single-stranded gaps may be involved directly in the DNA encapsidation process, or may act indirectly as a consequence of their effect on the organization of intracellular DNA. PMID:592466

Shah, D B; DeLorenzo, L

1977-01-01

63

Spectrum of ABCR gene mutations in autosomal recessive macular dystrophies  

Microsoft Academic Search

Stargardt disease (STGD) and late-onset fundus flavimaculatus (FFM) are autosomal recessive conditions leading to macular degenerations in childhood and adulthood, respectively. Recently, mutations of the photoreceptor cell-specific ATP binding transporter gene (ABCR) have been reported in Stargardt disease. Here, we report on the screening of the whole coding sequence of the ABCR gene in 40 unrelated STGD and 15 FFM

Jean-Michel Rozet; Sylvie Gerber; Eric Souied; Isabelle Perrault; Sophie Châtelin; Imad Ghazi; Corinne Leowski; Jean-Louis Dufier; Arnold Munnich; Josseline Kaplan; J-M Rozet

1998-01-01

64

Conditional lethal amber mutations in essential Escherichia coli genes.  

PubMed

The essential genes of microorganisms encode biological functions important for survival and thus tend to be of high scientific interest. Drugs that interfere with essential functions are likely to be interesting candidates for antimicrobials. However, these genes are hard to study genetically because knockout mutations in them are by definition inviable. We recently described a conditional mutation system in Escherichia coli that uses a plasmid to produce an amber suppressor tRNA regulated by the arabinose promoter. This suppressor was used here in the construction of amber mutations in seven essential E. coli genes. Amber stop codons were introduced as "tagalong" mutations in the flanking DNA of a downstream antibiotic resistance marker by lambda red recombination. The drug marker was removed by expression of I-SceI meganuclease, leaving a markerless mutation. We demonstrate the method with the genes frr, gcpE, lpxC, map, murA, ppa, and rpsA. We were unable to isolate an amber mutation in ftsZ. Kinetics of cell death and morphological changes were measured following removal of arabinose. As expected given the wide range of cellular mechanisms represented, different mutants showed widely different death curves. All of the mutations were bactericidal except the mutation in gcpE, which was bacteriostatic. The strain carrying an amber mutation in murA was by far the most sensitive, showing rapid killing in nonpermissive medium. The MurA protein is critical for peptidoglycan synthesis and is the target for the antibiotic fosfomycin. Such experiments may inexpensively provide valuable information for the identification and prioritization of targets for antibiotic development. PMID:15090508

Herring, Christopher D; Blattner, Frederick R

2004-05-01

65

Gene expression profile study in CFTR mutated bronchial cell lines  

Microsoft Academic Search

Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis conductance transmembrane regulator (CFTR).\\u000a Symptoms are pancreatic insufficiency, chronic obstructive lung disease, liver disease, chronic sinusitis and infertility\\u000a in male patients. The phenotypic variability may be explained only in part by the more than 1200 CFTR mutations, which are\\u000a grouped into six different classes, according to

M. R. D'Apice; F. Amati; F. Sangiuolo; A. Farcomeni; G. Chillemi; S. Bueno; A. Desideri; G. Novelli

2006-01-01

66

Gene Mutations Gene a finite segment of DNA specified  

E-print Network

polydactyly, achondroplasia, huntington's Chorea, and retinoblastoma #12;Recessive Mutation · Recessive division. The result is dwarfism and premature aging. · Ataxia telangrectasia is a disorder of the DNA

Massey, Thomas N.

67

Gene mutations and molecularly targeted therapies in acute myeloid leukemia.  

PubMed

Acute myelogenous leukemia (AML) can progress quickly and without treatment can become fatal in a short period of time. However, over the last 30 years fine-tuning of therapeutics have increased the rates of remission and cure. Cytogenetics and mutational gene profiling, combined with the option of allogeneic hematopoietic stem cell transplantation offered in selected patients have further optimized AML treatment on a risk stratification basis in younger adults. However there is still an unmet medical need for effective therapies in AML since disease relapses in almost half of adult patients becoming refractory to salvage therapy. Improvements in the understanding of molecular biology of cancer and identification of recurrent mutations in AML provide opportunities to develop targeted therapies and improve the clinical outcome. In the spectrum of identified gene mutations, primarily targetable lesions are gain of function mutations of tyrosine kinases FLT3, JAK2 and cKIT for which specific, dual and multi-targeted small molecule inhibitors have been developed. A number of targeted compounds such as sorafenib, quizartinib, lestaurtinib, midostaurin, pacritinib, PLX3397 and CCT137690 are in clinical development. For loss-of-function gene mutations, which are mostly biomarkers of favorable prognosis, combined therapeutic approaches can maximize the therapeutic efficacy of conventional therapy. Apart from mutated gene products, proteins aberrantly overexpressed in AML appear to be clinically significant therapeutic targets. Such a molecule for which targeted inhibitors are currently in clinical development is PLK1. We review characteristic gene mutations, discuss their biological functions and clinical significance and present small molecule compounds in clinical development, which are expected to have a role in treating AML subtypes with characteristic molecular alterations. PMID:23358589

Hatzimichael, Eleftheria; Georgiou, Georgios; Benetatos, Leonidas; Briasoulis, Evangelos

2013-01-01

68

Optimization of Gene Expression through Divergent Mutational Paths  

PubMed Central

SUMMARY Adaptation under similar selective pressure often leads to comparable phenotypes. A longstanding question is whether such phenotypic repeatability entails similar (parallelism) or different genotypic changes (convergence). To better understand this, we characterized mutations that optimized expression of a plasmid-borne metabolic pathway during laboratory evolution of a bacterium. Expressing these pathway genes was essential for growth but came with substantial costs. Starting from overexpression, replicate populations founded by this bacterium all evolved to reduce expression. Despite this phenotypic repetitiveness, the underlying mutational spectrum was highly diverse. Analysis of these plasmid mutations identified three distinct means to modulate gene expression: (1) reducing the gene copy number, (2) lowering transcript stability, and (3) integration of the pathway-bearing plasmid into the host genome. Our study revealed diverse molecular changes beneath convergence to a simple phenotype. This complex genotype-phenotype mapping presents a challenge to inferring genetic evolution based solely on phenotypic changes. PMID:22832162

Chou, Hsin-Hung; Marx, Christopher J.

2012-01-01

69

Frequent mutations in chromatin-remodeling genes in pulmonary carcinoids  

PubMed Central

Pulmonary carcinoids are rare neuroendocrine tumors of the lung. The molecular alterations underlying the pathogenesis of these tumors have not been systematically studied so far. Here we perform gene copy number analysis (n=54), genome/exome (n=44) and transcriptome (n=69) sequencing of pulmonary carcinoids and observe frequent mutations in chromatin-remodeling genes. Covalent histone modifiers and subunits of the SWI/SNF complex are mutated in 40% and 22.2% of the cases respectively, with MEN1, PSIP1 and ARID1A being recurrently affected. In contrast to small-cell lung cancer and large-cell neuroendocrine tumors, TP53 and RB1 mutations are rare events, suggesting that pulmonary carcinoids are not early progenitor lesions of the highly aggressive lung neuroendocrine tumors but arise through independent cellular mechanisms. These data also suggest that inactivation of chromatin remodeling genes is sufficient to drive transformation in pulmonary carcinoids. PMID:24670920

Lu, Xin; Sun, Ruping; Ozreti?, Luka; Seidal, Danila; Zander, Thomas; Leenders, Frauke; George, Julie; Müller, Christian; Dahmen, Ilona; Pinther, Berit; Bosco, Graziella; Konrad, Kathryn; Altmüller, Janine; Nürnberg, Peter; Achter, Viktor; Lang, Ulrich; Schneider, Peter M; Bogus, Magdalena; Soltermann, Alex; Brustugun, Odd Terje; Helland, Åslaug; Solberg, Steinar; Lund-Iversen, Marius; Ansén, Sascha; Stoelben, Erich; Wright, Gavin M.; Russell, Prudence; Wainer, Zoe; Solomon, Benjamin; Field, John K; Hyde, Russell; Davies, Michael PA.; Heukamp, Lukas C; Petersen, Iver; Perner, Sven; Lovly, Christine; Cappuzzo, Federico; Travis, William D; Wolf, Jürgen; Vingron, Martin; Brambilla, Elisabeth; Haas, Stefan A.; Buettner, Reinhard; Thomas, Roman K

2014-01-01

70

Analysis of ?-globin gene mutations in the Chinese population.  

PubMed

Although ?-globin gene (HBD MIM#142000) mutations have no immediate physical consequence, it can interfere with the diagnosis of ?-thalassemia (?-thal), which can be severe. In the present study, of 40,863 samples referred for thalassemia trait screening, 167 samples with lower than expected Hb A(2) levels, in the presence or absence of a second Hb A(2) fraction, were selected for our analysis and 152 samples (0.4%) were positive for ?-globin gene mutations. Twenty-one different mutations were detected, and of these 12 have not been previously described. We found that -77 (T>C) was the most common mutation in Chinese followed by -30 (T>C), together accounting for almost 82.3% of the total number of ?-globin gene defects. Since compound heterozygotes for ?-thal and a ?-globin gene mutation may have low mean cell volume (MCV) and normal Hb A(2) levels, and therefore be overlooked as ?-thal heterozygotes, a detailed molecular analysis for both ?- and ?-thal is necessary, especially when one partner has been identified to have ?-thal trait. PMID:23215833

Liu, Na; Xie, Xing-Mei; Zhou, Jian-Ying; Li, Ru; Liao, Can; Li, Dong-Zhi

2013-01-01

71

Heterozygous prothrombin gene mutation associated with livedoid vasculopathy.  

PubMed

A 53-year-old woman presented with a chronic history of recurrent, painful ulcers, predominantly involving her lower legs. Both her clinical picture and histopathological findings were consistent with a diagnosis of livedoid vasculopathy, although she did have unusual findings of deep tender nodules and the presence of lesions over her elbows. Multiple investigations were undertaken, the only abnormality being a heterozygous mutation of the prothrombin G2021A gene. Although various coagulopathic states have been associated with livedoid vasculopathy, the finding of an associated prothrombin gene mutation is quite rare. Warfarin has ameliorated the clinical course when anti-inflammatory drugs and other anticoagulants were unhelpful. PMID:17535202

Anavekar, Namrata S; Kelly, Robert

2007-05-01

72

Pregnancy and ABCB4 gene mutation: risk of recurrent cholelithiasis.  

PubMed

Cholelithiasis is a common problem in the Western world. Recurrent gallstones after cholecystectomy, however, are rare. We describe a case of a young woman with recurrent gallstones after a laparoscopic cholecystectomy leading to cholangitis during pregnancy. Additional testing revealed an ATP-binding cassette B4 (ABCB4) gene mutation. ABCB4 gene mutations leading to a multidrug resistance (MDR)3-P-glycoprotein deficiency are related to, among other diseases, recurrent cholelithiasis. Medical treatment consists of administering oral ursodeoxycholic acid. If untreated, MDR3 deficiency can lead to progressive liver failure requiring liver transplantation. PMID:25612754

Elderman, Jan H; Ter Borg, Pieter C J; Dees, Jan; Dees, Adriaan

2015-01-01

73

MADM methods in solving group decision support system on gene mutations detection simulation  

Microsoft Academic Search

Detection of gene mutation is an activity that can provide contribution in the medical field. Detection of mutated gene is needed to avoid the diseases caused by them such as cancer. The detection of gene mutations can be performed by utilizing computer-based system. Group Decision Support System (GDSS) is a computer-based system that can be utilized in detecting human gene

Ermatita; Sri Hartati; Retantyo Wardoyo; Agus Harjoko

2010-01-01

74

Mutator gene and hereditary non-polyposis colorectal cancer  

DOEpatents

The human MSH2 gene, responsible for hereditary non-polyposis colorectal cancer, was identified by virtue of its homology to the MutS class of genes, which are involved in DNA mismatch repair. The sequence of cDNA clones of the human gene are provided, and the sequence of the gene can be used to demonstrate the existence of germ line mutations in hereditary non-polyposis colorectal cancer (HNPCC) kindreds, as well as in replication error.sup.+ (RER.sup.+) tumor cells.

de la Chapelle, Albert (Helsingfors, FI); Vogelstein, Bert (Baltimore, MD); Kinzler, Kenneth W. (Baltimore, MD)

2008-02-05

75

[Gliomas and BRCA genes mutations: fortuitous association or imputability?].  

PubMed

BRCA is a tumor suppressor gene implicated in the major mechanisms of cellular stability in every type of cell. Its mutations are described in numerous cancers, mainly breast and ovarian in women. It was also found an increase of lifetime risk of pancreas, colon, prostate cancer or lymphoma in men carriers. We report the cases of two female patients aged 40 and 58-years-old female patients and one 35-years-old male patient, with brain or medullar gliomas, carriers of a germline mutation of BRCA gene. Those gliomas were particularly aggressive and were not responding to the standard treatment, with chemo and radiotherapy. The very unusual characteristics in location and evolutive profile of these central nervous system tumors raise the question of a genetical underlying mechanism, maybe linked to the BRCA gene mutation that carry these patients. In addition, a non-fortuitous association between germline mutation of BRCA and occurrence of a glioma can be evoked according to the embryological, epidemiological and biomolecular findings noted in the literature. Other clinical and experimental studies are necessary to precise the physiopathological link existing between BRCA mutations and the occurrence of a glioma; this could have therapeutical and clinical implications in the future. PMID:25295380

Girardstein-Boccara, Laura; Mari, Véronique; Met-Domestici, Marie; Burel-Vandenbos, Fanny; Berthet, Pascaline; Paquis, Philippe; Frenay, Marc Paul; Lebrun-Frenay, Christine

2014-09-01

76

Mutational study of the MAMLD1-gene in hypospadias  

Microsoft Academic Search

Hypospadias, when the urethral opening is situated on the ventral side of the penis, is a common genital malformation in boys and is partly caused by genetic factors. Mutations in the Mastermind-like domain containing 1 (MAMLD1 or CXorf6) gene have been reported in hypospadias cases. We have performed direct sequencing of the MAMLD1 gene in 99 sporadic hypospadias cases to

Yougen Chen; Hanh T. T. Thai; Johanna Lundin; Kristina Lagerstedt-Robinson; Shengtian Zhao; Ellen Markljung; Agneta Nordenskjöld

2010-01-01

77

Mutations in the deubiquitinase gene USP8 cause Cushing's disease.  

PubMed

Cushing's disease is caused by corticotroph adenomas of the pituitary. To explore the molecular mechanisms of endocrine autonomy in these tumors, we performed exome sequencing of 10 corticotroph adenomas. We found somatic mutations in the USP8 deubiquitinase gene in 4 of 10 adenomas. The mutations clustered in the 14-3-3 protein binding motif and enhanced the proteolytic cleavage and catalytic activity of USP8. Cleavage of USP8 led to increased deubiqutination of the EGF receptor, impairing its downregulation and sustaining EGF signaling. USP8 mutants enhanced promoter activity of the gene encoding proopiomelanocortin. In summary, our data show that dominant mutations in USP8 cause Cushing's disease via activation of EGF receptor signaling. PMID:25485838

Reincke, Martin; Sbiera, Silviu; Hayakawa, Akira; Theodoropoulou, Marily; Osswald, Andrea; Beuschlein, Felix; Meitinger, Thomas; Mizuno-Yamasaki, Emi; Kawaguchi, Kohei; Saeki, Yasushi; Tanaka, Keiji; Wieland, Thomas; Graf, Elisabeth; Saeger, Wolfgang; Ronchi, Cristina L; Allolio, Bruno; Buchfelder, Michael; Strom, Tim M; Fassnacht, Martin; Komada, Masayuki

2015-01-01

78

Identification of Constrained Cancer Driver Genes Based on Mutation Timing  

PubMed Central

Cancer drivers are genomic alterations that provide cells containing them with a selective advantage over their local competitors, whereas neutral passengers do not change the somatic fitness of cells. Cancer-driving mutations are usually discriminated from passenger mutations by their higher degree of recurrence in tumor samples. However, there is increasing evidence that many additional driver mutations may exist that occur at very low frequencies among tumors. This observation has prompted alternative methods for driver detection, including finding groups of mutually exclusive mutations and incorporating prior biological knowledge about gene function or network structure. Dependencies among drivers due to epistatic interactions can also result in low mutation frequencies, but this effect has been ignored in driver detection so far. Here, we present a new computational approach for identifying genomic alterations that occur at low frequencies because they depend on other events. Unlike passengers, these constrained mutations display punctuated patterns of occurrence in time. We test this driver–passenger discrimination approach based on mutation timing in extensive simulation studies, and we apply it to cross-sectional copy number alteration (CNA) data from ovarian cancer, CNA and single-nucleotide variant (SNV) data from breast tumors and SNV data from colorectal cancer. Among the top ranked predicted drivers, we find low-frequency genes that have already been shown to be involved in carcinogenesis, as well as many new candidate drivers. The mutation timing approach is orthogonal and complementary to existing driver prediction methods. It will help identifying from cancer genome data the alterations that drive tumor progression. PMID:25569148

Sakoparnig, Thomas; Fried, Patrick; Beerenwinkel, Niko

2015-01-01

79

International team identifies critical genes mutated in stomach cancer  

Cancer.gov

An international team of scientists, led by researchers from the Duke-NUS Graduate Medical School in Singapore and National Cancer Centre of Singapore, has identified hundreds of novel genes that are mutated in stomach cancer, the second-most lethal cancer worldwide.

80

Telomere stability genes are not mutated in osteosarcoma cell lines  

Microsoft Academic Search

Osteosarcoma (OS), the most common primary bone tumor in adolescents and young adults, is characterized by a high degree of chromosomal abnormalities. Because telomeres are important for maintaining chromosomal integrity, it is plausible that germ-line or somatic mutations in the genes responsible for stabilizing the telomere complex could contribute to OS. We performed bi-directional sequence analysis in five OS cell

Sharon A. Savage; Brian J. Stewart; Jason S. Liao; Lee J. Helman; Stephen J. Chanock

2005-01-01

81

Mutation analysis of BRCA1 and BRCA2 genes in Iranian high risk breast cancer families  

Microsoft Academic Search

Purpose: Germline mutations in either BRCA1 or BRCA2 genes are responsible for the majority of hereditary breast and ovarian cancers. At present, over thousand distinct BRCA1 and BRCA2 mutations have been identified. Specific mutations are found to be common within particular populations, resulting from genetic founder effects. To investigate the contribution of germline mutations in these two genes to inherited

Andrea Pietschmann; Parvin Mehdipour; Morteza Atri; Wera Hofmann; S. Said Hosseini-Asl; Siegfried Scherneck; Stefan Mundlos; Hartmut Peters

2005-01-01

82

40 CFR 798.5300 - Detection of gene mutations in somatic cells in culture.  

Code of Federal Regulations, 2012 CFR

...false Detection of gene mutations in somatic cells in culture. 798.5300 Section 798.5300...5300 Detection of gene mutations in somatic cells in culture. (a) Purpose. Mammalian cell culture systems may be used to detect...

2012-07-01

83

40 CFR 798.5300 - Detection of gene mutations in somatic cells in culture.  

Code of Federal Regulations, 2010 CFR

...true Detection of gene mutations in somatic cells in culture. 798.5300 Section 798.5300...5300 Detection of gene mutations in somatic cells in culture. (a) Purpose. Mammalian cell culture systems may be used to detect...

2010-07-01

84

40 CFR 798.5300 - Detection of gene mutations in somatic cells in culture.  

...false Detection of gene mutations in somatic cells in culture. 798.5300 Section 798.5300...5300 Detection of gene mutations in somatic cells in culture. (a) Purpose. Mammalian cell culture systems may be used to detect...

2014-07-01

85

40 CFR 798.5300 - Detection of gene mutations in somatic cells in culture.  

Code of Federal Regulations, 2013 CFR

...false Detection of gene mutations in somatic cells in culture. 798.5300 Section 798.5300...5300 Detection of gene mutations in somatic cells in culture. (a) Purpose. Mammalian cell culture systems may be used to detect...

2013-07-01

86

40 CFR 798.5300 - Detection of gene mutations in somatic cells in culture.  

Code of Federal Regulations, 2011 CFR

...false Detection of gene mutations in somatic cells in culture. 798.5300 Section 798.5300...5300 Detection of gene mutations in somatic cells in culture. (a) Purpose. Mammalian cell culture systems may be used to detect...

2011-07-01

87

[Analysis of PCCA and PCCB gene mutations in patients with propionic acidemia].  

PubMed

OBJECTIVE To analyze PCCA and PCCB gene mutations in 10 Chinese patients with propionic acidemia(PA). METHODS Genomic DNA was extracted from peripheral blood leukocytes. The 39 exons and flanking sequences of the PCCA and PCCB genes were amplified with polymerase chain reaction and subjected to direct DNA sequencing. RESULTS DNA sequencing has revealed that 7 patients have carried a PCCA gene mutation, 2 patients carried PCCB gene mutation and 1 patient carried mutations in both PCCA and PCCB genes. Ten PA mutations were confirmed, including 8 affecting the PCCA gene and 2 affecting the PCCB gene. Three PCCA mutations c.245G>A, IVS15+5del5, c.1288C>T and 2 PCCB mutations c.838insC, c.1087T>C were found for the first time. CONCLUSION Among Chinese patients with propionic acidemia patients, their genetic mutations are mainly found on the PCCA gene. PMID:25636094

Chen, Zhanling; Wen, Pengqiang; Wang, Guobing; Hu, Yuhui; Liu, Xiaohong; Chen, Li; Chen, Shuli; Wan, Lisheng; Cui, Dong; Shang, Yue; Li, Chengrong

2015-02-10

88

A stochastic model of gene evolution with chaotic mutations.  

PubMed

We develop here a new class of stochastic models of gene evolution in which the mutations are chaotic, i.e. a random subset of the 64 possible trinucleotides mutates at each evolutionary time t according to some substitution probabilities. Therefore, at each time t, the numbers and the types of mutable trinucleotides are unknown. Thus, the mutation matrix changes at each time t. The chaotic model developed generalizes the standard model in which all the trinucleotides mutate at each time t. It determines the occurrence probabilities at time t of trinucleotides which chaotically mutate according to three substitution parameters associated with the three trinucleotide sites. Two theorems prove that this chaotic model has a probability vector at each time t and that it converges to a uniform probability vector identical to that of the standard model. Furthermore, four applications of this chaotic model (with a uniform random strategy for the 64 trinucleotides and with a particular strategy for the three stop codons) allow an evolutionary study of the three circular codes identified in both eukaryotic and prokaryotic genes. A circular code is a particular set of trinucleotides whose main property is the retrieval of the frames in genes locally, i.e. anywhere in genes and particularly without start codons, and automatically with a window of a few nucleotides. After a certain evolutionary time and with particular values for the three substitution parameters, the chaotic models retrieve the main statistical properties of the three circular codes observed in genes. These applications also allow an evolutionary comparison between the standard and chaotic models. PMID:18706428

Bahi, Jacques M; Michel, Christian J

2008-11-01

89

Detecting negative selection on recurrent mutations using gene genealogy  

PubMed Central

Background Whether or not a mutant allele in a population is under selection is an important issue in population genetics, and various neutrality tests have been invented so far to detect selection. However, detection of negative selection has been notoriously difficult, partly because negatively selected alleles are usually rare in the population and have little impact on either population dynamics or the shape of the gene genealogy. Recently, through studies of genetic disorders and genome-wide analyses, many structural variations were shown to occur recurrently in the population. Such “recurrent mutations” might be revealed as deleterious by exploiting the signal of negative selection in the gene genealogy enhanced by their recurrence. Results Motivated by the above idea, we devised two new test statistics. One is the total number of mutants at a recurrently mutating locus among sampled sequences, which is tested conditionally on the number of forward mutations mapped on the sequence genealogy. The other is the size of the most common class of identical-by-descent mutants in the sample, again tested conditionally on the number of forward mutations mapped on the sequence genealogy. To examine the performance of these two tests, we simulated recurrently mutated loci each flanked by sites with neutral single nucleotide polymorphisms (SNPs), with no recombination. Using neutral recurrent mutations as null models, we attempted to detect deleterious recurrent mutations. Our analyses demonstrated high powers of our new tests under constant population size, as well as their moderate power to detect selection in expanding populations. We also devised a new maximum parsimony algorithm that, given the states of the sampled sequences at a recurrently mutating locus and an incompletely resolved genealogy, enumerates mutation histories with a minimum number of mutations while partially resolving genealogical relationships when necessary. Conclusions With their considerably high powers to detect negative selection, our new neutrality tests may open new venues for dealing with the population genetics of recurrent mutations as well as help identifying some types of genetic disorders that may have escaped identification by currently existing methods. PMID:23651527

2013-01-01

90

Mutations of the tyrosinase gene produce autosomal recessive ocular albinism  

SciTech Connect

Albinism has historically been divided into ocular (OA) and oculocutaneous (OCA) types based on the presence or absence of clinically apparent skin and hair involvement in an individual with the ocular features of albinism. The major genes for OCA include the tyrosinase gene in OCA1 and the P gene in OCA2. X-linked and autosomal recessive OA have been described and the responsible genes have not been identified. We now present six Caucasian individuals who have the phenotype of autosomal recessive OA but who have OCA1 as shown by the presence of mutations of the tyrosinase. They had white or very light hair and white skin at birth, and cutaneous pigment developed in the first decade of life. At ages ranging from 1.5-23 years, hair color was dark blond to light brown. The skin had generalized pigment and well developed tan was present on the exposed arm and face skin of four. Iris pigment was present and iris translucency varied. Molecular analysis of the tyrosinase gene, using PCR amplification and direct di-deoxy sequencing showed the following mutations: E398Z/E398Q, P406S/g346a, R402E/T373K, ?/D383N, and H211N/T373K. The homozygous individual was not from a known consanguineous mating. T373K is the most common tyrosinase gene mutation in our laboratory. Three of these mutations are associated with a total loss of tyrosinase activity (g346a splice-site, T373K, and D383N), while four are associated with residual enzyme activity (H211N, R402E, E398Q, and P406S). These studies show that mutations of the tyrosinase gene can produce the phenotype of autosomal recessive OA in an individual who has normal amounts of cutaneous pigment and the ability to tan after birth. This extends the phenotypic range of OCA1 to normal cutaneous pigment after early childhood, and suggest that mutations of the tyrosinase gene account for a significant number of individuals with autosomal recessive OA.

King, R.A.; Summers, C.G.; Oetting, W.S. [Univ. of Minnesota, Minneapolis, MN (United States)] [and others

1994-09-01

91

THE GENE STRUCTURES OF SPONTANEOUS MUTATIONS AFFECTING A CAENORHABDZTZS ELEGANS MYOSIN HEAVY CHAIN GENE  

Microsoft Academic Search

We have isolated spontaneous mutations affecting the unc-54 major myosin heavy chain gene of Caenorhabditis elegans (variety Bristol). Spontaneous unc- 54 mutants occur in C. elegans populations at a frequency of approximately 3 X We have studied the gene structure of 65 independent unc-54 muta- tions using filter-transfer hybridization techniques. Most unc-54 mutations (50 of 65) exhibit no abnormalities detected

DAVID EIDE; PHILIP ANDERSON

92

Novel mutation in VCP gene causes atypical amyotrophic lateral sclerosis  

PubMed Central

Objective: To identify the genetic variant that causes autosomal dominantly inherited motor neuron disease in a 4-generation Israeli-Arab family using genetic linkage and whole exome sequencing. Methods: Genetic linkage analysis was performed in this family using Illumina single nucleotide polymorphism chips. Whole exome sequencing was then undertaken on DNA samples from 2 affected family members using an Illumina 2000 HiSeq platform in pursuit of potentially pathogenic genetic variants that comigrate with the disease in this pedigree. Variants meeting these criteria were then screened in all affected individuals. Results: A novel mutation (p.R191G) in the valosin-containing protein (VCP) gene was identified in the index family. Direct sequencing of the VCP gene in a panel of DNA from 274 unrelated individuals with familial amyotrophic lateral sclerosis (FALS) revealed 5 additional mutations. Among them, 2 were previously identified in pedigrees with a constellation of inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD) and in FALS, and 2 other mutations (p.R159C and p.R155C) in IBMPFD alone. We did not detect VCP gene mutations in DNA from 178 cases of sporadic amyotrophic lateral sclerosis. Conclusions: We report a novel VCP mutation identified in an amyotrophic lateral sclerosis family (p.R191G) with atypical clinical features. In our experience, VCP mutations arise in approximately 1.5% of FALS cases. Our study supports the view that motor neuron disease is part of the clinical spectrum of VCP-associated disease. PMID:23152587

González-Pérez, Paloma; Cirulli, Elizabeth T.; Drory, Vivian E.; Dabby, Ron; Nisipeanu, Puiu; Carasso, Ralph L.; Sadeh, Menachem; Fox, Andrew; Festoff, Barry W.; Sapp, Peter C.; McKenna-Yasek, Diane; Goldstein, David B.

2012-01-01

93

Mutational analysis of adrenoleukodystrophy (ALD) gene in Japanese ALD patients  

SciTech Connect

Recently a putative ALD gene containing a striking homology with peroxisomal membrane protein (PMP70) has been identified. Besides childhood ALD, various clinical phenotypes have been identified with the onset in adolescence or adulthood (adrenomyeloneuropathy (AMN), adult cerebral ALD or cerebello-brainstem dominant type). The different clinical phenotypes occasionally coexist even in the same family. To investigate if there is a correlation between the clinical phenotypes and genotypes of the mutations in the ALD gene, we have analyzed 43 Japanese ALD patients. By Southern blot analysis, we identified non-overlapping deletions of 0.5 kb to 10.4 kb involving the ALD gene in 3 patients with adult onset cerebello-brainstem dominant type. By detailed direct sequence analysis, we found 4 patients who had point mutations in the coding region. An AMN patient had a point mutation leading to {sup 266}Gly{r_arrow}Arg change, and another patient with adult cerebral ALD had a 3 bp deletion resulting in the loss of glutamic acid at codon 291, which is a conserved amino acid both in ALD protein and PMP70. Two patients with childhood ALD had point mutations leading to {sup 507}Gly{r_arrow}Val, and {sup 518}Arg{r_arrow}Gln, respectively. Since amino acids from 507 to 520 are highly conserved as ATP-binding cassette transporter proteins, mutations in this region are expected to result in dramatic changes of the function of this protein. Although there is a tendancy for mutation in childhood ALD to be present within the ATP-binding site motif, we found two adult patients who had large deletions involving the region. Taken together, strong correlation between genotypes and clinical phenotypes is unlikely to exist, and some other modifying factors might well play an important role for the clinical manifestations of ALD.

Koike, R.; Onodera, O.; Tabe, H. [Miigate Univ. (Japan)] [and others

1994-09-01

94

40 CFR 799.9530 - TSCA in vitro mammalian cell gene mutation test.  

Code of Federal Regulations, 2012 CFR

...2012-07-01 false TSCA in vitro mammalian cell gene mutation test. 799.9530 Section... § 799.9530 TSCA in vitro mammalian cell gene mutation test. (a) Scope. ...section 4 of TSCA. The in vitro mammalian cell gene mutation test can be used to...

2012-07-01

95

40 CFR 799.9530 - TSCA in vitro mammalian cell gene mutation test.  

Code of Federal Regulations, 2010 CFR

...2010-07-01 true TSCA in vitro mammalian cell gene mutation test. 799.9530 Section... § 799.9530 TSCA in vitro mammalian cell gene mutation test. (a) Scope. ...section 4 of TSCA. The in vitro mammalian cell gene mutation test can be used to...

2010-07-01

96

40 CFR 799.9530 - TSCA in vitro mammalian cell gene mutation test.  

...2014-07-01 false TSCA in vitro mammalian cell gene mutation test. 799.9530 Section... § 799.9530 TSCA in vitro mammalian cell gene mutation test. (a) Scope. ...section 4 of TSCA. The in vitro mammalian cell gene mutation test can be used to...

2014-07-01

97

40 CFR 799.9530 - TSCA in vitro mammalian cell gene mutation test.  

Code of Federal Regulations, 2013 CFR

...2013-07-01 false TSCA in vitro mammalian cell gene mutation test. 799.9530 Section... § 799.9530 TSCA in vitro mammalian cell gene mutation test. (a) Scope. ...section 4 of TSCA. The in vitro mammalian cell gene mutation test can be used to...

2013-07-01

98

40 CFR 799.9530 - TSCA in vitro mammalian cell gene mutation test.  

Code of Federal Regulations, 2011 CFR

...2011-07-01 false TSCA in vitro mammalian cell gene mutation test. 799.9530 Section... § 799.9530 TSCA in vitro mammalian cell gene mutation test. (a) Scope. ...section 4 of TSCA. The in vitro mammalian cell gene mutation test can be used to...

2011-07-01

99

TGFBI gene mutations in a Korean population with corneal dystrophy  

PubMed Central

Purpose To investigate the clinical and genetic features of Korean patients with corneal dystrophies associated with mutations in the human transforming growth factor-?-induced (TGFBI) gene. Methods In this study, 387 subjects (71 families and 89 individuals - 268 patients having TGFBI corneal dystrophies and 119 normal relatives) were assessed. All subjects underwent a complete ophthalmologic evaluation, including biomicroscopic inspection and dilated fundus examination. As a control, 100 individuals without corneal disease were selected from the general population. The polymerase chain reaction (PCR) and direct sequencing were used to screen for mutations in TGFBI. Results All subjects recruited exhibited a range of corneal dystrophies, including Thiel-Behnke corneal dystrophy (TBCD, R555Q; 6 families and 4 individuals), granular corneal dystrophy type 2 (GCD2, R124H; 61 families and 80 individuals), lattice corneal dystrophy (LCD; 4 families and 5 individuals; 7 with type 1 [R124C], and 2 with a variant [L527R, P542R]). The disease showed an autosomal dominant inheritance pattern in all families. Conclusions R124H in GCD2 was the most common mutation. GCD1 and Reis-Bucklers corneal dystrophy were not found. In the GCD2 patients there were a large number of laser refractive surgery-induced corneal opacities. A spontaneous R124H mutation was confirmed in an already mutated allele that resulted in a change from a heterozygous into a homozygous form. Also, a novel mutation, P527R, was identified in LCD. PMID:22876129

Cho, Kyong Jin; Mok, Jee Won; Na, Kyung Sun; Rho, Chang Rae; Byun, Yong Soo; Hwang, Ho Sik; Hwang, Kyu Yeon

2012-01-01

100

PEN-2 gene mutation in a familial Alzheimer's disease case.  

PubMed

Genetic evidence indicates a central role of cerebral accumulation of beta-amyloid (Abeta) in the pathogenesis of Alzheimer's disease (AD). Beside presenilin 1 and 2, three other recently discovered proteins (Aph 1, PEN 2 and nicastrin) are associated with gamma-secretase activity, the enzymatic complex generating Abeta. Alterations in genes encoding these proteins were candidates for a role in AD. The PEN 2 gene was examined for unknown mutations and polymorphisms in sporadic and familial Alzheimer patients. Samples from age-matched controls (n=253), sporadic AD (SAD, n=256) and familial AD (FAD, n=140) were screened with DHPLC methodology followed by sequencing. Scanning the gene identified for the first time a missense mutation (D90N) in a patient with FAD. Three intronic polymorphisms were also identified, one of which had a higher presence of the mutated allele in AD subjects carrying the allele epsilon4 of apolipoprotein E than controls. The pathogenic role of the PEN-2 D90N mutation in AD is not clear, but the findings might lead to new studies on its functional and genetic role. PMID:16170650

Sala Frigerio, C; Piscopo, P; Calabrese, E; Crestini, A; Malvezzi Campeggi, L; Civita di Fava, R; Fogliarino, S; Albani, D; Marcon, G; Cherchi, R; Piras, R; Forloni, G; Confaloni, A

2005-09-01

101

Identification of novel mutations in the human HPRT gene.  

PubMed

Inherited mutation of the purine salvage enzyme, hypoxanthine guanine phosphoribosyltransferase (HPRT) gives rise to Lesch-Nyhan syndrome (LNS) or Lesch-Nyhan variants (LNVs). We report three novel independent mutations in the coding region of HPRT gene: exon 3: c.141delA, p.D47fs53X; exon 5: c.400G>A, p.E134K; exon 7: c.499A>G, p.R167G from three LNS affected male patients. PMID:23473102

Nguyen, Khue Vu; Nyhan, William L

2013-01-01

102

Rapid detection of common mutations in the arylsulfatase A gene  

SciTech Connect

Metachromatic leukodystrophy (MLD), an autosomal recessive lysosomal storage disease results from a deficiency of arylsulfatase A activity. This disease is usually fatal within a few years of onset in the pediatric age group. A pseuodeficiency occurs in up to 15% of alleles in the general population which significantly decreases enzyme activity. Although there is no clinical phenotype associated with the pseudodeficiency, the decreased enzyme activity can complicate interpretation of biochemical assay results particularly in the case of potential heterozygous carriers of MLD. Two mutations have been found to be simultaneously associated with the pseudodeficiency: one at a glycosylatin site in exon 6 and one in the polyA addition signal. Another mutation, the `I` allele has been reported in up to 50% of alleles in the severe infantile onset form of MLD. The deleterious mutation in this case is in the +1 position of intron 2. In order to screen for these commonly occurring mutations in the arylsulfatase A gene, a simple combination of PCR amplification from genomic DNA and restriction enzyme digestions was developed for each situation. In the case of the pseuodeficiency mutations, oligonucleotide primers were designed which incorporated a single base mismatch 3 bases upstream from the 3{prime} end of the primer so that the presence of the mutation created new MaeIII restriction site in the case of the glycosylation site or an RsaI site in the case of the polyA site. The `I` allele mutation creates a new MvaI site without the use of mismatches. These tests have successfully detected the mutations in individuals suspected of having the pseudodeficiency on the basis of biochemical assay. The `I` allele was detected in 1 of 16 MLD alleles analyzed.

Coulter-Mackie, M.B. [Univ. of Western Ontario (Canada)]|[CPRI, London, Ontario (Canada)

1994-09-01

103

Mutations of the p53 and PTCH gene in basal cell carcinomas: UV mutation signature and strand bias  

Microsoft Academic Search

Mutations of p53 and PTCH gene, two candidate tumor suppressor genes for basal cell carcinoma (BCC), were screened in 15 cases of sporadic BCCs that developed in sun-exposed skin region in a Korean population. p53 and PTCH mutations were detected at a frequency of 33 and 40%, respectively, and the mutations were predominantly UV-signature transition, C?T transitions at dipyrimidine sites

Mi-Yeon Kim; Hyun Jeong Park; Seung-Cheol Baek; Dae Gyoo Byun; Dong Houh

2002-01-01

104

Nuclear and mitochondrial genes mutated in nonsyndromic impaired hearing.  

PubMed

Half of the cases with congenital impaired hearing are hereditary (HIH). HIH may occur as part of a multisystem disease (syndromic HIH) or as disorder restricted to the ear and vestibular system (nonsyndromic HIH). Since nonsyndromic HIH is almost exclusively caused by cochlear defects, affected patients suffer from sensorineural hearing loss. One percent of the total human genes, i.e. 300-500, are estimated to cause syndromic and nonsyndromic HIH. Of these, approximately 120 genes have been cloned thus far, approximately 80 for syndromic HIH and 42 for nonsyndromic HIH. In the majority of the cases, HIH manifests before (prelingual), and rarely after (postlingual) development of speech. Prelingual, nonsyndromic HIH follows an autosomal recessive trait (75-80%), an autosomal dominant trait (10-20%), an X-chromosomal, recessive trait (1-5%), or is maternally inherited (0-20%). Postlingual nonsyndromic HIH usually follows an autosomal dominant trait. Of the 41 mutated genes that cause nonsyndromic HIH, 15 cause autosomal dominant HIH, 15 autosomal recessive HIH, 6 both autosomal dominant and recessive HIH, 2 X-linked HIH, and 3 maternally inherited HIH. Mutations in a single gene may not only cause autosomal dominant, nonsyndromic HIH, but also autosomal recessive, nonsyndromic HIH (GJB2, GJB6, MYO6, MYO7A, TECTA, TMC1), and even syndromic HIH (CDH23, COL11A2, DPP1, DSPP, GJB2, GJB3, GJB6, MYO7A, MYH9, PCDH15, POU3F4, SLC26A4, USH1C, WFS1). Different mutations in the same gene may cause variable phenotypes within a family and between families. Most cases of recessive HIH result from mutations in a single locus, but an increasing number of disorders is recognized, in which mutations in two different genes (GJB2/GJB6, TECTA/KCNQ4), or two different mutations in a single allele (GJB2) are involved. This overview focuses on recent advances in the genetic background of nonsyndromic HIH. PMID:15850684

Finsterer, Josef; Fellinger, Johannes

2005-05-01

105

Mutations of epigenetic regulatory genes are common in thymic carcinomas  

PubMed Central

Genetic alterations and etiology of thymic epithelial tumors (TETs) are largely unknown, hampering the development of effective targeted therapies for patients with TETs. Here TETs of advanced-stage patients enrolled in a clinical trial of molecularly-guided targeted therapies were employed for targeted sequencing of 197 cancer-associated genes. Comparative sequence analysis of 78?TET/blood paired samples obtained from 47 thymic carcinoma (TC) and 31 thymoma patients revealed a total of 86 somatic non-synonymous sequence variations across 39 different genes in 33 (42%) TETs. TCs (62%; 29/47) showed higher incidence of somatic non-synonymous mutations than thymomas (13%; 4/31; p < 0.0001). TP53 was the most frequently mutated gene in TETs (n = 13; 17%), especially in TCs (26%), and was associated with a poorer overall survival (p < 0.0001). Genes in histone modification [BAP1 (n = 6; 13%), SETD2 (n = 5; 11%), ASXL1 (n = 2; 4%)], chromatin remodeling [SMARCA4 (n = 2; 4%)], and DNA methylation [DNMT3A (n = 3; 7%), TET2 (n = 2; 4%), WT1 (n = 2; 4%)] pathways were recurrently mutated in TCs, but not in thymomas. Our results suggest a potential disruption of epigenetic homeostasis in TCs, and a substantial difference in genetic makeup between TCs and thymomas. Further investigation is warranted into the roles of epigenetic dysregulation in TC development and its potential for targeted therapy. PMID:25482724

Wang, Yisong; Thomas, Anish; Lau, Christopher; Rajan, Arun; Zhu, Yuelin; Killian, J. Keith; Petrini, Iacopo; Pham, Trung; Morrow, Betsy; Zhong, Xiaogang; Meltzer, Paul S.; Giaccone, Giuseppe

2014-01-01

106

Mutations of epigenetic regulatory genes are common in thymic carcinomas.  

PubMed

Genetic alterations and etiology of thymic epithelial tumors (TETs) are largely unknown, hampering the development of effective targeted therapies for patients with TETs. Here TETs of advanced-stage patients enrolled in a clinical trial of molecularly-guided targeted therapies were employed for targeted sequencing of 197 cancer-associated genes. Comparative sequence analysis of 78?TET/blood paired samples obtained from 47 thymic carcinoma (TC) and 31 thymoma patients revealed a total of 86 somatic non-synonymous sequence variations across 39 different genes in 33 (42%) TETs. TCs (62%; 29/47) showed higher incidence of somatic non-synonymous mutations than thymomas (13%; 4/31; p < 0.0001). TP53 was the most frequently mutated gene in TETs (n = 13; 17%), especially in TCs (26%), and was associated with a poorer overall survival (p < 0.0001). Genes in histone modification [BAP1 (n = 6; 13%), SETD2 (n = 5; 11%), ASXL1 (n = 2; 4%)], chromatin remodeling [SMARCA4 (n = 2; 4%)], and DNA methylation [DNMT3A (n = 3; 7%), TET2 (n = 2; 4%), WT1 (n = 2; 4%)] pathways were recurrently mutated in TCs, but not in thymomas. Our results suggest a potential disruption of epigenetic homeostasis in TCs, and a substantial difference in genetic makeup between TCs and thymomas. Further investigation is warranted into the roles of epigenetic dysregulation in TC development and its potential for targeted therapy. PMID:25482724

Wang, Yisong; Thomas, Anish; Lau, Christopher; Rajan, Arun; Zhu, Yuelin; Killian, J Keith; Petrini, Iacopo; Pham, Trung; Morrow, Betsy; Zhong, Xiaogang; Meltzer, Paul S; Giaccone, Giuseppe

2014-01-01

107

Ataxia telangiectasia gene mutations in leukaemia and lymphoma  

PubMed Central

Ataxia telangiectasia (AT) is a rare multisystem, autosomal, recessive disease characterised by neuronal degeneration, genome instability, and an increased risk of cancer. Approximately 10% of AT homozygotes develop cancer, mostly of the lymphoid system. Lymphoid malignancies in patients with AT are of both B cell and T cell origin, and include Hodgkin's lymphoma, non-Hodgkin's lymphoma, and several forms of leukaemia. The AT locus was mapped to the chromosomal region 11q22–23 using genetic linkage analysis in the late 1980s and the causative gene was identified by positional cloning several years later. The ATM gene encodes a large protein that belongs to a family of kinases possessing a highly conserved C-terminal kinase domain related to the phosphatidylinositol 3-kinase domain. Members of this kinase family have been shown to function in DNA repair and cell cycle checkpoint control following DNA damage. Recent studies indicate that ATM is activated primarily in response to double strand breaks and may be considered a caretaker of the genome. Most mutations in ATM result in truncation and destabilisation of the protein, but certain missense and splicing errors have been shown to produce a less severe phenotype. AT heterozygotes have a slightly increased risk of breast cancer. Atm deficient mice exhibit many of the symptoms found in patients with AT and have a high frequency of thymic lymphoma. The association between mutation of the ATM gene and a high incidence of lymphoid malignancy in patients with AT, together with the development of lymphoma in Atm deficient mice, supports the proposal that inactivation of the ATM gene may be of importance in the pathogenesis of sporadic lymphoid malignancy. Loss of heterozygosity at 11q22–23 (the location of the ATM gene) is a common event in lymphoid malignancy. Frequent inactivating mutations of the ATM gene have been reported in patients with rare sporadic T cell prolymphocytic leukaemia (T-PLL), B cell chronic lymphocytic leukaemia (B-CLL), and most recently, mantle cell lymphoma (MCL). In contrast to the ATM mutation pattern in AT, the most frequent nucleotide changes in these sporadic lymphoid malignancies were missense mutations. The presence of inactivating mutations, together with the deletion of the normal copy of the ATM gene in some patients with T-PLL, B-CLL, and MCL, establishes somatic inactivation of the ATM gene in the pathogenesis of lymphoid malignancies, and strongly suggests that ATM functions as a tumour suppressor. The presence of missense mutations in the germline of patients with B-CLL has been reported, suggesting that some patients with B-CLL may be constitutional AT heterozygotes. The putative hereditary predisposition of B-CLL, although intriguing, warrants further investigation. Key Words: lymphoid malignancy • mutation • ataxia telangiectasia gene PMID:11429421

Boultwood, J

2001-01-01

108

Endemic polycythemia in Russia: mutation in the VHL gene.  

PubMed

Chuvash polycythemia (CP) is an autosomal recessive condition that is endemic in the Russian mid-Volga River region of Chuvashia. We previously found that CP patients may have increased serum erythropoietin (EPO) levels, ruled out linkage to both the EPO and EPO receptor (EPOR) gene loci, and hypothesized that the defect may lie in the oxygen homeostasis pathway. We now report a study of five multiplex Chuvash families which confirms that CP is associated with significant elevations of serum EPO levels and rules out a location for the CP gene on chromosome 11 as had been reported by other investigators or a mutation of the HIF-1 alpha gene. Using a genome-wide screen, we localized a region on chromosome 3 with a LOD score >2. After sequencing three candidate genes, we identified a C to T transition at nucleotide 598 (an R200W mutation) in the von Hippel-Lindau (VHL) gene. The VHL protein (pVHL) downregulates the alpha subunit of hypoxia-inducible factor 1 (HIF-1 alpha), the main regulator of hypoxia adaptation, by targeting the protein for degradation. In the simplest scenario, disruption of pVHL function causes a failure to degrade HIF-1 alpha resulting in accumulation of HIF-1 alpha, upregulation of downstream target genes such as EPO, and the clinical manifestation of polycythemia. These findings strongly suggest that CP is a congenital disorder of oxygen homeostasis. PMID:11987242

Ang, Sonny O; Chen, Hua; Gordeuk, Victor R; Sergueeva, Adelina I; Polyakova, Lydia A; Miasnikova, Galina Y; Kralovics, Robert; Stockton, David W; Prchal, Josef T

2002-01-01

109

Molecular screening of pituitary adenomas for gene mutations and rearrangements  

SciTech Connect

Although pituitary tumors arise as benign monoclonal neoplasms, genetic alterations have not readily been identified in these adenomas. The authors studied restriction fragment abnormalities involving the GH gene locus, and mutations in the p53 and H-, K-, and N-ras genes in 22 human GH cell adenomas. Twenty two nonsecretory adenomas were also examined for p53 and ras gene mutations. Seven prolactinoma DNA samples were tested for deletions in the multiple endocrine neoplasia-1 (MEN-1) locus, as well as for rearrangements in the hst gene, a member of the fibroblast growth factor family. In DNA from GH-cell adenomas, identical GH restriction patterns were detected in both pituitary and lymphocyte DNA in all patients and in one patient with a mixed GH-TSH cell adenoma. Using polymerase chain reaction (PCR)-single stranded conformation polymorphism analysis, no mutations were detected in exons 5, 6, 7 and 8 of the p53 gene in GH cell adenomas nor in 22 nonsecretory adenomas. Codons 12/13 and 61 of H-ras, K-ras, and N-ras genes were also intact on GH cell adenomas and in nonsecretory adenomas. Site-specific probes for chromosome 11q13 including, PYGM, D11S146, and INT2 were used in 7 sporadic PRL-secreting adenomas to detect deletions of the MEN-1 locus on chromosome 11. One patient was identified with a loss of 11p, and the remaining 6 patients did not demonstrate loss of heterozygosity in the pituitary 11q13 locus, compared to lymphocyte DNA. None of these patients demonstrated hst gene rearrangements which also maps to this locus. These results show that p53 and ras gene mutations are not common events in the pathogenesis of acromegaly and nonsecretory tumors. Although hst gene rearrangements and deletions of 11q13 are not associated with sporadic PRl-cell adenoma formation, a single patient was detected with a partial loss of chromosome 11, including the putative MEN-1 site. 31 refs., 5 figs., 2 tabs.

Herman, V.; Drazin, N.Z.; Gonskey, R.; Melmed, S. (Cedars-Sinai Medical Center, Los Angeles, CA (United States))

1993-07-01

110

Mutational Analysis of Angiogenin Gene in Parkinson's Disease  

PubMed Central

Mutations in the angiogenic factor, angiogenin (ANG), have been identified in patients with both familial and sporadic amyotrophic lateral sclerosis (ALS) and are thought to have a neuroprotective function. Parkinsonism has been noted in kindreds with ANG mutations and variants in the ANG gene have been found to associate with PD in two Caucasian populations. We therefore hypothesized that mutations in ANG may also contribute to idiopathic Parkinson's disease (PD). We sequenced ANG gene in a total of 1498 participants comprising 750 PD patients and 748 age/gender matched controls from Taiwan. We identified one novel synonymous substitution, c.C100T (p.L10L), in a single heterozygous state in one PD patient, which was not observed in controls. The clinical phenotypes and [99mTc]-TORDAT-SPECT images of the p.L10L carrier were similar to that seen in idiopathic PD. In addition, we also identified one common variant, c.T330G (p.G110G, rs11701), which was previously reported to associate with PD risk in Caucasians. However, the frequency of TG/GG genotype was comparable between PD cases and controls (odds ratio: 0.85, 95% confidence interval: 0.29–2.55, P?=?0.78). Our results did not support that ANG rs11701 variant is a genetic risk factor for PD in our population. We conclude that mutations in ANG are not a common cause for idiopathic PD. PMID:25386690

Chen, Meng-Ling; Wu, Ruey-Meei; Tai, Chun-Hwei; Lin, Chin-Hsien

2014-01-01

111

Common filaggrin gene mutations and risk of cervical cancer.  

PubMed

Abstract Background. As carriers of filaggrin gene (FLG) mutations may have a compromised cervical mucosal barrier against human papillomavirus infection, our primary objective was to study their risk of cervical cancer. Methods. We genotyped 586 cervical cancer patients for the two most common FLG mutations, R501X and 2282del4, using blood from the Copenhagen Hospital Biobank, Denmark. Controls (n = 8050) were genotyped in previous population-based studies. Information on cervical cancer, mortality and emigration were obtained from national registers. Odds ratios (OR) were estimated by logistic regression with adjustment for age at blood sampling, and weighted by the genotype-specific inverse probability of death between diagnosis and sampling. Hazard ratios (HR) were estimated by Cox regression with time since diagnosis as underlying time, and with adjustment for age at diagnosis and stratification by cancer stage. Results. The primary results showed that FLG mutations were not associated with the risk of cervical cancer (6.3% of cases and 7.7% of controls were carriers; OR adjusted 0.81, 95% CI 0.57-1.14; OR adjusted+ weighted 0.96, 95% CI 0.58-1.57). Among cases, FLG mutations increased mortality due to cervical cancer (HR 4.55, 95% CI 1.70-12.2), however, the association was reduced after stratification by cancer stage (HR 2.53, 95% CI 0.84-7.59). Conclusion. Carriage of FLG mutations was not associated with the risk of cervical cancer. PMID:25383447

Bager, Peter; Wohlfahrt, Jan; Sørensen, Erik; Ullum, Henrik; Høgdall, Claus Kim; Palle, Connie; Husemoen, Lise Lotte Nystrup; Linneberg, Allan; Kjær, Susanne K; Melbye, Mads; Thyssen, Jacob P

2015-02-01

112

Perspective on Genes and Mutations Causing Retinitis Pigmentosa  

PubMed Central

Exceptional progress has been made during the past two decades in identifying genes causing inherited retinal diseases such as retinitis pigmentosa. An inescapable consequence is that the relationship between genes, mutations, and clinical findings has become very complex. Success in identifying the causes of inherited retinal diseases has many implications, including a better understanding of the biological basis of vision and insights into the processes involved in retinal pathology. From a clinical point of view, there are two important questions arising from these developments: where do we stand today in finding disease-causing mutations in affected individuals, and what are the implications of this information for clinical practice? This perspective addresses these questions specifically for retinitis pigmentosa, but the observations apply generally to other forms of inherited eye disease. PMID:17296890

Daiger, Stephen P.; Bowne, Sara J.; Sullivan, Lori S.

2008-01-01

113

A new spontaneous mouse mutation in the Kcne1 gene.  

PubMed

A new mouse mutant, punk rocker (allele symbol Kcne1(pkr)), arose spontaneously on a C57BL/10J inbred strain background and is characterized by a distinctive head-tossing, circling, and ataxic phenotype. It is also profoundly and bilaterally deaf. The mutation resides in the Kcne1 gene on Chromosome (Chr) 16 and has been identified as a single base change within the coding region of the third exon. The C to T nucleotide substitution causes an arginine to be altered to a termination codon at amino acid position 67, and predictably this will result in a significantly truncated protein product. The Kcne1(pkr) mutant represents the first spontaneous mouse model for the human disorder, Jervell and Lange-Nielsen syndrome, associated with mutations in the homologous KCNE1 gene on human Chr 21. PMID:11003695

Letts, V A; Valenzuela, A; Dunbar, C; Zheng, Q Y; Johnson, K R; Frankel, W N

2000-10-01

114

Fifty-four novel mutations in the NF1 gene and integrated analyses of the mutations that modulate splicing  

PubMed Central

Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder caused by mutations in the NF1 gene. One of the hallmarks of NF1 is the high mutation rate in this gene. In this study, we present 127 different NF1 mutations and 54 novel mutations detected at both the genomic DNA and mRNA level using a retrospective case series review. We found that 25.2% of these different mutations induced aberrant splicing. Of note, 40.6% of these splicing errors were caused by exonic variants. In addition, one mutation produced mosaicism in the post-transcriptional profile. However, studies investigating these splicing aberrations are limited. In order to better understand the pathogenicity of NF1 and to provide a more accurate interpretation in molecular diagnostic testing, combined computational analyses were employed to elucidate the underlying mechanisms of the variants modulating NF1 gene splicing. PMID:24789688

XU, WEIHONG; YANG, XIAO; HU, XIAOXIA; LI, SHIBO

2014-01-01

115

Hereditary pancreatitis and mutation of the trypsinogen gene.  

PubMed

Hereditary pancreatitis is a rare form of chronic recurrent pancreatitis. A family, in which 11 members had chronic pancreatitis, five had diabetes, and two had pancreatic cancer, was studied, and hereditary pancreatitis was diagnosed in all patients by demonstrating the mutation in exon 3 of the cationic trypsinogen gene (R117H). The clinical implications of genotypic analysis in hereditary pancreatitis are discussed. PMID:10208958

Weber, P; Keim, V; Zimmer, K P

1999-05-01

116

Combining gene mutation with gene expression data improves outcome prediction in myelodysplastic syndromes.  

PubMed

Cancer is a genetic disease, but two patients rarely have identical genotypes. Similarly, patients differ in their clinicopathological parameters, but how genotypic and phenotypic heterogeneity are interconnected is not well understood. Here we build statistical models to disentangle the effect of 12 recurrently mutated genes and 4 cytogenetic alterations on gene expression, diagnostic clinical variables and outcome in 124 patients with myelodysplastic syndromes. Overall, one or more genetic lesions correlate with expression levels of ~20% of all genes, explaining 20-65% of observed expression variability. Differential expression patterns vary between mutations and reflect the underlying biology, such as aberrant polycomb repression for ASXL1 and EZH2 mutations or perturbed gene dosage for copy-number changes. In predicting survival, genomic, transcriptomic and diagnostic clinical variables all have utility, with the largest contribution from the transcriptome. Similar observations are made on the TCGA acute myeloid leukaemia cohort, confirming the general trends reported here. PMID:25574665

Gerstung, Moritz; Pellagatti, Andrea; Malcovati, Luca; Giagounidis, Aristoteles; Porta, Matteo G Della; Jädersten, Martin; Dolatshad, Hamid; Verma, Amit; Cross, Nicholas C P; Vyas, Paresh; Killick, Sally; Hellström-Lindberg, Eva; Cazzola, Mario; Papaemmanuil, Elli; Campbell, Peter J; Boultwood, Jacqueline

2015-01-01

117

Sarcomeric gene mutations in sudden infant death syndrome (SIDS).  

PubMed

In developed countries, sudden infant death syndrome (SIDS) represents the most prevalent cause of death in children between 1 month and 1 year of age. SIDS is a diagnosis of exclusion, a negative autopsy which requires the absence of structural organ disease. Although investigators have confirmed that a significant percentage of SIDS cases are actually channelopathies, no data have been made available as to whether other sudden cardiac death-associated diseases, such as hypertrophic cardiomyopathy (HCM), could be responsible for some cases of SIDS. The presence of a genetic mutation in the sarcomeric protein usually affects the force of contraction of the myocyte, whose weakness is compensated with progressive hypertrophy and disarray. However, it is unclear whether in the most incipient forms, that is, first years of life, the lack of these phenotypes still confers a risk of arrhythmogenesis. The main goal of the present study is to wonder whether genetic defects in the sarcomeric proteins, previously associated with HCM, could be responsible for SIDS. We have analysed 286 SIDS cases for the most common genes implicated in HCM in adults. A total of 680 mutations localised in 16 genes were analysed by semi-automated matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDITOF-MS) using the Sequenom MassARRAY(®) System. Ten subjects with completely normal hearts showed mutated alleles at nine of the genetic variants analysed, and one additional novel mutation was detected by conventional sequencing. Therefore, a genetic mutation associated with HCM may cause sudden cardiac death in the absence of an identifiable phenotype. PMID:22361390

Brion, Maria; Allegue, Catarina; Santori, Montserrat; Gil, Rocio; Blanco-Verea, Alejandro; Haas, Cordula; Bartsch, Christine; Poster, Simone; Madea, Burkhard; Campuzano, Oscar; Brugada, Ramon; Carracedo, Angel

2012-06-10

118

Clinical and Neuropathological Features of the Arctic APP Gene Mutation Causing Early-Onset Alzheimer Disease  

Microsoft Academic Search

Background: A majority of mutations within the - amyloid region of the amyloid precursor protein (APP) gene cause inherited forms of intracerebral hemor- rhage. Most of these mutations may also cause cognitive impairment, but the Arctic APP mutation is the only known intra--amyloid mutation to date causing the more typical clinical picture of Alzheimer disease. Objective: To describe features of

Hans Basun; Nenad Bogdanovic; Martin Ingelsson; Ove Almkvist; Jan Naslund; Karin Axelman; Thomas D. Bird; David Nochlin; Gerard D. Schellenberg; Lars-Olof Wahlund; Lars Lannfelt

2008-01-01

119

Mutational analysis of genes coding for cell surface proteins in colorectal cancer cell lines reveal novel altered pathways, druggable mutations and mutated epitopes for targeted therapy.  

PubMed

We carried out a mutational analysis of 3,594 genes coding for cell surface proteins (Surfaceome) in 23 colorectal cancer cell lines, searching for new altered pathways, druggable mutations and mutated epitopes for targeted therapy in colorectal cancer. A total of 3,944 somatic non-synonymous substitutions and 595 InDels, occurring in 2,061 (57%) Surfaceome genes were catalogued. We identified 48 genes not previously described as mutated in colorectal tumors in the TCGA database, including genes that are mutated and expressed in >10% of the cell lines (SEMA4C, FGFRL1, PKD1, FAM38A, WDR81, TMEM136, SLC36A1, SLC26A6, IGFLR1). Analysis of these genes uncovered important roles for FGF and SEMA4 signaling in colorectal cancer with possible therapeutic implications. We also found that cell lines express on average 11 druggable mutations, including frequent mutations (>20%) in the receptor tyrosine kinases AXL and EPHA2, which have not been previously considered as potential targets for colorectal cancer. Finally, we identified 82 cell surface mutated epitopes, however expression of only 30% of these epitopes was detected in our cell lines. Notwithstanding, 92% of these epitopes were expressed in cell lines with the mutator phenotype, opening new venues for the use of "general" immune checkpoint drugs in this subset of patients. PMID:25193853

Donnard, Elisa; Asprino, Paula F; Correa, Bruna R; Bettoni, Fabiana; Koyama, Fernanda C; Navarro, Fabio C P; Perez, Rodrigo O; Mariadason, John; Sieber, Oliver M; Strausberg, Robert L; Simpson, Andrew J G; Jardim, Denis L F; Reis, Luiz Fernando L; Parmigiani, Raphael B; Galante, Pedro A F; Camargo, Anamaria A

2014-10-15

120

TP53 gene mutations of lung cancer patients in upper northern Thailand and environmental risk factors  

E-print Network

TP53 gene mutations of lung cancer patients in upper northern Thailand and environmental risk mutations are observed in about 40e70% of lung cancer tissues, and the hot spot codon mu- tations factors that influence TP53 gene mutation in lung cancer patients residing areas with high lung cancer

121

Free-Radical-Induced Mutation vs Redox Regulation: Costs and Benefits of Genes in Organelles  

E-print Network

Focus Free-Radical-Induced Mutation vs Redox Regulation: Costs and Benefits of Genes in Organelles of movement of genes to the nucleus is decreased mutation: plastids and mitochondria have high volume-specific rates of re- dox reactions, producing oxygen free radicals that chemically modify DNA. These mutations

Allen, John F.

122

Analysis of delta-globin gene mutations in Greek cypriots.  

PubMed

We recently described four delta-globin gene mutations in Greek Cypriots studied by polymerase chain reaction (PCR) amplification and automated fluorescence-based DNA sequence analysis (Blood 78:3298, 1991). Selective restriction enzyme digestion of PCR products facilitated direct mutation detection. Twenty-eight additional samples from unrelated Cypriots with Hb A2 levels ranging from 0.6% to 3.6% were studied by PCR and showed the following: twelve had the delta 27 (ala-->ser) mutation, one was heterozygous for the delta IVS-2 AG-->GG change, and none had either the delta 116 (arg-->cys) or delta 141 (leu-->pro) mutations. The remaining samples were divided into two groups: 11 with borderline normal Hb A2 values that were not pursued; and four with abnormal Hb A2 values. The delta-globin genes from these four samples were sequenced and the same four changes identified in each: a C-->T at -199, a C-->T at codon 4 (thr-->ile), a silent C-->T at codon 97, and an AT deletion at position 722 in IVS-2. The codon 4 change abolishes a Ple I site whereas the codon 97 creates an Nla III site, thus facilitating rapid identification. All four changes are in cis position, suggesting that the -199 C-->T, the C-->T at codon 97, and the AT deletion in IVS-2 are neutral polymorphisms present on the codon 4 (thr-->ile) chromosome. DNA haplotype analysis suggests all five delta-globin gene mutant alleles arose independently on different chromosomal backgrounds. PMID:8364213

Trifillis, P; Kyrri, A; Kalogirou, E; Kokkofitou, A; Ioannou, P; Schwartz, E; Surrey, S

1993-09-01

123

Atrichia Caused by Mutations in the Vitamin D Receptor Gene is a Phenocopy of Generalized Atrichia Caused by Mutations in the Hairless Gene  

Microsoft Academic Search

Generalized atrichia with papules is a rare disorder characterized by loss of hair shortly after birth and development of cutaneous cysts. Mutations in the hairless gene (HR) cause this phenotype in both mouse and human. Here we present a case of atrichia with papules in a patient with a normal HAIRLESS gene but with mutations in both alleles of the

Jeffrey Miller; Karima Djabali; Tai Chen; Yaping Liu; Michael Ioffreda; Stephen Lyle; Angela M. Christiano; Michael Holick; George Cotsarelis

2001-01-01

124

BSE Case Associated with Prion Protein Gene Mutation  

PubMed Central

Bovine spongiform encephalopathy (BSE) is a transmissible spongiform encephalopathy (TSE) of cattle and was first detected in 1986 in the United Kingdom. It is the most likely cause of variant Creutzfeldt-Jakob disease (CJD) in humans. The origin of BSE remains an enigma. Here we report an H-type BSE case associated with the novel mutation E211K within the prion protein gene (Prnp). Sequence analysis revealed that the animal with H-type BSE was heterozygous at Prnp nucleotides 631 through 633. An identical pathogenic mutation at the homologous codon position (E200K) in the human Prnp has been described as the most common cause of genetic CJD. This finding represents the first report of a confirmed case of BSE with a potential pathogenic mutation within the bovine Prnp gene. A recent epidemiological study revealed that the K211 allele was not detected in 6062 cattle from commercial beef processing plants and 42 cattle breeds, indicating an extremely low prevalence of the E211K variant (less than 1 in 2000) in cattle. PMID:18787697

Richt, Jürgen A.; Hall, S. Mark

2008-01-01

125

Mutations and a polymorphism in the tuberin gene  

SciTech Connect

Two deletions and a polymorphism have been identified in the recently described tuberin gene. The tuberin gene (designated TSC2) when mutated causes tuberous sclerosis complex (TSC). Fifty-three affected individuals (30 from families with multiple affected and 23 isolated cases) were screened with the tuberin cDNA for gross deletions or rearrangements. Both deletions were found in families with multiple affected members (family designations: HOU-5 and HOU-22). The approximate size of the deletion in HOU-5 is ten kilobases and eliminates a BamHI restriction site. The deletion includes a portion of the 5{prime} half of the tuberin cDNA. The deletion in HOU-22 occurs in the 3{prime} half of the gene. The deletions are being further characterized. A HindIII restriction site polymorphism was detected by a 0.5 kilobase probe from the 5{prime} coding region of the tuberin gene in an individual from a family linked to chromosome 9 (posterior probability of linkage 93%). The polymorphism did not segregate with TSC in the family. The family had previously been shown to give negative results with multiple markers on chromosome 16. The polymorphism was also seen in one individual among a panel of 20 randomly selected unaffected individuals. Thirty-five additional affected probands (five from families and 30 isolated cases) are being tested with the tuberin cDNA. Testing for subtle mutations is our panel of 80 affected probands is underway utilizing SSCP. Additional mutations or polymorphisms detected will be reported. The tuberin cDNA was a kind gift of The European Chromosome 16 Tuberous Sclerosis Consortium.

Northup, H.; Rodriguez, J.A.; Au, K.S.; Rodriguez, E. [Univ. of Texas Medical School, Houston, TX (United States)

1994-09-01

126

NIH Researchers Identify New Gene Mutation Associated with ALS and Dementia  

MedlinePLUS

... identify new gene mutation associated with ALS and dementia April 7, 2014 A rare mutation in a ... several people had been diagnosed with ALS and dementia, the investigators used exome sequencing—a technique in ...

127

Case report: prenatal diagnosis of Hb Hammersmith [?42(CD1)Phe?Ser; HBB: c.128T?>?C] in a family with an adult male patient.  

PubMed

Hb Hammersmith [?42(CD1)Phe???Ser; HBB: c.128T?>?C] is a rare, unstable hemoglobin (Hb) variant. In this case report, we describe another male case of Hb Hammersmith. A 39-year-old male had hemolytic anemia, cyanosis and splenomegaly since 6 months after birth. He passed the disease allele to his daughter, a 3-year-old girl, who also had hemolytic anemia and splenomegaly. This mutation was not identified in the parents and two brothers of the father. Early prenatal diagnosis was performed in the second pregnancy in this family. This is the first case of Hb Hammersmith in an adult male patient. PMID:24471820

Li, Ru; Wang, Ting; Xie, Xing-Mei; Li, Dong-Zhi

2014-01-01

128

Cohesin gene mutations in tumorigenesis: from discovery to clinical significance  

PubMed Central

Cohesin is a multi-protein complex composed of four core subunits (SMC1A, SMC3, RAD21, and either STAG1 or STAG2) that is responsible for the cohesion of sister chromatids following DNA replication until its cleavage during mitosis thereby enabling faithful segregation of sister chromatids into two daughter cells. Recent cancer genomics analyses have discovered a high frequency of somatic mutations in the genes encoding the core cohesin subunits as well as cohesin regulatory factors (e.g. NIPBL, PDS5B, ESPL1) in a select subset of human tumors including glioblastoma, Ewing sarcoma, urothelial carcinoma, acute myeloid leukemia, and acute megakaryoblastic leukemia. Herein we review these studies including discussion of the functional significance of cohesin inactivation in tumorigenesis and potential therapeutic mechanisms to selectively target cancers harboring cohesin mutations. [BMB Reports 2014; 47(6): 299-310] PMID:24856830

Solomon, David A.; Kim, Jung-Sik; Waldman, Todd

2014-01-01

129

Mutation screening of the HGD gene identifies a novel alkaptonuria mutation with significant founder effect and high prevalence.  

PubMed

Alkaptonuria (AKU) is an autosomal recessive disorder; caused by the mutations in the homogentisate 1, 2-dioxygenase (HGD) gene located on Chromosome 3q13.33. AKU is a rare disorder with an incidence of 1: 250,000 to 1: 1,000,000, but Slovakia and the Dominican Republic have a relatively higher incidence of 1: 19,000. Our study focused on studying the frequency of AKU and identification of HGD gene mutations in nomads. HGD gene sequencing was used to identify the mutations in alkaptonurics. For the past four years, from subjects suspected to be clinically affected, we found 16 positive cases among a randomly selected cohort of 41 Indian nomads (Narikuravar) settled in the specific area of Tamil Nadu, India. HGD gene mutation analysis showed that 11 of these patients carry the same homozygous splicing mutation c.87 + 1G > A; in five cases, this mutation was found to be heterozygous, while the second AKU-causing mutation was not identified in these patients. This result indicates that the founder effect and high degree of consanguineous marriages have contributed to AKU among nomads. Eleven positive samples were homozygous for a novel mutation c.87 + 1G > A, that abolishes an intron 2 donor splice site and most likely causes skipping of exon 2. The prevalence of AKU observed earlier seems to be highly increased in people of nomadic origin. PMID:24575791

Sakthivel, Srinivasan; Zatkova, Andrea; Nemethova, Martina; Surovy, Milan; Kadasi, Ludevit; Saravanan, Madurai P

2014-05-01

130

Adaptation to an automated platform of algorithmic combinations of advantageous mutations in genes generated using amino acid scanning mutational strategy.  

Technology Transfer Automated Retrieval System (TEKTRAN)

Recent mutational strategies for generating and screening of genes for optimized traits, including directed evolution, domain shuffling, random mutagenesis, and site-directed mutagenesis, have been adapted for automated platforms. Here we discuss the amino acid scanning mutational strategy and its ...

131

Mutation analysis of the MSMB gene in familial prostate cancer  

PubMed Central

Background: MSMB, a gene coding for ?-microseminoprotein, has been identified as a candidate susceptibility gene for prostate cancer (PrCa) in two genome-wide association studies (GWAS). SNP rs10993994 is 2?bp upstream of the transcription initiation site of MSMB and was identified as an associated PrCa risk variant. The MSMB protein is underexpressed in PrCa and it was previously proposed to be an independent marker for the recurrence of cancer after radical prostatectomy. Methods: In this study, the coding region of this gene and 1500?bp upstream of the 5?UTR has been sequenced in germline DNA in 192 PrCa patients with family history. To evaluate the possible effects of these variants we used in silico analysis. Results: No deleterious mutations were identified, however, nine new sequence variants were found, most of these in the promoter and 5?UTR region. In silico analysis suggests that four of these SNPs are likely to have some effect on gene expression either by affecting ubiquitous or prostate-specific transcription factor (TF)-binding sites or modifying splicing efficiency. Interpretation We conclude that MSMB is unlikely to be a familial PrCa gene and propose that the high-risk alleles of the SNPs in the 5?UTR effect PrCa risk by modifying MSMB gene expression in response to hormones in a tissue-specific manner. PMID:19997100

Kote-Jarai, Z; Leongamornlert, D; Tymrakiewicz, M; Field, H; Guy, M; Al Olama, A A; Morrison, J; O'Brien, L; Wilkinson, R; Hall, A; Sawyer, E; Muir, K; Hamdy, F; Donovan, J; Neal, D; Easton, D; Eeles, R

2009-01-01

132

Genetic epidemiology of muscular dystrophies resulting from sarcoglycan gene mutations.  

PubMed Central

BACKGROUND: The autosomal recessive limb-girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous muscle diseases characterised by progressive proximal limb muscle weakness. Six different loci have been mapped and pathogenetic mutations in the genes encoding the sarcoglycan complex components (alpha-, beta-, gamma-, and delta-sarcoglycan) have been documented. LGMD patients affected with primary "sarcoglycanopathies" are classified as LGMD2D, 2E, 2C, and 2F, respectively. METHODS: A geographical area in north east Italy (2,319,147 inhabitants) was selected for a genetic epidemiological study on primary sarcoglycanopathies. Within the period 1982 to 1996, all patients living in this region and diagnosed with muscular dystrophy were seen at our centre. Immunohistochemical and immunoblot screening for alpha-sarcoglycan protein deficiency was performed on all muscle biopsies from patients with a progressive muscular dystrophy of unknown aetiology and normal dystrophin. Sarcoglycan mutation analyses were conducted on all patient muscle biopsies shown to have complete or partial absence of alpha-sarcoglycan immunostaining or a decreased quantity of alpha-sarcoglycan protein on immunoblotting. RESULTS: Two hundred and four patient muscle biopsies were screened for alpha-sarcoglycan protein deficiency and 18 biopsies showed a deficiency. Pathogenetic mutations involving one gene for sarcoglycan complex components were identified in 13 patients: alpha-sarcoglycan in seven, beta-sarcoglycan in two, gamma-sarcoglycan in four, and none in the delta-sarcoglycan gene. The overall prevalence of primary sarcoglycanopathies, as of 31 December 1996, was estimated to be 5.6 x 10(-6) inhabitants. CONCLUSION: The prevalence rate estimated in this study is the first to be obtained after biochemical and molecular genetic screening for sarcoglycan defects. PMID:9429136

Fanin, M; Duggan, D J; Mostacciuolo, M L; Martinello, F; Freda, M P; Sorarù, G; Trevisan, C P; Hoffman, E P; Angelini, C

1997-01-01

133

The gene structures of spontaneous mutations affecting a Caenorhabditis elegans myosin heavy chain gene.  

PubMed

We have isolated spontaneous mutations affecting the unc-54 major myosin heavy chain gene of Caenorhabditis elegans (variety Bristol). Spontaneous unc-54 mutants occur in C. elegans populations at a frequency of approximately 3 X 10(-7). We have studied the gene structure of 65 independent unc-54 mutations using filter-transfer hybridization techniques. Most unc-54 mutations (50 of 65) exhibit no abnormalities detected with these techniques; these mutations are small lesions affecting less than 100 base pairs. Approximately 17% of the mutations (11 of 65) are simple deletions, ranging in size from less than 100 base pairs to greater than 17 kilobases. One isolate contains two separate deletions, each of which affects unc-54. Two mutants contain tandem genetic duplications that include a portion of unc-54 and extend 8-10 kilobases beyond the 5' terminus of the mRNA. Conspicuously absent from our collection of spontaneous unc-54 mutations are any resulting from insertion of transposable genetic elements. Such mutants, if they occur, must arise at a frequency of less than 5 X 10(-9). PMID:2981757

Eide, D; Anderson, P

1985-01-01

134

Sporadic ALS is not associated with VAPB gene mutations in Southern Italy  

Microsoft Academic Search

Mutations in the Cu\\/Zn superoxide dismutase (Sod1) gene have been reported to cause adult-onset autosomal dominant Amyotrophic Lateral Sclerosis (FALS). In sporadic cases (SALS) de novo mutations in the Sod1 gene have occasionally been observed. The recent finding of a mutation in the VAMP\\/synaptobrevin-associated membrane protein B (VAPB) gene as the cause of amyotrophic lateral sclerosis (ALS8), prompted us to

Francesca Luisa Conforti; Teresa Sprovieri; Rosalucia Mazzei; Carmine Ungaro; Alessandro Tessitore; Gioacchino Tedeschi; Alessandra Patitucci; Angela Magariello; AnnaLia Gabriele; Vincenzo Labella; Isabella Laura Simone; Giovanni Majorana; Maria Rosaria Monsurrò; Paola Valentino; Maria Muglia; Aldo Quattrone

2006-01-01

135

Mutations of the synapse genes and intellectual disability syndromes.  

PubMed

Intellectual disability syndromes have been found associated to numerous mutated genes that code for proteins functionally involved in synapse formation, the regulation of dendritic spine morphology, the regulation of the synaptic cytoskeleton or the synthesis and degradation of specific synapse proteins. These studies have strongly demonstrated that even mild alterations in synapse morphology and function give rise to mild or severe alteration in intellectual abilities. Interestingly, pharmacological agents that are able to counteract these morphological and functional synaptic anomalies can also improve the symptoms of some of these conditions. This review is summarizing recent discoveries on the functions of some of the genes responsible for intellectual disability syndromes connected with synapse dysfunctions. PMID:23872408

Verpelli, Chiara; Montani, Caterina; Vicidomini, Cinzia; Heise, Christopher; Sala, Carlo

2013-11-01

136

Homology modeling and molecular dynamics studies of Wilms’ tumor gene 1 frameshift mutations in exon 7  

PubMed Central

As a transcription factor, the Wilms' tumor 1 (WT1) gene plays an important role in leukemogenesis. The impact of WT1 gene mutations has been reported in acute myeloid leukemia (AML). However, the number of available studies on the spatial configuration changes following WT1 mutation is limited. In this study, we sequenced the mutation in exon 7 of the WT1 gene in 60 children with newly diagnosed AML and the spatial configuration of WT1 with frameshift mutations in exon 7 was evaluated using the software for homology modeling and optimization of molecular dynamics. Three cases with frameshift mutations in exon 7 were identified (3/60; mutation rate, 5%). One case had a mutation that had been previously described, whereas the remaining two mutations were first described in our study. Of the three cases, one case presented with antecedent myelodysplastic syndrome (MDS) and the remaining two cases exhibited primary resistance to induction chemotherapy. The spatial configuration analysis demonstrated that the three mutations affected the spatial structure of exon 7 and even affected exon 8 compared to its wild-type. This study demonstrated that the frameshift mutation in exon 7 of the WT1 gene is a poor prognostic factor for children with AML, partly through the spatial configuration changes following frameshift mutations of WT1, which highlights the structure-based function analysis and may facilitate the elucidation of the pathogenesis underlying WT1 gene mutations. PMID:24649013

HU, SHAOYAN; WANG, YING; WU, SHUIYAN; ZHANG, MINGYING; PAN, JIAN; SHEN, HONGJIE; QI, XIAOFEI; CEN, JIANNONG; CHEN, ZIXING; SHEN, BAIRONG; CHEN, RUIHUA

2013-01-01

137

The landscape of cancer genes and mutational processes in breast cancer.  

PubMed

All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here we examine the genomes of 100 tumours for somatic copy number changes and mutations in the coding exons of protein-coding genes. The number of somatic mutations varied markedly between individual tumours. We found strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, and observed multiple mutational signatures, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides. Driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. Among the 100 tumours, we found driver mutations in at least 40 cancer genes and 73 different combinations of mutated cancer genes. The results highlight the substantial genetic diversity underlying this common disease. PMID:22722201

Stephens, Philip J; Tarpey, Patrick S; Davies, Helen; Van Loo, Peter; Greenman, Chris; Wedge, David C; Nik-Zainal, Serena; Martin, Sancha; Varela, Ignacio; Bignell, Graham R; Yates, Lucy R; Papaemmanuil, Elli; Beare, David; Butler, Adam; Cheverton, Angela; Gamble, John; Hinton, Jonathan; Jia, Mingming; Jayakumar, Alagu; Jones, David; Latimer, Calli; Lau, King Wai; McLaren, Stuart; McBride, David J; Menzies, Andrew; Mudie, Laura; Raine, Keiran; Rad, Roland; Chapman, Michael Spencer; Teague, Jon; Easton, Douglas; Langerød, Anita; Lee, Ming Ta Michael; Shen, Chen-Yang; Tee, Benita Tan Kiat; Huimin, Bernice Wong; Broeks, Annegien; Vargas, Ana Cristina; Turashvili, Gulisa; Martens, John; Fatima, Aquila; Miron, Penelope; Chin, Suet-Feung; Thomas, Gilles; Boyault, Sandrine; Mariani, Odette; Lakhani, Sunil R; van de Vijver, Marc; van 't Veer, Laura; Foekens, John; Desmedt, Christine; Sotiriou, Christos; Tutt, Andrew; Caldas, Carlos; Reis-Filho, Jorge S; Aparicio, Samuel A J R; Salomon, Anne Vincent; Børresen-Dale, Anne-Lise; Richardson, Andrea L; Campbell, Peter J; Futreal, P Andrew; Stratton, Michael R

2012-06-21

138

The landscape of cancer genes and mutational processes in breast cancer  

PubMed Central

All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis1, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here we examine the genomes of 100 tumours for somatic copy number changes and mutations in the coding exons of protein-coding genes. The number of somatic mutations varied markedly between individual tumours. We found strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, and observed multiple mutational signatures, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides. Driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. Among the 100 tumours, we found driver mutations in at least 40 cancer genes and 73 different combinations of mutated cancer genes. The results highlight the substantial genetic diversity underlying this common disease. PMID:22722201

Stephens, Philip J.; Tarpey, Patrick S.; Davies, Helen; Loo, Peter Van; Greenman, Chris; Wedge, David C.; Nik-Zainal, Serena; Martin, Sancha; Varela, Ignacio; Bignell, Graham R.; Yates, Lucy R.; Papaemmanuil, Elli; Beare, David; Butler, Adam; Cheverton, Angela; Gamble, John; Hinton, Jonathan; Jia, Mingming; Jayakumar, Alagu; Jones, David; Latimer, Calli; Lau, King Wai; McLaren, Stuart; McBride, David J.; Menzies, Andrew; Mudie, Laura; Raine, Keiran; Rad, Roland; Chapman, Michael Spencer; Teague, Jon; Easton, Douglas; Langerød, Anita; OSBREAC; Lee, Ming Ta Michael; Shen, Chen-Yang; Tee, Benita Tan Kiat; Huimin, Bernice Wong; Broeks, Annegien; Vargas, Ana Cristina; Turashvili, Gulisa; Martens, John; Fatima, Aquila; Miron, Penelope; Chin, Suet-Feung; Thomas, Gilles; Boyault, Sandrine; Mariani, Odette; Lakhani, Sunil R.; van de Vijver, Marc; van ’t Veer, Laura; Foekens, John; Desmedt, Christine; Sotiriou, Christos; Tutt, Andrew; Caldas, Carlos; Reis-Filho, Jorge S.; Aparicio, Samuel A. J. R.; Salomon, Anne Vincent; Børresen-Dale, Anne-Lise; Richardson, Andrea L.; Campbell, Peter J.; Futreal, P. Andrew; Stratton, Michael R.

2012-01-01

139

Mutation analysis of the Fanconi Anemia Gene FACC  

SciTech Connect

Fanconi anemia (FA) is a genetically heterogeneous autosomal recessive disorder characterized by a unique hypersensitivity of cells to DNA cross-linking agents; a gene for complementation group C (FACC) has recently been cloned. The authors have amplified FACC exons with their flanking intron sequences from genomic DNA from 174 racially and ethnically diverse families in the International Fanconi Anemia Registry and have screened for mutations by using SSCP analysis. They have identified eight different variants in 32 families; three were detected in exon 1, one in exon 4, one in intron 4, two in exon 6, and one in exon 14. Two of the eight variants, in seven families, did not segregate with the disease allele in multiplex families, suggesting that these variants represented benign polymorphisms. Disease-associated mutations in FACC were detected in a total of 25 (14.4%) of 174 families screened. The most frequent mutations were IVS4 + 4 A [yields] T (intron 4; 12 families) and 322delG (exon 1; 9 families). Other, less common mutations include Q13X in exon 1, R185X and D195V in exon 6, and L554P in exon 14. The polymorphisms were S26F in exon 1 and G139E in exon 4. All patients in the study with 322delG, Q13X, R185X, and D195V are of northern or eastern European or southern Italian ancestry, and 18 of 19 have a mild form of the disease, while the 2 patients with L554P, both from the same family, have a severe phenotype. All 19 patients with IVS4 + 4 A [yields] T have Jewish ancestry and have a severe phenotype. 19 refs., 1 fig., 3 tabs.

Verlander, P.C.; Lin, J.D.; Udono, M.U.; Zhang, Q.; Auerbach, A.D. (Rockefeller Univ., New York, NY (United States)); Gibson, R.A.; Mathew, C.G. (Guy's Hospital, London (United Kingdom))

1994-04-01

140

Founder mutation(s) in the RSPH9 gene leading to primary ciliary dyskinesia in two inbred Bedouin families.  

PubMed

A rare mutation in the RSPH9 gene leading to primary ciliary dyskinesia was previously identified in two Bedouin families, one from Israel and one from the United Arab Emirates (UAE). Herein we analyse mutation segregation in the Israeli family, present the clinical disease spectrum, and estimate mutation age in the two families. Mutation segregation was studied by restriction fragment length analysis. Mutation ages were estimated using a model of the decrease in the length of ancestral haplotypes. The mutations in each of the two families had a common ancestor less than 95 and less than 17 generations in the past. If the mutations in the two families are descended from a common ancestor, that mutation would have to have arisen at least 150 generations ago. If the Bedouin population has been roughly constant in size for at least 6000 years, it is possible that the mutations in the two families are identical by descent. If there were substantial fluctuations in the size of the Bedouin population, it is more likely that there were two independent mutations. Based on the available data, the population genetic analysis does not strongly favour one conclusion over the other. PMID:20070851

Reish, Orit; Slatkin, Montgomery; Chapman-Shimshoni, Daphne; Elizur, Arnon; Chioza, Barry; Castleman, Victoria; Mitchison, Hannah M

2010-03-01

141

Founder mutation(s) in the RSPH9 gene leading to primary ciliary dyskinesia in two inbred Bedouin families  

PubMed Central

A rare mutation in the RSPH9 gene leading to Primary Ciliary Dyskinesia was previously identified in two Bedouin families, one from Israel and one from the United Arab Emirates (UAE). Herein we analyze mutation segregation in the Israeli family, present the clinical disease spectrum, and estimate mutation age in the two families. Mutation segregation was studied by restriction fragment length analysis. Mutation ages were estimated using a model of the decrease in the length of ancestral haplotypes. The mutations in each of the two families had a common ancestor less than 95 and 17 generations in the past. If the mutations in the two families are descended from a common ancestor, that mutation would have to have arisen at least 150 generations ago. If the Bedouin population has been roughly constant in size for at least 6000 years, it is possible that the mutations in the two families are identical by descent. If there were substantial fluctuations in the size of the Bedouin population, it is more likely that there were two independent mutations. Based on the available data, the population genetic analysis does not strongly favor one conclusion over the other. PMID:20070851

Reish, Orit; Slatkin, Montgomery; Chapman-Shimshoni, Daphne; Elizur, Arnon; Chioza, Barry; Castleman, Victoria; Mitchison, Hannah M.

2010-01-01

142

Induction of skin fibrosis in mice expressing a mutated fibrillin-1 gene.  

PubMed Central

BACKGROUND: Tight skin mice (TSK) bear a mutated Fibrillin-1 (Fbn-1) gene. Genetic studies show that the TSK mutation is closely associated with the Fbn-1 locus (0-0.7 cM). A previous study showed two recombinants between the Fbn-1 locus and the TSK mutation. TSK mutation and mutated Fbn-1 gene cosegregate in F1 mice. MATERIALS AND METHODS: To elucidate the role of the mutated Fbn-1 gene in occurrence of TSK syndrome, we generated transgenic (Tg) mice expressing mutated Fbn-1 gene. In another set of experiments, we injected normal mice after birth with a plasmid bearing mutated Fbn-1 gene (pdFbn-1). RESULTS: Our results demonstrate that the pdFbn-1 Tg mice developed permanent cutaneous hyperplasia that was permanent. In mice injected as newborns with a plasmid bearing the sense pdFbn-1 gene, cutaneous hyperplasia was transient. In contrast to TSK mice, neither Tg nor mice injected with plasmid developed lung emphysema. The pdFbn-1 Tg and TSK mice spontaneously produced anti-topoisomerase I and anti-Fbn- antibodies, as do humans afflicted by scleroderma; whereas, those injected with a plasmid containing the pdFbn-1 gene produced only anti-Fbn-1 autoantibodies. CONCLUSIONS: The results suggest that, although cutaneous hyperplasia is due to mutated Fbn-1 gene, the TSK syndrome may be multifactorial. PMID:11126198

Saito, S.; Nishimura, H.; Phelps, R. G.; Wolf, I.; Suzuki, M.; Honjo, T.; Bona, C.

2000-01-01

143

Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region  

Microsoft Academic Search

A large number of familial Alzheimer disease (FAD) kindreds were examined to determine whether mutations in the amyloid precursor protein (APP) gene could be responsible for the disease. Previous studies have identified three mutations at APP codon 717 which are pathogenic for Alzheimer disease (AD). Samples from affected subjects were examined for mutations in exons 16 and 17 of the

K. Kamino; L. Anderson; S. Odahl; E. Nemens; T. D. Bird; G. D. Schellenberg; E. M. Wijsman; W. Kukall; E. Larson; L. L. Heston

1992-01-01

144

CLINICAL STUDY Mutational analysis of the necdin gene in patients with  

E-print Network

with Prader­Willi syndrome. Aim: To investigate necdin gene (NDN) variants in patients with isolated by CHD7 gene mutations, responsible for CHARGE syndrome, recently associated with IHH (4). Prader­ Willi

Mellon, Pamela L.

145

Heterozygous germ-line mutations in the NBN gene predispose to medulloblastoma in pediatric patients  

Microsoft Academic Search

The NBN (NBS1) gene belongs to a group of double-strand break repair genes. Mutations in any of these genes cause genome instability syndromes\\u000a and contribute to carcinogenesis. NBN gene mutations cause increased tumor risk in Nijmegen breakage syndrome (NBS) homozygotes as well as in NBN heterozygotes. NBS patients develop different types of malignancies; among solid tumors, medulloblastoma (MB), an embryonal

El?bieta Ciara; Dorota Piekutowska-Abramczuk; Ewa Popowska; Wies?awa Grajkowska; S?awomir Barszcz; Danuta Perek; Bo?enna Dembowska-Bagi?ska; Marta Perek-Polnik; Ewa Kowalewska; Aneta Czaj?ska; Ma?gorzata Syczewska; Kamila Czornak; Ma?gorzata Krajewska-Walasek; Marcin Roszkowski; Krystyna H. Chrzanowska

2010-01-01

146

Mutation analysis of LMX1B gene in nail-patella syndrome patients.  

PubMed Central

Nail-patella syndrome (NPS), a pleiotropic disorder exhibiting autosomal dominant inheritance, has been studied for >100 years. Recent evidence shows that NPS is the result of mutations in the LIM-homeodomain gene LMX1B. To determine whether specific LMX1B mutations are associated with different aspects of the NPS phenotype, we screened a cohort of 41 NPS families for LMX1B mutations. A total of 25 mutations were identified in 37 families. The nature of the mutations supports the hypothesis that NPS is the result of haploinsufficiency for LMX1B. There was no evidence of correlation between aspects of the NPS phenotype and specific mutations. PMID:9837817

McIntosh, I; Dreyer, S D; Clough, M V; Dunston, J A; Eyaid, W; Roig, C M; Montgomery, T; Ala-Mello, S; Kaitila, I; Winterpacht, A; Zabel, B; Frydman, M; Cole, W G; Francomano, C A; Lee, B

1998-01-01

147

Hyperinsulinism–hyperammonaemia syndrome: novel mutations in the GLUD1 gene and genotype–phenotype correlations  

PubMed Central

Background Activating mutations in the GLUD1 gene (which encodes for the intra-mitochondrial enzyme glutamate dehydrogenase, GDH) cause the hyperinsulinism–hyperammonaemia (HI/HA) syndrome. Patients present with HA and leucine-sensitive hypoglycaemia. GDH is regulated by another intra-mitochondrial enzyme sirtuin 4 (SIRT4). Sirt4 knockout mice demonstrate activation of GDH with increased amino acid-stimulated insulin secretion. Objectives To study the genotype–phenotype correlations in patients with GLUD1 mutations. To report the phenotype and functional analysis of a novel mutation (P436L) in the GLUD1 gene associated with the absence of HA. Patients and methods Twenty patients with HI from 16 families had mutational analysis of the GLUD1 gene in view of HA (n=19) or leucine sensitivity (n=1). Patients negative for a GLUD1 mutation had sequence analysis of the SIRT4 gene. Functional analysis of the novel P436L GLUD1 mutation was performed. Results Heterozygous missense mutations were detected in 15 patients with HI/HA, 2 of which are novel (N410D and D451V). In addition, a patient with a normal serum ammonia concentration (21??mol/l) was heterozygous for a novel missense mutation P436L. Functional analysis of this mutation confirms that it is associated with a loss of GTP inhibition. Seizure disorder was common (43%) in our cohort of patients with a GLUD1 mutation. No mutations in the SIRT4 gene were identified. Conclusion Patients with HI due to mutations in the GLUD1 gene may have normal serum ammonia concentrations. Hence, GLUD1 mutational analysis may be indicated in patients with leucine sensitivity; even in the absence of HA. A high frequency of epilepsy (43%) was observed in our patients with GLUD1 mutations. PMID:19690084

Kapoor, Ritika R; Flanagan, Sarah E; Fulton, Piers; Chakrapani, Anupam; Chadefaux, Bernadette; Ben-Omran, Tawfeg; Banerjee, Indraneel; Shield, Julian P; Ellard, Sian; Hussain, Khalid

2009-01-01

148

Mutation screening of the RYR1 gene in malignant hyperthermia: Detection of a novel Tyr to ser mutation in a pedigree with associated centrl cores  

Microsoft Academic Search

The ryanodine receptor gene (RYR1) has been shown to be mutated in a small number of malignant hyperthermia (MH) predigrees. Missense mutations in this gene have also been identified in two families with central core disease (CCD), a rare myopathy closely associated with MH. In an effort to identify other RYR1 mutations responsible for MH and CCD, we used a

K. A. Quane; K. E. Keating; J. M. S. Healy

1994-01-01

149

LYS2 gene and its mutation in Kluyveromyces lactis.  

PubMed

The KlLYS2 gene, encoding the alpha-aminoadipate reductase of Kluyveromyces lactis, was isolated by complementation of a lysA1 mutant. The deduced amino acid sequence shared an identity of 73% with the LYS2 product of Saccharomyces cerevisiae. Despite the high sequence homology of the alpha-aminoadipate reductase genes, the two yeast species differently responded to the presence of alpha-aminoadipate in the medium. Wild-type S. cerevisiae is known to be sensitive to alpha-aminoadipate, but becomes resistant when mutated to lys2. In contrast, K. lactis strains were found to be naturally resistant to alpha-aminoadipate. Therefore, the positive selection procedure for the isolation of lys2 mutants on alpha-aminoadipate, as practised in S. cerevisiae, cannot be applied to K. lactis. A possible reason of this difference may be that the catalytic rate of the alpha-aminoadipate reductase differs in the two yeasts. The EMBL/Genbank Accession No. for the KlLYS2 gene is AJ504405. PMID:14587101

Alberti, Adriana; Ferrero, Iliana; Lodi, Tiziana

2003-10-30

150

Genotype/phenotype correlation of multiple endocrine neoplasia type 1 gene mutations in sporadic gastrinomas.  

PubMed

Multiple endocrine neoplasia type 1 (MEN1) gene mutations are reported in some gastrinomas occurring in patients without MEN1 as well as in some other pancreatic endocrine tumors (PETs). In some inherited syndromes phenotype-genotype correlations exist for disease severity, location, or other manifestations. The purpose of the present study was to correlate mutations of the MEN1 gene in a large cohort of patients with sporadic gastrinomas to disease activity, tumor location, extent, and growth pattern. DNA was extracted from frozen gastrinomas from 51 patients and screened by dideoxyfinger-printing (ddF) for abnormalities in the 9 coding exons and adjacent splice junctions of the MEN1 gene. Tumor DNA exhibiting abnormal ddF patterns was sequenced for mutations. The findings were correlated with clinical manifestations of the disease, primary tumor site, disease extent, and tumor growth postoperatively. Tumor growth was determined by serial imaging studies. Sixteen different MEN1 gene mutations in the 51 sporadic gastrinomas (31%) were identified (11 truncating, 4 missense, and 1 in-frame deletion). Nine of the 16 mutations were located in exon 2 compared to 7 of 16 in the remaining 8 coding exons (P = 0.005 on a per nucleotide basis). Primary pancreatic or lymph node gastrinomas with a mutation had only exon 2 mutations, whereas duodenal tumors uncommonly harbored exon 2 mutations (P = 0.011). Similarly, small primary tumors (<1 cm) more frequently contained a nonexon 2 mutation (P = 0.02). There was no difference between patients with or without a mutation with respect to clinical characteristics, primary tumor site, disease extent, or proportion of patients disease free after surgery. Postoperative tumor growth tended to be more aggressive in patients with a mutation (P = 0.09). No correlation in the rate of disease-free status or postoperative tumor growth in patients with active disease to the location of the mutation was seen. These results demonstrate that the MEN1 gene is mutated in 31% of sporadic gastrinomas, and mutations are clustered between amino acids 66-166, which differs from patients with familial MEN1, in whom mutations occur throughout the gene. The presence of an MEN1 gene mutation does not correlate with clinical characteristics of patients with gastrinomas, gastrinoma extent, or growth pattern; however, the location of the mutation differed with gastrinoma location. These data suggest that mutations in the MEN1 gene are important in a proportion of sporadic gastrinomas, but the presence or absence of these mutations will not identify the clinically important subgroups with different growth patterns. PMID:10634374

Goebel, S U; Heppner, C; Burns, A L; Marx, S J; Spiegel, A M; Zhuang, Z; Lubensky, I A; Gibril, F; Jensen, R T; Serrano, J

2000-01-01

151

Mutation in the Mismatch Repair Gene Msh6 Causes Cancer Susceptibility  

Microsoft Academic Search

Mice carrying a null mutation in the mismatch repair gene Msh6 were generated by gene targeting. Cells that were homozygous for the mutation did not produce any detectable MSH6 protein, and extracts prepared from these cells were defective for repair of single nucleotide mismatches. Repair of 1, 2, and 4 nucleotide insertion\\/deletion mismatches was unaffected. Mice that were homozygous for

Winfried Edelmann; Kan Yang; Asad Umar; Joerg Heyer; Kirkland Lau; Kunhua Fan; Wolfgang Liedtke; Paula E Cohen; Michael F Kane; James R Lipford; Nianjun Yu; Gray F Crouse; Jeffrey W Pollard; Thomas Kunkel; Martin Lipkin; Richard Kolodner; Raju Kucherlapati

1997-01-01

152

Frequent Somatic Mutations of the APC Gene in Human Pancreatic Cancer 1  

Microsoft Academic Search

The APC (adenomatous polyposis coli) gene is responsible for famil- ial adenomatous polyposis and is also associated with the development of sporadic tumors of the colon and stomach. To investigate whether or not mutations of APC play any role in tumors arising in other organs, we examined somatic mutations of this gene in sporadic (nonfamilial) renal cell carcinomas, hepatocellular carcinomas,

Akira Horii; Shuichi Nakatsuru; Yasuo Miyoshi; Hiroki Nagase; Hiroshi Ando; Akio Yanagisawa; Eiju Tsuchiya; Yo Kato; Yusuke Nakamura

153

Gene replacement without selection: regulated suppression of amber mutations in Escherichia coli  

Microsoft Academic Search

We have developed a method called ‘gene gorging’ to make precise mutations in the Escherichia coli genome at frequencies high enough (1–15%) to allow direct identification of mutants by PCR or other screen rather than by selection. Gene gorging begins by establishing a donor plasmid carrying the desired mutation in the target cell. This plasmid is linearized by in vivo

Christopher D. Herring; Jeremy D. Glasner; Frederick R. Blattner

2003-01-01

154

A novel mutation of coproporphyrinogen oxidase (CPO) gene in a Japanese family  

Microsoft Academic Search

Hereditary coproporphyria (HCP) is an autosomal dominant disease characterized by a deficiency of coproporphyrinogen oxidase\\u000a (CPO). Only 11 mutations of the gene have been reported to date as the mutations responsible for HCP. We report here a novel\\u000a mutation of the gene responsible for the disease in a Japanese family. Analysis of the polymerase chain reaction (PCR) amplified\\u000a DNA fragments

Shinji Susa; Makoto Daimon; Ikuo Yamamori; Masao Kondo; Keiichi Yamatani; Hideo Sasaki; Takeo Kato

1998-01-01

155

A novel gain-of-function mutation of c- kit gene in gastrointestinal stromal tumors  

Microsoft Academic Search

Background & Aims: The c-kit gene encodes a receptor tyrosine kinase (KIT). Recently, we found gain-of-function mutations of the c-kit gene in gastrointestinal stromal tumors (GISTs). All mutations were confined within the 11 amino acids (Lys-550 to Val-560) in the juxtamembrane domain, but one GIST showed a novel deletion-type mutation at codon 579 (Asp) in the juxtamembrane domain. The aim

Masanori Nakahara; Koji Isozaki; Seiichi Hirota; Jun-Ichiro Miyagawa; Naoko Hase-Sawada; Masahiko Taniguchi; Toshirou Nishida; Suji Kanayama; Yukihiko Kitamura; Yasuhisa Shinomura; Yuji Matsuzawa

1998-01-01

156

Mutation analysis of the spastin gene (SPG4) in patients with hereditary spastic paraparesis  

PubMed Central

BACKGROUND—Hereditary spastic paraparesis is a genetically heterogeneous condition. Recently, mutations in the spastin gene were reported in families linked to the common SPG4 locus on chromosome 2p21-22.?OBJECTIVES—To study a population of patients with hereditary spastic paraparesis for mutations in the spastin gene (SPG4) on chromosome 2p21-22.?METHODS—DNA from 32 patients (12 from families known to be linked to SPG4) was analysed for mutations in the spastin gene by single strand conformational polymorphism analysis and sequencing. All patients were also examined clinically.?RESULTS—Thirteen SPG4 mutations were identified, 11 of which are novel. These mutations include missense, nonsense, frameshift, and splice site mutations, the majority of which affect the AAA cassette. We also describe a nucleotide substitution outside this conserved region which appears to behave as a recessive mutation.?CONCLUSIONS—Recurrent mutations in the spastin gene are uncommon. This reduces the ease of mutation detection as a part of the diagnostic work up of patients with hereditary spastic paraparesis. Our findings have important implications for the presumed function of spastin and schemes for mutation detection in HSP patients.???Keywords: spastin; hereditary spastic paraparesis; mutation; recessive PMID:11015453

Lindsey, J; Lusher, M; McDermott, C; White, K; Reid, E; Rubinsztein, D; Bashir, R; Hazan, J; Shaw, P; Bushby, K

2000-01-01

157

Gene Mutation Patterns in Patients with Minimally Differentiated Acute Myeloid Leukemia?  

PubMed Central

Minimally differentiated acute myeloid leukemia (AML-M0) is a rare subtype of AML with poor prognosis. Although genetic alterations are increasingly reported in AML, the gene mutations have not been comprehensively studied in AML-M0. We aimed to examine a wide spectrum of gene mutations in patients with AML-M0 to determine their clinical relevance. Twenty gene mutations including class I, class II, class III of epigenetic regulators (IDH1, IDH2, TET2, DNMT3A, MLL-PTD, ASXL1, and EZH2), and class IV (tumor suppressor genes) were analyzed in 67 patients with AML-M0. Mutational analysis was performed with polymerase chain reaction–based assays followed by direct sequencing. The most frequent gene mutations from our data were FLT3-ITD/FLT3-TKD (28.4%), followed by mutations in IDH1/IDH2 (28.8%), RUNX1 (23.9%), N-RAS/K-RAS (12.3%), TET2 (8.2%), DNMT3A (8.1%), MLL-PTD (7.8%), and ASXL1 (6.3%). Seventy-nine percent (53/67) of patients had at least one gene mutation. Class I genes (49.3%) were the most common mutated genes, which were mutually exclusive. Class III genes of epigenetic regulators were also frequent (43.9%). In multivariate analysis, old age [hazard ratio (HR) 1.029, 95% confidence interval (CI) 1.013-1.044, P = .001) was the independent adverse factor for overall survival, and RUNX1 mutation (HR 2.326, 95% CI 0.978-5.533, P = .056) had a trend toward inferior survival. In conclusion, our study showed a high frequency of FLT3, RUNX1, and IDH mutations in AML-M0, suggesting that these mutations played a role in the pathogenesis and served as potential therapeutic targets in this rare and unfavorable subtype of AML. PMID:25022553

Kao, Hsiao-Wen; Liang, Der-Cherng; Wu, Jin-Hou; Kuo, Ming-Chung; Wang, Po-Nan; Yang, Chao-Ping; Shih, Yu-Shu; Lin, Tung-Huei; Huang, Yu-Hui; Shih, Lee-Yung

2014-01-01

158

Detecting recurrent gene mutation in interaction network context using multi-scale graph diffusion  

PubMed Central

Background Delineating the molecular drivers of cancer, i.e. determining cancer genes and the pathways which they deregulate, is an important challenge in cancer research. In this study, we aim to identify pathways of frequently mutated genes by exploiting their network neighborhood encoded in the protein-protein interaction network. To this end, we introduce a multi-scale diffusion kernel and apply it to a large collection of murine retroviral insertional mutagenesis data. The diffusion strength plays the role of scale parameter, determining the size of the network neighborhood that is taken into account. As a result, in addition to detecting genes with frequent mutations in their genomic vicinity, we find genes that harbor frequent mutations in their interaction network context. Results We identify densely connected components of known and putatively novel cancer genes and demonstrate that they are strongly enriched for cancer related pathways across the diffusion scales. Moreover, the mutations in the clusters exhibit a significant pattern of mutual exclusion, supporting the conjecture that such genes are functionally linked. Using multi-scale diffusion kernel, various infrequently mutated genes are found to harbor significant numbers of mutations in their interaction network neighborhood. Many of them are well-known cancer genes. Conclusions The results demonstrate the importance of defining recurrent mutations while taking into account the interaction network context. Importantly, the putative cancer genes and networks detected in this study are found to be significant at different diffusion scales, confirming the necessity of a multi-scale analysis. PMID:23343428

2013-01-01

159

Three novel mutations of the APC gene in Korean patients with familial adenomatous polyposis.  

PubMed

Germline mutations within the adenomatous polyposis coli (APC) gene are associated with familial adenomatous polyposis (FAP), an autosomal dominant disease predisposing individuals to colorectal cancer. Identification of APC mutations has important implications for genetic counseling and management of FAP patients. We examined the APC mutation status of 10 Korean FAP patients by polymerase chain reaction-direct sequencing method and found six APC mutations, including three novel mutations. Testing for MUTYH mutation was done for FAP patients in whom no mutation in the APC gene was identified. Three novel mutations (c.1654_1663delTCTTGGCGAG, c.3709C>T, and c.6092_6094delinsTT) and three previously reported mutations (c.3631_3632delAT, c.4438C>T, and c.4612_4613delGA) were detected. The MUTYH mutation was not detected in any of the four FAP patients without an APC mutation. This finding of three novel mutations in a group of Korean FAP patients broadens the spectrum of APC mutations. PMID:20513532

Jang, Yun Ha; Lim, Seok-Byung; Kim, Mi-Jung; Chung, Hee-Jung; Yoo, Han-Wook; Byeon, Jeong-Sik; Myung, Seung-Jae; Lee, Woochang; Chun, Sail; Min, Won-Ki

2010-07-01

160

Identification of a novel mutation in the presenilin 1 gene in a Chinese Alzheimer's disease family.  

PubMed

This study has identified a gene mutation in a Chinese family with Alzheimer's disease (AD). Family members were screened by a set of medical examinations and neuropsychological tests. Their DNA was extracted from blood cells and sequenced for gene mutation in the amyloid precursor protein (APP), the presenilin 1 (PS1) and the presenilin 2 (PS2) genes. Genetic analysis showed that the AD patients in the family harbored a T to G missense mutation at the position 314 in exon 4 of the PS1 gene, resulting in a change of F105C in amino acid sequence. Clinical manifestation of these patients included memory loss, counting difficulty, personality change, disorientation, dyscalculia, agnosia, aphasia, and apraxia, which was similar to that of the familial AD (FAD) patients harboring other PS1 mutations. We intend to add a novel mutation F105C of the PS1 gene to the pool of FAD mutations. With the current available genetic data, mutations of the PS1 gene account for the majority of gene mutations in Chinese FAD. PMID:24737487

Deng, Bo; Lian, Yan; Wang, Xin; Zeng, Fan; Jiao, Bin; Wang, Ye-Ran; Liang, Chun-Rong; Liu, Yu-Hui; Bu, Xian-Le; Yao, Xiu-Qing; Zhu, Chi; Shen, Lu; Zhou, Hua-Dong; Zhang, Tao; Wang, Yan-Jiang

2014-10-01

161

Mutations that alter the timing and pattern of cubitus interruptus gene expression in Drosophila melanogaster  

Microsoft Academic Search

The cubitus interruptus (ci) gene is a member of the Drosophila segment polarity gene family and encodes a protein with a zinc finger domain homologous to the vertebrate Gli genes and the nematode tra-1 gene. Three classes of existing mutations in the ci locus alter the regulation of ci expression and can be used to examine ci function during development.

D. C. Slusarski; C. K. Motzny; R. Holmgren

1995-01-01

162

Mutation analysis of Leber congenital amaurosis?associated genes in patients with retinitis pigmentosa.  

PubMed

The genetic defects underlying approximately half of all retinitis pigmentosa (RP) cases are unknown. A number of genes responsible for Leber congenital amaurosis (LCA) may also cause RP when they are mutated. Our previous study revealed that variants in the most frequently mutated nine exons accounted for approximately half of the mutations detected in a cohort of patients with LCA. The aim of the present study was to detect mutations in LCA-associated genes in patients with RP using two different strategies. Sanger sequencing was used to screen mutations in the nine exons in 293 patients with RP and exome sequencing was used to detect variants in 12 LCA-associated genes in 157 of the 293 patients with RP and then to validate the variants by Sanger sequencing. Potential pathogenic mutations were identified in four patients with early onset RP, including homozygous CRB1 mutations in two patients, compound heterozygous CRB1 mutations in one patient and compound heterozygous CEP290 mutations in one patient. The present study indicated that mutations in CEP290 may also be associated with RP but not with LCA. With the exception of CEP290, the remaining 11 genes known to be associated with LCA but not with RP are unlikely to be a common cause of RP. PMID:25377065

Shen, Tao; Guan, Liping; Li, Shiqiang; Zhang, Jianguo; Xiao, Xueshan; Jiang, Hui; Yang, Jianhua; Guo, Xiangming; Wang, Jun; Zhang, Qingjiong

2015-03-01

163

Mutations predisposing to breast cancer in 12 candidate genes in breast cancer patients from Poland.  

PubMed

A number of genes other than BRCA1 and BRCA2 have been associated with breast cancer predisposition, and extended genetic testing panels have been proposed. It is of interest to establish the full spectrum of deleterious mutations in women with familial breast cancer.We performed whole-exome sequencing of 144 women with familial breast cancer and negative for 11 Polish founder mutations in BRCA1, CHEK2 and NBS1, and we evaluated the sequences of 12 known breast cancer susceptibility genes. A truncating mutation in a breast cancer gene was detected in 24 of 144 women (17%) with familial breast cancer. A BRCA2 mutation was detected in 12 cases, a (non-founder) BRCA1 mutation was detected in 5 cases, a PALB2 mutation was detected in 4 cases and an ATM mutation was detected in 2 cases. Polish women with familial breast cancer who are negative for founder mutations in BRCA1, CHEK2 and NBS1 should be fully screened for mutations in BRCA1, BRCA2 and PALB2. The PALB2 founder mutation c.509_519delGA should be included in the panel of Polish founder mutations. PMID:25330149

Cybulski, C; Lubi?ski, J; Woko?orczyk, D; Ku?niak, W; Kashyap, A; Sopik, V; Huzarski, T; Gronwald, J; Byrski, T; Szwiec, M; Jakubowska, A; Górski, B; D?bniak, T; Narod, S A; Akbari, M R

2014-10-20

164

UNSTABLE MUTATIONS IN THE FMR1 GENE AND THE PHENOTYPES  

PubMed Central

Fragile X syndrome (FXS), a severe neurodevelopmental anomaly, and one of the earliest disorders linked to an unstable (‘dynamic’) mutation, is caused by the large (>200) CGG repeat expansions in the noncoding portion of the FMR1 (Fragile X Mental Retardation-1) gene. These expansions, termed full mutations, normally silence this gene's promoter through methylation, leading to a gross deficit of the Fragile X Mental Retardation Protein (FMRP) that is essential for normal brain development. Rare individuals with the expansion but with an unmethylated promoter (and thus, FMRP production), present a much less severe form of FXS. However, a unique feature of the relationship between the different sizes of CGG expanded tract and phenotypic changes is that smaller expansions (<200) generate a series of different clinical manifestations and/or neuropsychological changes. The major part of this chapter is devoted to those FMR1 alleles with small (55-200) CGG expansions, termed ‘premutations’, which have the potential for generating the full mutation alleles on mother-offspring transmission, on the one hand, and are associated with some phenotypic changes, on the other. Thus, the role of several factors known to determine the rate of CGG expansion in the premutation alleles is discussed first. Then, an account of various neurodevelopmental, congnitive, behavioural and physical changes reported in carriers of these small expansions is given, and possible association of these conditions with a toxicity of the elevated FMR1 gene's transcript (mRNA) is discussed. The next two sections are devoted to major and well defined clinical conditions associated with the premutation alleles. The first one is the late onset neurodegenerative disorder termed fragile X-associated tremor ataxia syndrome (FXTAS). The wide range of clinical and neuropsychological manifestations of this syndrome, and their relevance to elevated levels of the FMR1 mRNA, are described. Another distinct disorder linked to the CGG repeat expansions within the premutation range is fragile X-associated primary ovarian insufficiency (FXPOI) in females, and an account of the spectrum of manifestations of this disorder, together with the latest findings suggesting an early onset of the ovarian changes, is given. In the following section, the most recent findings concerning the possible contribution of FMR1 ‘grey zone’ alleles (those with the smallest repeat expansions overlapping with the normal range i.e., 41-54 CGGs), to the psychological and clinical manifestations, already associated with premutation alleles, are discussed. Special emphasis has been placed on the possibility that the modest elevation of ‘toxic’ FMR1 mRNA in the carriers of grey zone alleles may present an additional risk for some neurodegenerative diseases, such as those associated with parkinsonism, by synergizing with either other susceptibility genes or environmental poisons. The present status of the treatment of fragile X-related disorders, especially FXS, is presented in the last section of this chapter. Pharmacological interventions in this syndrome have recently extended beyond stimulants and antipsychotic medications, and the latest trials involving a group of GluR5 antagonists aim to ascertain if these substances have the potential to reverse some of the neurobiological abnormalities of FXS. PMID:23560306

Loesch, Danuta; Hagerman, Randi

2014-01-01

165

Genetic basis of congenital erythrocytosis: mutation update and online databases.  

PubMed

Congenital erythrocytosis (CE), or congenital polycythemia, represents a rare and heterogeneous clinical entity. It is caused by deregulated red blood cell production where erythrocyte overproduction results in elevated hemoglobin and hematocrit levels. Primary congenital familial erythrocytosis is associated with low erythropoietin (Epo) levels and results from mutations in the Epo receptor gene (EPOR). Secondary CE arises from conditions causing tissue hypoxia and results in increased Epo production. These include hemoglobin variants with increased affinity for oxygen (HBB, HBA mutations), decreased production of 2,3-bisphosphoglycerate due to BPGM mutations, or mutations in the genes involved in the hypoxia sensing pathway (VHL, EPAS1, and EGLN1). Depending on the affected gene, CE can be inherited either in an autosomal dominant or recessive mode, with sporadic cases arising de novo. Despite recent important discoveries in the molecular pathogenesis of CE, the molecular causes remain to be identified in about 70% of the patients. With the objective of collecting all the published and unpublished cases of CE the COST action MPN&MPNr-Euronet developed a comprehensive Internet-based database focusing on the registration of clinical history, hematological, biochemical, and molecular data (http://www.erythrocytosis.org/). In addition, unreported mutations are also curated in the corresponding Leiden Open Variation Database. PMID:24115288

Bento, Celeste; Percy, Melanie J; Gardie, Betty; Maia, Tabita Magalhães; van Wijk, Richard; Perrotta, Silverio; Della Ragione, Fulvio; Almeida, Helena; Rossi, Cedric; Girodon, François; Aström, Maria; Neumann, Drorit; Schnittger, Susanne; Landin, Britta; Minkov, Milen; Randi, Maria Luigia; Richard, Stéphane; Casadevall, Nicole; Vainchenker, William; Rives, Susana; Hermouet, Sylvie; Ribeiro, M Leticia; McMullin, Mary Frances; Cario, Holger; Chauveau, Aurelie; Gimenez-Roqueplo, Anne-Paule; Bressac-de-Paillerets, Brigitte; Altindirek, Didem; Lorenzo, Felipe; Lambert, Frederic; Dan, Harlev; Gad-Lapiteau, Sophie; Catarina Oliveira, Ana; Rossi, Cédric; Fraga, Cristina; Taradin, Gennadiy; Martin-Nuñez, Guillermo; Vitória, Helena; Diaz Aguado, Herrera; Palmblad, Jan; Vidán, Julia; Relvas, Luis; Ribeiro, Maria Leticia; Luigi Larocca, Maria; Luigia Randi, Maria; Pedro Silveira, Maria; Percy, Melanie; Gross, Mor; Marques da Costa, Ricardo; Beshara, Soheir; Ben-Ami, Tal; Ugo, Valérie

2014-01-01

166

An Ashkenazi founder mutation in the MSH6 gene leading to HNPCC.  

PubMed

Mutations in DNA mismatch repair genes underlie lynch syndrome (HNPCC). Lynch syndrome resulting from mutations in MSH6 is considered to be attenuated in comparison to that caused by mutations in MLH1 and MSH2, thus more likely to be under diagnosed. In this study we report of a common mutation in the MSH6 gene in Ashkenazi Jews. Genetic counseling and diagnostic work-up for HNPCC was conducted in families who attended the high risk clinic for inherited cancer. We identified the mutation c.3984_3987dup in the MSH6 gene in 19 members of four unrelated Ashkenazi families. This mutation results in truncation of the transcript and in loss of expression of the MSH6 protein in tumors. Tumor spectrum among carriers included colon, endometrial, gastric, ovarian, urinary, and breast cancer. All but one family qualified for the Bethesda guidelines and none fulfilled the Amsterdam Criteria. Members of one family also co-inherited the c.6174delT mutation in the BRCA2 gene. The c.3984_3987dup in the MSH6 gene is a mutation leading to HNPCC among Ashkenazi Jews. This is most probably a founder mutation. In contrast to the c.1906G>C founder mutation in the MSH2 gene, tumors tend to occur later in life, and none of the families qualified for the Amsterdam criteria. c.3984_3987dup is responsible for 1/6 of the mutations identified among Ashkenazi HNPCC families in our cohort. Both mutations: c.3984_3987dup and c.1906G>C account for 61% of HNPCC Ashkenazi families in this cohort. These findings are of great importance for counseling, diagnosis, management and surveillance for Ashkenazi families with Lynch syndrome. PMID:19851887

Goldberg, Yael; Porat, Rinnat M; Kedar, Inbal; Shochat, Chen; Galinsky, Daliah; Hamburger, Tamar; Hubert, Ayala; Strul, Hana; Kariiv, Revital; Ben-Avi, Liat; Savion, Moran; Pikarsky, Eli; Abeliovich, Dvorah; Bercovich, Dani; Lerer, Israela; Peretz, Tamar

2010-06-01

167

De novo mutations in the BMPR2 gene in patients with heritable pulmonary arterial hypertension.  

PubMed

A substantial proportion of patients with pulmonary arterial hypertension (PAH) have mutations in the Bone Morphogenetic Protein Receptor type-2 (BMPR2) gene. PAH due to BMPR2 mutations is inherited as an autosomal dominant trait with several unique features, including a wide variety of mutations, reduced penetrance, a skewed gender ratio, variable expressivity and genetic anticipation. To address the genetic background of these unique features of BMPR2 mutation, we conducted a systematic analysis of 15 PAH families with BMPR2 mutation. The exonic protein coding sequence of BMPR2 was amplified by polymerase chain reaction and the products were sequenced directly to detect point mutations in BMPR2. Parental identification was carried out to confirm the parental relationship using multiplex 15 loci analysis. Combining mutation detection in family members with parental identification, we described three cases of de novo mutation in the BMPR2 gene by different modes in a PAH family. These de novo mutations may account for the wide variety of mutations in BMPR2. Taken together with the juvenile onset of the disease, there is possibly some balance of de novo mutations and untransmittable mutations which keeps the frequency of PAH low in the general population. PMID:25612240

Momose, Yuichi; Aimi, Yuki; Hirayama, Tomomi; Kataoka, Masaharu; Ono, Masae; Yoshino, Hideaki; Satoh, Toru; Gamou, Shinobu

2015-03-01

168

p53 Gene Mutations Occur in Combination with 17p Allelic Deletions as Late Events in Colorectal Tumorigenesis1  

Microsoft Academic Search

Coordinate loss of one copy of the p53 gene and mutation of the remaining copy occur in colorectal carcinomas and in many other human malignancies. However, the prevalence of p53 gene mutations in carci nomas which maintain both parental copies of p53 has not previously been evaluated. Moreover, it is not known whether p53 gene mutations are limited to malignant

Suzanne J. Baker; Antonette C. Preisinger; J. Milburn Jessup; Christos Paraskeva; Sanford Markowitz; J. K. V. Willson; Bert Vogelstein

1990-01-01

169

Polymorphism analysis and new JAG1 gene mutations of Alagille syndrome in Mexican population?  

PubMed Central

Alagille syndrome is a multisystem disorder with an autosomic dominant pattern of inheritance that affects the liver, heart, eyes, kidneys, skeletal system and presents characteristic facial features. Mutations of the JAG1 gene have been identified in 20–89% of the patients with Alagille syndrome, this gene encodes for a ligand that activates the Notch signaling pathway. In the present study we analyzed 9 Mexican patients with Alagille syndrome who presented the clinical criteria for the classical presentation of the disease. By using the denaturing high performance liquid chromatography mutation analysis we were able to identify different mutations in 7 of the patients (77.77%), importantly, we found 5 novel mutations in JAG1 gene. The allelic frequency distribution of 13 polymorphisms in Mexican population is also reported. The overall results demonstrated an expanding mutational spectrum of JAG1 gene in the Mexican population. PMID:25606387

Vázquez-Martínez, Edgar Ricardo; Varela-Fascinetto, Gustavo; García-Delgado, Constanza; Rodríguez-Espino, Benjamín Antonio; Sánchez-Boiso, Adriana; Valencia-Mayoral, Pedro; Heller-Rosseau, Solange; Pelcastre-Luna, Erika Lisselly; Zenteno, Juan C.; Cerbón, Marco; Morán-Barroso, Verónica Fabiola

2013-01-01

170

Polymorphism analysis and new JAG1 gene mutations of Alagille syndrome in Mexican population.  

PubMed

Alagille syndrome is a multisystem disorder with an autosomic dominant pattern of inheritance that affects the liver, heart, eyes, kidneys, skeletal system and presents characteristic facial features. Mutations of the JAG1 gene have been identified in 20-89% of the patients with Alagille syndrome, this gene encodes for a ligand that activates the Notch signaling pathway. In the present study we analyzed 9 Mexican patients with Alagille syndrome who presented the clinical criteria for the classical presentation of the disease. By using the denaturing high performance liquid chromatography mutation analysis we were able to identify different mutations in 7 of the patients (77.77%), importantly, we found 5 novel mutations in JAG1 gene. The allelic frequency distribution of 13 polymorphisms in Mexican population is also reported. The overall results demonstrated an expanding mutational spectrum of JAG1 gene in the Mexican population. PMID:25606387

Vázquez-Martínez, Edgar Ricardo; Varela-Fascinetto, Gustavo; García-Delgado, Constanza; Rodríguez-Espino, Benjamín Antonio; Sánchez-Boiso, Adriana; Valencia-Mayoral, Pedro; Heller-Rosseau, Solange; Pelcastre-Luna, Erika Lisselly; Zenteno, Juan C; Cerbón, Marco; Morán-Barroso, Verónica Fabiola

2014-12-01

171

The presence of MEFV gene mutations in patients with primary osteoarthritis who require surgery  

PubMed Central

Background/Aims Chronic arthritis of familial Mediterranean fever (FMF) involves weight-bearing joints and can occur in patients without a history of acute attack. Our aim was to investigate a possible causal relationship between FMF and osteoarthritis in a population in which FMF is quite common. Methods Patients with late stage primary osteoarthritis were enrolled, and five MEFV gene mutations were investigated. The frequency of MEFV gene mutations was compared among patients with osteoarthritis and a previous healthy group from our center. Results One hundred patients with primary osteoarthritis and 100 healthy controls were studied. The frequency of MEFV gene mutations was significantly lower in the osteoarthritis group (9% vs. 19%). M694V was the most frequent mutation (5%) in the osteoarthritis group, whereas in the control group, E148Q was the most common (16%). In subgroup analyses, the mutation frequency of patients with hip osteoarthritis was not different from that of patients with knee osteoarthritis and controls (7.1%, 9.7%, and 19%, respectively). There were no differences among the three groups with respect to MEFV gene mutations other than E148Q (8.1% vs. 3.6%). E148Q was significantly lower in the osteoarthritis group than in the controls (16% vs. 1%), although the mutations did not differ between patients with knee osteoarthritis and controls. Conclusions In a population with a high prevalence of MEFV gene mutations, we did not find an increased mutation rate in patients with primary osteoarthritis. Furthermore, we found that some mutations were significantly less frequent in patients with osteoarthritis. Although the number of patients studied was insufficient to claim that E148Q gene mutation protects against osteoarthritis, the potential of this gene merits further investigation. PMID:24009456

Erdem, Hakan; Tunay, Servet; Torun, Deniz; Genc, Halil; Tunca, Yusuf; Karadag, Omer; Simsek, Ismail; Bahce, Muhterem; Pay, Salih; Dinc, Ayhan

2013-01-01

172

Software and database for the analysis of mutations in the human FBN1 gene.  

PubMed Central

Fibrillin is the major component of extracellular microfibrils. Mutations in the fibrillin gene on chromosome 15 (FBN1) were described at first in the heritable connective tissue disorder, Marfan syndrome (MFS). More recently, FBN1 has also been shown to harbor mutations related to a spectrum of conditions phenotypically related to MFS and many mutations will have to be accumulated before genotype/phenotype relationships emerge. To facilitate mutational analysis of the FBN1 gene, a software package along with a computerized database (currently listing 63 entries) have been created. PMID:8594563

Collod, G; Béroud, C; Soussi, T; Junien, C; Boileau, C

1996-01-01

173

Novel mutations of PKD genes in the Czech population with autosomal dominant polycystic kidney disease  

PubMed Central

Background Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder caused by mutation in either one of two genes, PKD1 and PKD2. High structural and sequence complexity of PKD genes makes the mutational diagnostics of ADPKD challenging. The present study is the first detailed analysis of both PKD genes in a cohort of Czech patients with ADPKD using High Resolution Melting analysis (HRM) and Multiplex Ligation-dependent Probe Amplification (MLPA). Methods The mutational analysis of PKD genes was performed in a set of 56 unrelated patients. For mutational screening of the PKD1 gene, the long-range PCR (LR-PCR) strategy followed by nested PCR was used. Resulting PCR fragments were analyzed by HRM; the positive cases were reanalyzed and confirmed by direct sequencing. Negative samples were further examined for sequence changes in the PKD2 gene by the method of HRM and for large rearrangements of both PKD1 and PKD2 genes by MLPA. Results Screening of the PKD1 gene revealed 36 different likely pathogenic germline sequence changes in 37 unrelated families/individuals. Twenty-five of these sequence changes were described for the first time. Moreover, a novel large deletion was found within the PKD1 gene in one patient. Via the mutational analysis of the PKD2 gene, two additional likely pathogenic mutations were detected. Conclusions Probable pathogenic mutation was detected in 71% of screened patients. Determination of PKD mutations and their type and localization within corresponding genes could help to assess clinical prognosis of ADPKD patients and has major benefit for prenatal and/or presymptomatic or preimplantational diagnostics in affected families as well. PMID:24694054

2014-01-01

174

EpilepsyGene: a genetic resource for genes and mutations related to epilepsy.  

PubMed

Epilepsy is one of the most prevalent chronic neurological disorders, afflicting about 3.5-6.5 per 1000 children and 10.8 per 1000 elderly people. With intensive effort made during the last two decades, numerous genes and mutations have been published to be associated with the disease. An organized resource integrating and annotating the ever-increasing genetic data will be imperative to acquire a global view of the cutting-edge in epilepsy research. Herein, we developed EpilepsyGene (http://61.152.91.49/EpilepsyGene). It contains cumulative to date 499 genes and 3931 variants associated with 331 clinical phenotypes collected from 818 publications. Furthermore, in-depth data mining was performed to gain insights into the understanding of the data, including functional annotation, gene prioritization, functional analysis of prioritized genes and overlap analysis focusing on the comorbidity. An intuitive web interface to search and browse the diversified genetic data was also developed to facilitate access to the data of interest. In general, EpilepsyGene is designed to be a central genetic database to provide the research community substantial convenience to uncover the genetic basis of epilepsy. PMID:25324312

Ran, Xia; Li, Jinchen; Shao, Qianzhi; Chen, Huiqian; Lin, Zhongdong; Sun, Zhong Sheng; Wu, Jinyu

2015-01-28

175

Investigation of the gene mutations in two Chinese families with X-linked infantile nystagmus  

PubMed Central

Purpose To identify the gene mutations causing X-linked infantile nystagmus in two Chinese families (NYS003 and NYS008), of which the NYS003 family was assigned to the FERM domain–containing 7 (FRMD7) gene linked region in our previous study, and no mutations were found by direct sequencing. Methods Two microsatellites, DXS1047 and DXS1001, were amplified using a PCR reaction for the linkage study in the NYS008 family. FRMD7 was sequenced and mutations were analyzed. Multiplex ligation-dependent probe amplification (MLPA) was used to detect FRMD7 mutations in the NYS003 family. Results The NYS008 family yielded a maximum logarithm of odds (LOD) score of 1.91 at ?=0 with DXS1001. FRMD7 sequencing showed a nucleotide change of c. 623A>G in exon7 of the patients’ FRMD7 gene, which was predicted to result in an H208R amino acid change. This novel mutation was absent in 100 normal Han Chinese controls. No FRMD7 gene mutations were detected by MLPA in the NYS003 family. Conclusions We identified a novel mutation, c. 623A>G (p. H208R), in a Han Chinese family with infantile nystagmus. This mutation expands the mutation spectrum of FRMD7 and contributes to the research on the molecular pathogenesis of FRMD7. PMID:21365021

Li, Ningdong; Wang, Xiaojuan; Wang, Yuchuan; Wang, Liming; Ying, Ming; Han, Ruifang; Liu, Yuyan

2011-01-01

176

Dominant mutations affecting muscle structure in Caenorhabditis elegans that map near the actin gene cluster.  

PubMed

By examining F1 progeny of mutagenized Caenorhabditis elegans larvae, we recovered several dominant mutations which affect muscle structure. Five of these new mutations resulted in phenotypes unlike the previously recognized unc-54 and unc-15 dominant alleles. Mapping studies placed all five mutations in the same small region of linkage group V. Polarized light, fluorescence and electron microscopic studies showed that a prominent feature of the disorganized myofilament lattice is the abnormal placement of thin filaments within the body wall muscle cells. Pharyngeal musculature is also affected by three of the mutations when homozygous. Of the five mutations only three are homozygous viable. All three of these have unusually high intragenic reversion rates either spontaneously (approximately 10(-6)) or after ethyl methanesulfonate mutagenesis (2 X 10(-5)), suggesting that reversion occurs through loss of function mutations. No unlinked suppressor mutations were found. The dominance of the mutations, the effect on thin filaments and the reversion properties suggested that these new dominant mutations lie in a gene or genes specifying a structural component of the thin filament. The positioning of a set of three actin sequences in the same region (Files et al., 1983) led us to speculate that these mutations lie in actin genes. PMID:6527380

Waterston, R H; Hirsh, D; Lane, T R

1984-12-15

177

VCP gene analyses in Japanese patients with sporadic amyotrophic lateral sclerosis identify a new mutation.  

PubMed

Accumulating evidence has proven that mutations in the VCP gene encoding valosin-containing protein (VCP) cause inclusion body myopathy with Paget disease of the bone and frontotemporal dementia. This gene was later found to be causative for amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, occurring typically in elderly persons. We thus sequenced the VCP gene in 75 Japanese patients with sporadic ALS negative for mutations in other genes causative for ALS and found a novel mutation, p.Arg487His, in 1 patient. The newly identified mutant as well as known mutants rendered neuronal cells susceptible to oxidative stress. The presence of the mutation in the Japanese population extends the geographic region for involvement of the VCP gene in sporadic ALS to East Asia. PMID:25457024

Hirano, Makito; Nakamura, Yusaku; Saigoh, Kazumasa; Sakamoto, Hikaru; Ueno, Shuichi; Isono, Chiharu; Mitsui, Yoshiyuki; Kusunoki, Susumu

2014-10-16

178

Two cases of Wiskott-Aldrich syndrome in neonates due to gene mutations.  

PubMed

Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia and immune deficiency. WAS gene mutations impair WAS protein function which cause WAS. The WAS-related disorders of X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN) may have similar but less severe symptoms those are also caused by mutations of the same gene. We present two cases of WAS in neonates with WAS gene mutations. Early genetic diagnosis can help to the treatment and prevention this disease. PMID:23301916

Zhang, Shulian; Zhang, Rong; Chen, Chao; Sun, Jinqiao

2013-07-01

179

Software and database for the analysis of mutations in the human LDL receptor gene.  

PubMed Central

The low-density lipoprotein receptor (LDLr) plays a pivotal role in cholesterol homeostasis. Mutations in the LDLr gene (LDLR), which is located on chromosome 19, cause familial hypercholesterolemia (FH), an autosomal dominant disorder characterized by severe hypercholesterolemia associated with premature coronary atherosclerosis. To date almost 300 mutations have been identified in the LDLR gene. To facilitate the mutational analysis of the LDLR gene, and promote the analysis of the relationship between genotype and phenotype, a software package along with a computerized database (currently listing 210 entries) have been created. PMID:9016531

Varret, M; Rabès, J P; Collod-Béroud, G; Junien, C; Boileau, C; Béroud, C

1997-01-01

180

BMPR2 gene mutation in pulmonary arteriovenous malformation and pulmonary hypertension: a case report.  

PubMed

The transforming growth factor-? superfamily signaling pathway is thought to be involved in the pathogenesis of pulmonary arteriovenous malformation (PAVM). However, the association between bone morphogenetic protein receptor type 2 (BMPR2) gene mutations and PAVM remains unclear. We present a case of concurrent PAVM and pulmonary arterial hypertension (PAH), with a deletion mutation in exon 6 and exon 7 of the BMPR2 gene. Drug treatment for PAH improved the patient's hemodynamics and exercise capacity, but worsened oxygenation. This case suggests that BMPR2 gene mutation may be associated with the complex presentation of PAVM combined with PAH. PMID:24853021

Handa, Tomohiro; Okano, Yoshiaki; Nakanishi, Norifumi; Morisaki, Takayuki; Morisaki, Hiroko; Mishima, Michiaki

2014-05-01

181

Mutations in the Cystic Fibrosis Transmembrane Regulator Gene and In Vivo Transepithelial Potentials  

PubMed Central

Aim: To examine the relationship between cystic fibrosis transmembrane regulator gene mutations (CFTR) and in vivo transepithelial potentials. Methods: We prospectively evaluated 162 men including 31 healthy subjects, 21 obligate heterozygotes, 60 with congenital bilateral absence of the vas deferens (CBAVD) and 50 with CF by extensive CFTR genotyping, sweat chloride and nasal potential difference testing. Results: Six (10%) men with CBAVD carried no CFTR mutations, 18 (30%) carried one mutation, including the 5T variant, and 36 (60%) carried mutations on both alleles, for a significantly higher rate carrying one or more mutations than healthy controls (90% versus 19%, p < 0.001). There was an overlapping spectrum of ion channel measurements among the men with CBAVD, ranging from values in the control and obligate heterozygote range at one extreme, to values in the CF range at the other. All pancreatic-sufficient patients with CF and 34 of 36 patients with CBAVD with mutations on both alleles carried at least one mild mutation. However, the distribution of mild mutations in the two groups differed greatly. Genotyping, sweat chloride and nasal potential difference (alone or in combination) excluded CF in all CBAVD men with no mutations. CF was confirmed in 56% and 67% of CBAVD men carrying 1 and 2 CFTR mutations, respectively. Conclusion: Abnormalities of CFTR transepithelial function correlate with the number and severity of CFTR gene mutations. PMID:16840743

Wilschanski, Michael; Dupuis, Annie; Ellis, Lynda; Jarvi, Keith; Zielenski, Julian; Tullis, Elizabeth; Martin, Sheelagh; Corey, Mary; Tsui, Lap-Chee; Durie, Peter

2006-01-01

182

Clinical Significance of a Point Mutation in DNA Polymerase Beta (POLB) Gene in Gastric Cancer  

PubMed Central

Gastric cancer (GC) is a major cause of global cancer mortality. Genetic variations in DNA repair genes can modulate DNA repair capability and, consequently, have been associated with risk of developing cancer. We have previously identified a T to C point mutation at nucleotide 889 (T889C) in DNA polymerase beta (POLB) gene, a key enzyme involved in base excision repair in primary GCs. The purpose of this study was to evaluate the mutation and expression of POLB in a larger cohort and to identify possible prognostic roles of the POLB alterations in GC. Primary GC specimens and their matched normal adjacent tissues were collected at the time of surgery. DNA, RNA and protein samples were isolated from GC specimens and cell lines. Mutations were detected by PCR-RFLP/DHPLC and sequencing analysis. POLB gene expression was examined by RT-PCR, tissue microarray, Western blotting and immunofluorescence assays. The function of the mutation was evaluated by chemosensitivity, MTT, Transwell matrigel invasion and host cell reactivation assays. The T889C mutation was detected in 18 (10.17%) of 177 GC patients. And the T889C mutation was associated with POLB overexpression, lymph nodes metastases and poor tumor differentiation. In addition, patients with- the mutation had significantly shorter survival time than those without-, following postoperative chemotherapy. Furthermore, cell lines with T889C mutation in POLB gene were more resistant to the treatment of 5-fluorouracil, cisplatin and epirubicin than those with wild type POLB. Forced expression of POLB gene with T889C mutation resulted in enhanced cell proliferation, invasion and resistance to anticancer drugs, along with increased DNA repair capability. These results suggest that POLB gene with T889C mutation in surgically resected primary gastric tissues may be clinically useful for predicting responsiveness to chemotherapy in patients with GC. The POLB gene alteration may serve as a prognostic biomarker for GC.

Tan, Xiaohui; Wang, Hongyi; Luo, Guangbin; Ren, Shuyang; Li, Wenmei; Cui, Jiantao; Gill, Harindarpal S.; Fu, Sidney W.; Lu, Youyong

2015-01-01

183

Remarkable difference of somatic mutation patterns between oncogenes and tumor suppressor genes.  

PubMed

Cancers arise owing to mutations that confer selective growth advantages on the cells in a subset of tumor suppressor and/or oncogenes. To understand oncogenesis and diagnose cancers, it is crucial to discriminate these two groups of genes by using the difference in their mutation patterns. Here, we investigated>120,000 mutation samples in 66 well-known tumor suppressor genes and oncogenes of the COSMIC database, and found a set of significant differences in mutation patterns (e.g., non-3n-indel, non-sense SNP and mutation hotspot) between them. By screening the best measurement, we developed indices to readily distinguish one from another and predict clearly the unknown oncogenesis genes as tumor suppressors (e.g., ASXL1, HNF1A and KDM6A) or oncogenes (e.g., FOXL2, MYD88 and TSHR). Based on our results, a third gene group can be classified, which has a mutational pattern between tumor suppressors and oncogenes. The concept of the third gene group could help to understand gene function in different cancers or individual patients and to know the exact function of genes in oncogenesis. In conclusion, our study provides further insights into cancer-related genes and identifies several potential therapeutic targets. PMID:21887471

Liu, Haoxuan; Xing, Yuhang; Yang, Sihai; Tian, Dacheng

2011-12-01

184

Hybrid curation of gene–mutation relations combining automated extraction and crowdsourcing  

PubMed Central

Background: This article describes capture of biological information using a hybrid approach that combines natural language processing to extract biological entities and crowdsourcing with annotators recruited via Amazon Mechanical Turk to judge correctness of candidate biological relations. These techniques were applied to extract gene– mutation relations from biomedical abstracts with the goal of supporting production scale capture of gene–mutation–disease findings as an open source resource for personalized medicine. Results: The hybrid system could be configured to provide good performance for gene–mutation extraction (precision ?82%; recall ?70% against an expert-generated gold standard) at a cost of $0.76 per abstract. This demonstrates that crowd labor platforms such as Amazon Mechanical Turk can be used to recruit quality annotators, even in an application requiring subject matter expertise; aggregated Turker judgments for gene–mutation relations exceeded 90% accuracy. Over half of the precision errors were due to mismatches against the gold standard hidden from annotator view (e.g. incorrect EntrezGene identifier or incorrect mutation position extracted), or incomplete task instructions (e.g. the need to exclude nonhuman mutations). Conclusions: The hybrid curation model provides a readily scalable cost-effective approach to curation, particularly if coupled with expert human review to filter precision errors. We plan to generalize the framework and make it available as open source software. Database URL: http://www.mitre.org/publications/technical-papers/hybrid-curation-of-gene-mutation-relations-combining-automated PMID:25246425

Burger, John D.; Doughty, Emily; Khare, Ritu; Wei, Chih-Hsuan; Mishra, Rajashree; Aberdeen, John; Tresner-Kirsch, David; Wellner, Ben; Kann, Maricel G.; Lu, Zhiyong; Hirschman, Lynette

2014-01-01

185

Novel ABCC8 (SUR1) gene mutations in Asian Indian children with congenital hyperinsulinemic hypoglycemia.  

PubMed

Congenital hyperinsulinemic hypoglycemia (HI) is a heterogeneous genetic disorder of insulin secretion characterized by persistent hypoglycemia, most commonly associated with inactivating mutations of the ?-cell ATP-sensitive K(+) channel (K(ATP) channel) genes ABCC8 (encoding SUR1) and KCNJ11(encoding Kir6.2). This study aimed to screen the mutations in the genes associated with congenital HI in Asian Indian children. Recessive mutations of these genes cause hyperinsulinism that is unresponsive to treatment with channel agonists like diazoxide. Dominant K(ATP) mutations have been associated with diazoxide-responsive disease. The KCNJ11, ABCC8, GCK, HNF4A, and GLUD1 genes were analyzed by sequence analysis in 22 children with congenital HI. We found 10 novel mutations (c.1delA, c.61delG, c.267delT, c.619-629delCCCGAGGACCT, Gln444*, Leu724Pro, Ala847Thr, Trp898*, IVS30-2A>C, and Leu1454Arg) and two known mutations (Gly111Arg and Arg598*) in the ABCC8 gene. This study describes novel and known ABCC8 gene mutations in children with congenital HI. This is the first large genetic screening study on HI in India and our results will help clinicians in providing optimal treatment for patients with hyperinsulinemia and in assisting affected families with genetic counseling. PMID:25117148

Jahnavi, Suresh; Poovazhagi, Varadarajan; Kanthimathi, Sekar; Balamurugan, Kandasamy; Bodhini, Dhanasekaran; Yadav, Jaivinder; Jain, Vandana; Khadgawat, Rajesh; Sikdar, Mahuya; Bhavatharini, Ayurchelvan; Das, Ashok Kumar; Kaur, Tanvir; Mohan, Viswanathan; Radha, Venkatesan

2014-09-01

186

DNA repair genes are selectively mutated in diffuse large B cell lymphomas  

PubMed Central

DNA repair mechanisms are fundamental for B cell development, which relies on the somatic diversification of the immunoglobulin genes by V(D)J recombination, somatic hypermutation, and class switch recombination. Their failure is postulated to promote genomic instability and malignant transformation in B cells. By performing targeted sequencing of 73 key DNA repair genes in 29 B cell lymphoma samples, somatic and germline mutations were identified in various DNA repair pathways, mainly in diffuse large B cell lymphomas (DLBCLs). Mutations in mismatch repair genes (EXO1, MSH2, and MSH6) were associated with microsatellite instability, increased number of somatic insertions/deletions, and altered mutation signatures in tumors. Somatic mutations in nonhomologous end-joining (NHEJ) genes (DCLRE1C/ARTEMIS, PRKDC/DNA-PKcs, XRCC5/KU80, and XRCC6/KU70) were identified in four DLBCL tumors and cytogenetic analyses revealed that translocations involving the immunoglobulin-heavy chain locus occurred exclusively in NHEJ-mutated samples. The novel mutation targets, CHEK2 and PARP1, were further screened in expanded DLBCL cohorts, and somatic as well as novel and rare germline mutations were identified in 8 and 5% of analyzed tumors, respectively. By correlating defects in a subset of DNA damage response and repair genes with genomic instability events in tumors, we propose that these genes play a role in DLBCL lymphomagenesis. PMID:23960188

de Miranda, Noel FCC; Peng, Roujun; Georgiou, Konstantinos; Wu, Chenglin; Sörqvist, Elin Falk; Berglund, Mattias; Chen, Longyun; Gao, Zhibo; Lagerstedt, Kristina; Lisboa, Susana; Roos, Fredrik; van Wezel, Tom; Teixeira, Manuel R.; Rosenquist, Richard; Sundström, Christer; Enblad, Gunilla; Nilsson, Mats; Zeng, Yixin; Kipling, David

2013-01-01

187

Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene  

Microsoft Academic Search

Induction of testis development in mammals requires the presence of the Y-chromosome gene SPY. This gene must exert its effect by interacting with other genes in the sex-determination pathway. Cloning of a translocation chromosome breakpoint from a sex-reversed patient with campomelic dysplasia, followed by mutation analysis of an adjacent gene, indicates that SOX9, an SRY-related gene, is involved in both

Jamie W. Foster; Marina A. Dominguez-Steglich; Silvana Guioli; Cheni Kwok; Polly A. Weller; Milena Stevanovic; Jean Weissenbach; Sahar Mansour; Ian D. Young; Peter N. Goodfellow; J. David Brook; Alan J. Schafer

1994-01-01

188

A Japanese case with Frasier syndrome caused by the splice junction mutation of WT1 gene.  

PubMed

The Wilms' tumor suppressor gene, WT1, plays an important role in the development of the urogenital system and also subsequent normal function of this system. Recently, the splice mutations in intron 9 of WT1 gene have been detected in Frasier syndrome, which is characterized by streak gonads, pseudohermaphroditism, slowly progressive nephropathy and frequent development of gonadoblastoma. Here to elucidate the molecular basis in a Japanese patient of Frasier syndrome, WT1 gene was analyzed by polymerase-chain-reaction (PCR) and direct sequencing. We identified the splice junction mutation in intron 9 of WT1, which is recognized as a mutation hot-spot in intron 9. This finding concludes that 1) the mutation in intron 9 might be the cause of Frasier syndrome, and 2) the mutation hot-spot in Japanese and Caucasian patients is similar. PMID:10670748

Okuhara, K; Tajima, S; Nakae, J; Sasaki, S; Tochimaru, H; Abe, S; Fujieda, K

1999-10-01

189

[Identification of mutation and polymorphic changes in the CFTR gene of patients with obstructive azoospermia].  

PubMed

Obstructive azoospermia is one of the symptoms of congenital bilateral absence of the vas deferens (CBAVD)--disease which is suggested as primarily genital form of cystic fibrosis. CBAVD is a result of mutations and polymorphisms in CFTR gene. We studied 9 the most common mutations and identified 3 mutations (delta F508, R117H, G542X). The study showed that: 37.1% of CBAVD patients (13 out of 35 examined patients) carried mutations in a single or both copies of the gene. We also found the increased frequency of IVS8-5T allele in this group. No increased frequency of mutations in CFTR gene was found in group of men with incorrect spermatogenesis. PMID:11247407

Sobczy?ska-Tomaszewska, A; Wolski, J K; Bal, J

2000-01-01

190

Mutations of the CYP1B1 gene in congenital anterior staphylomas  

PubMed Central

Purpose Here, we present two patients with congenital anterior staphyloma, with mutations in the CYP1B1 gene. Methods We reviewed the medical records, including the genetic analysis. Results Two unrelated patients presented with congenital anterior staphylomas. Both patients showed mutations in the CYP1B1 gene. The first patient, the product of a consanguineous marriage, showed a homozygous misssense mutation g.3987G>A (p.G61E). The second patient had compound heterozygous misssense mutations [g.4160 G>T (p.A119S) and g.8131 C>G (p.L432V)]. Conclusion CYP1B1 gene mutation may be associated with congenital anterior staphylomas. PMID:24591815

Al Judaibi, Ramzi; Abu-Amero, Khaled K; Morales, Jose; Al Shahwan, Sami; Edward, Deepak P

2014-01-01

191

Identification of a novel mutation of the CPO gene in a Japanese hereditary coproporphyria family.  

PubMed

Hereditary coproporphyria (HCP) is an autosomal dominant disease characterized by a deficiency of coproporphyrinogen oxidase (CPO) caused by a mutation in the CPO gene. Only 11 mutations of the gene have been reported in HCP patients. We report another mutation in a Japanese family. Polymerase chain reaction-single strand conformational polymorphism and direct sequence analyses demonstrated a C to T substitution in exon 1 of the CPO gene at nucleotide position 85, which lies in the putative presequence for targeting to mitochondria. This mutation changes the codon for glutamine to a termination codon at amino acid position 29. MaeI restriction analysis showed two other carriers in the family. The C-T mutation is located within a recently proposed putative alternative translation initiation codon (TIC-1), supporting that TIC-1 is the real TIC rather than TIC-2. PMID:9843038

Susa, S; Daimon, M; Kondo, H; Kondo, M; Yamatani, K; Sasaki, H

1998-11-16

192

Mutation analysis of the G4.5 gene in patients with isolated left ventricular noncompaction  

Microsoft Academic Search

Mutations in the gene G4.5, originally associated with Barth syndrome, have been reported to result in a wide spectrum of severe infantile X-linked cardiomyopathies. The purpose of this study was to investigate patients with isolated left ventricular noncompaction (LVNC) for disease-causing mutations in G4.5. In 27 patients including 10 families with isolated LVNC, mutation analysis of G4.5 was performed using

Rui Chen; Tohru Tsuji; Fukiko Ichida; Karla R Bowles; Xianyi Yu; Sayaka Watanabe; Keiichi Hirono; Shinichi Tsubata; Yuji Hamamichi; Jun Ohta; Yasuharu Imai; Neil E Bowles; Toshio Miyawaki; Jeffrey A Towbin

2002-01-01

193

A Differential Wiring Analysis of Expression Data Correctly Identifies the Gene Containing the Causal Mutation  

Microsoft Academic Search

Transcription factor (TF) regulation is often post-translational. TF modifications such as reversible phosphorylation and missense mutations, which can act independent of TF expression level, are overlooked by differential expression analysis. Using bovine Piedmontese myostatin mutants as proof-of-concept, we propose a new algorithm that correctly identifies the gene containing the causal mutation from microarray data alone. The myostatin mutation releases the

Nicholas J. Hudson; Antonio Reverter; Brian P. Dalrymple

2009-01-01

194

Two mismatch repair gene mutations found in a colon cancer patient - which one is pathogenic?  

Microsoft Academic Search

Hereditary nonpolyposis colorectal cancer (HNPCC) is a dominantly inherited cancer syndrome. Germline mutations in five different mismatch repair (MMR) genes, MSH2, MSH6, MLH1, MLH3, and PMS2 are linked to HNPCC. Here, we describe two colon cancer families in which the index patients carry missense mutations in both MSH2 and MSH6. The MSH2 mutation, I145M, is the same in both families,

Reetta Kariola; Robyn Otway; Karin E. Lönnqvist; Tiina E. Raevaara; Finlay Macrae; Yvonne J. Vos; Maija Kohonen-Corish; Robert M. Hofstra; Minna Nyström-Lahti

2003-01-01

195

Mutational analysis of the NPHP4 gene in 250 patients with nephronophthisis.  

PubMed

Nephronophthisis (NPH), a recessive cystic kidney disease, is the most frequent genetic cause for end-stage renal disease in the first two decades of life. Mutations in three genes (NPHP1, 2, and 3) were identified as causative. Extrarenal manifestations are known, such as retinitis pigmentosa (Senior-Loken syndrome, SLS) and ocular motor apraxia type Cogan. Recently, we identified a novel gene (NPHP4) as mutated in NPH. To date, a total of only 13 different NPHP4 mutations have been described. To determine the frequency of NPHP4 mutations, we performed mutational analysis by direct sequencing of all 30 NPHP4 exons in 250 different patients with isolated NPH, SLS, or Cogan syndrome ascertained worldwide over 14 years. We identified 23 novel NPHP4 sequence variants in 26/250 different patients (10%). Interestingly, we detected homozygous or compound heterozygous mutations of NPHP4 in only 6/250 different patients (2.4%), but only one heterozygous NPHP4 sequence variant in 20/250 different patients (8%). In the six patients with two NPHP4 mutations, 5/8 mutations (63%) were likely loss-of-function mutations, whereas in the 20 patients with only one sequence variant, only 1/20 (5%) was a likely loss-of-function (i.e., truncating) mutation. We conclude that: i) two recessive mutations in NPHP4 are a rare cause of nephronophthisis; ii) single heterozygous NPHP4 sequence variants are three times more prevalent than two recessive mutations; iii) there is no genotype/phenotype correlation; iv) there must exist further genes causing nephronophthisis, since in 224/250 (90%) patients, no sequence variants in either of the four NPH genes were detected. PMID:15776426

Hoefele, Julia; Sudbrak, Ralf; Reinhardt, Richard; Lehrack, Silvia; Hennig, Steffen; Imm, Anita; Muerb, Ulla; Utsch, Boris; Attanasio, Massimo; O'Toole, John F; Otto, Edgar; Hildebrandt, Friedhelm

2005-04-01

196

Characterization of phenylalanine hydroxylase gene mutations in phenylketonuria in Xinjiang of China.  

PubMed

To investigate the spectrum and frequency of phenylalanine hydroxylase (PAH) gene mutations in phenylketonuria (PKU) patients in Xinjiang, China. Polymerase chain reaction (PCR), in combination with single-strand conformation polymorphism (SSCP) and DNA sequencing analyses were performed, to screen potential mutations in the PAH gene in 46 individual PKU patients. Direct DNA sequencing was used to analyze the all of the exons in the PAH gene, including the promoter and flanking intron regions, in another 15 PKU patients. Our results indicated that, 30 different mutation types were identified in all 122 PAH alleles, with the mutation detection rate of 78.7% (96/122). Four novel mutations, i.e., 5'-Flanking -626G>A, 5'-Flanking -480DelACT, S196fsX4, and IVS8+1G>C, were identified for the first time. Similar to other regions in North China, R243Q, EX6-96A>G, IVS4-1A>G, R111X, and Y356X were the most prevalent PAH mutations in PKU patients from Xinjiang. Additionally, common mutations showed different frequencies in Xinjiang, when compared to other areas. Furthermore, sixteen different PAH gene mutation types were identified for the first time in the minorities in Xinjiang. Distinctive mutation spectrum of PAH gene in PKU patients from Xinjiang were characterized, which may promote the construction of PAH gene mutation database and serve as valuable tools for genetic diagnosis and counseling, and prognostic evaluation for PKU cases in the local area. PMID:25550961

Yu, Wuzhong; He, Jiang; Yang, Xi; Zou, Hongyun; Gui, Junhao; Wang, Rui; Yang, Liu; Wang, Zheng; Lei, Quan

2014-01-01

197

Characterization of phenylalanine hydroxylase gene mutations in phenylketonuria in Xinjiang of China  

PubMed Central

To investigate the spectrum and frequency of phenylalanine hydroxylase (PAH) gene mutations in phenylketonuria (PKU) patients in Xinjiang, China. Polymerase chain reaction (PCR), in combination with single-strand conformation polymorphism (SSCP) and DNA sequencing analyses were performed, to screen potential mutations in the PAH gene in 46 individual PKU patients. Direct DNA sequencing was used to analyze the all of the exons in the PAH gene, including the promoter and flanking intron regions, in another 15 PKU patients. Our results indicated that, 30 different mutation types were identified in all 122 PAH alleles, with the mutation detection rate of 78.7% (96/122). Four novel mutations, i.e., 5’-Flanking -626G>A, 5’-Flanking -480DelACT, S196fsX4, and IVS8+1G>C, were identified for the first time. Similar to other regions in North China, R243Q, EX6-96A>G, IVS4-1A>G, R111X, and Y356X were the most prevalent PAH mutations in PKU patients from Xinjiang. Additionally, common mutations showed different frequencies in Xinjiang, when compared to other areas. Furthermore, sixteen different PAH gene mutation types were identified for the first time in the minorities in Xinjiang. Distinctive mutation spectrum of PAH gene in PKU patients from Xinjiang were characterized, which may promote the construction of PAH gene mutation database and serve as valuable tools for genetic diagnosis and counseling, and prognostic evaluation for PKU cases in the local area.

Yu, Wuzhong; He, Jiang; Yang, Xi; Zou, Hongyun; Gui, Junhao; Wang, Rui; Yang, Liu; Wang, Zheng; Lei, Quan

2014-01-01

198

Mutations in planar cell polarity gene SCRIB are associated with spina bifida.  

PubMed

Neural tube defects (NTDs) (OMIM #182940) including anencephaly, spina bifida and craniorachischisis, are severe congenital malformations that affect 0.5-1 in 1,000 live births in the United States, with varying prevalence around the world. Mutations in planar cell polarity (PCP) genes are believed to cause a variety of NTDs in both mice and humans. SCRIB is a PCP-associated gene. Mice that are homozygous for the Scrib p.I285K and circletail (Crc) mutations, present with the most severe form of NTDs, namely craniorachischisis. A recent study reported that mutations in SCRIB were associated with craniorachischisis in humans, but whether SCRIB mutations contribute to increased spina bifida risk is still unknown. We sequenced the SCRIB gene in 192 infants with spina bifida and 190 healthy controls. Among the spina bifida patients, we identified five novel missense mutations that were predicted-to-be-deleterious by the PolyPhen software. Of these five mutations, three of them (p.P1043L, p.P1332L, p.L1520R) significantly affected the subcellular localization of SCRIB. In addition, we demonstrated that the craniorachischisis mouse line-90 mutation I285K, also affected SCRIB subcellular localization. In contrast, only one novel missense mutation (p.A1257T) was detected in control samples, and it was predicted to be benign. This study demonstrated that rare deleterious mutations of SCRIB may contribute to the multifactorial risk for human spina bifida. PMID:23922697

Lei, Yunping; Zhu, Huiping; Duhon, Cody; Yang, Wei; Ross, M Elizabeth; Shaw, Gary M; Finnell, Richard H

2013-01-01

199

Relation of Gene Expression Phenotype to Immunoglobulin Mutation Genotype in B Cell Chronic Lymphocytic Leukemia  

Microsoft Academic Search

The most common human leukemia is B cell chronic lymphocytic leukemia (CLL), a malig- nancy of mature B cells with a characteristic clinical presentation but a variable clinical course. The rearranged immunoglobulin (Ig) genes of CLL cells may be either germ-line in sequence or somatically mutated. Lack of Ig mutations defined a distinctly worse prognostic group of CLL patients raising

Andreas Rosenwald; Ash A. Alizadeh; George Widhopf; Richard Simon; R. Eric Davis; Xin Yu; Liming Yang; Oxana K. Pickeral; Laura Z. Rassenti; John Powell; David Botstein; John C. Byrd; Michael R. Grever; Bruce D. Cheson; Nicholas Chiorazzi; Wyndham H. Wilson; Thomas J. Kipps; Patrick O. Brown; Louis M. Staudt

2001-01-01

200

A mutation in CTSK gene in an autosomal recessive pycnodysostosis family of Pakistani origin  

Microsoft Academic Search

BACKGROUND: Pycnodysostosis is a rare autosomal recessive skeletal dysplasia characterized by short stature, osteosclerosis, acro-osteolysis, frequent fractures and skull deformities. Mutations in the gene encoding cathepsin K (CTSK), a lysosomal cysteine protease, have been found to be responsible for this disease. OBJECTIVES: To identify pathogenic mutation in a consanguineous Pakistani family with 3 affected individuals demonstrating autosomal recessive pycnodysostosis. METHODS:

Muhammad Naeem; Sabeen Sheikh; Wasim Ahmad

2009-01-01

201

Mutational hot spot in the p53 gene in human hepatocellular carcinomas  

Microsoft Academic Search

HUMAN hepatocellular carcinomas (HCC) from patients in Qidong, an area of high incidence in China, in which both hepatitis B virus and aflatoxin B1 are risk factors1, were analysed for mutations in p53, a putative tumour-suppressor gene. Eight of the 16 HCC had a point mutation at the third base position of codon 249. The G --> T transversion in

I. C. Hsu; R. A. Metcalf; T. Sun; J. A. Welsh; N. J. Wang; C. C. Harris

1991-01-01

202

Osteogenesis imperfecta without features of type V caused by a mutation in the IFITM5 gene  

PubMed Central

Osteogenesis imperfecta (OI) is typically caused by mutations in type 1 collagen genes, but in recent years new recessive and dominant forms caused by mutations in a plethora of different genes have been characterized. OI type V is a dominant form caused by the recurrent (c.-14C>T) mutation in the 5?UTR of the IFITM5 gene. The mutation adds 5 residues to the N-terminus of the IFITM5 but the pathophysiology of the disease still remains to be elucidated. Typical clinical features present in the majority of OI type V patients include interosseous membrane calcification between the radius and ulna, and the tibia and fibula, radial head dislocation and significant hyperplastic callus formation at the site of fractures. We report a 5 year-old child with clinical features of OI type III or severe OI type IV (characteristic facies, grey sclerae, typical fractures) and absence of classical features of OI type V with a de novo recurrent IFITM5 mutation (c.-14C>T), now typical of OI type V. This highlights the variability of OI caused by IFITM5 mutations and suggests screening for mutations in this gene in most cases of OI where type 1 collagen mutations are absent. PMID:23674381

Grover, Monica; Campeau, Philippe M.; Lietman, Caressa Dee; Lu, James T.; Gibbs, Richard A.; Schlesinger, Alan E.; Lee, Brendan H.

2013-01-01

203

p53 gene mutations in rectal cancer associated with schistosomiasis japonica in Chinese patients  

Microsoft Academic Search

Mutations in p53 tumor suppressor gene were examined in 44 Chinese patients with rectal cancer, including 22 cases with advanced schistosomiasis japonica and 22 cases without schistosomiasis. In schistosomal rectal cancer (SRC), 13 mutations were found in 10 cases, which included 11 base-pair substitutions and two deletions. Of 11 base substitutions, nine were transitions and two were transversions and seven

Renli Zhang; Satoru Takahashi; Shin-ichiro Orita; Ayako Yoshida; Haruhiko Maruyama; Tomoyuki Shirai; Nobuo Ohta

1998-01-01

204

Mutation frequencies of Xlinked mental retardation genes in families from the EuroMRX consortium.  

E-print Network

Mutation frequencies of Xlinked mental retardation genes in families from the EuroMRX consortium Xlinked mental retardation (XLMR). After exclusion of Fragile X (Fra X) syndrome, probands from carriers, the mental retardation phenotype could be explained by a mutation. There was no difference

Institut des Sciences Cognitives, CNRS

205

Mutation patterns of 16 genes in primary and secondary acute myeloid leukemia (AML) with normal cytogenetics.  

PubMed

Acute myeloid leukemia patients with normal cytogenetics (CN-AML) account for almost half of AML cases. We aimed to study the frequency and relationship of a wide range of genes previously reported as mutated in AML (ASXL1, NPM1, FLT3, TET2, IDH1/2, RUNX1, DNMT3A, NRAS, JAK2, WT1, CBL, SF3B1, TP53, KRAS and MPL) in a series of 84 CN-AML cases. The most frequently mutated genes in primary cases were NPM1 (60.8%) and FLT3 (50.0%), and in secondary cases ASXL1 (48.5%) and TET2 (30.3%). We showed that 85% of CN-AML patients have mutations in at least one of ASXL1, NPM1, FLT3, TET2, IDH1/2 and/or RUNX1. Serial samples from 19 MDS/CMML cases that progressed to AML were analyzed for ASXL1/TET2/IDH1/2 mutations; seventeen cases presented mutations of at least one of these genes. However, there was no consistent pattern in mutation acquisition during disease progression. This report concerns the analysis of the largest number of gene mutations in CN-AML studied to date, and provides insight into the mutational profile of CN-AML. PMID:22912701

Fernandez-Mercado, Marta; Yip, Bon Ham; Pellagatti, Andrea; Davies, Carwyn; Larrayoz, María José; Kondo, Toshinori; Pérez, Cristina; Killick, Sally; McDonald, Emma-Jane; Odero, María Dolores; Agirre, Xabier; Prósper, Felipe; Calasanz, María José; Wainscoat, James S; Boultwood, Jacqueline

2012-01-01

206

Buxbaum et al. 1 Mutation screening of the PTEN gene in patients with autism spectrum  

E-print Network

Buxbaum et al. 1 Mutation screening of the PTEN gene in patients with autism spectrum disorders, New York, USA 2 Department of Psychiatry and Seaver Autism Research Center, Mount Sinai School: PTEN mutation screening in autism HALauthormanuscriptinserm-00125293,version1 HAL author manuscript

207

RESEARCH ARTICLE Open Access Germline mutation in the RAD51B gene confers  

E-print Network

, and BRIP1 and PALB2, associated with a moderate risk [7-9]. While breast cancer predisposition is conferred by mono-allelic germline mutations in these genes, bi-allelic germline mutations in BRCA2, BRIP1 and PALB2

Paris-Sud XI, Université de

208

Interactions between cut wing mutations and mutations in zeste , and the enhancer of yellow and Polycomb group genes of Drosophila melanogaster  

Microsoft Academic Search

The phenotypic expression of several mutations in thecut locus ofDrosophila melanogaster is modified by mutations in thezeste, e(y)2 ande(y)3 genes and in some genes of thePolycomb group. All tested sensitivecut mutations have a partially inactivated cut wing enhancer.e(y)3ul, zv77h andSu(z)25 mutations enhance, whilee(y)2ul, zOp6, Psc1, Su(z)301, Su(z)302 andScmD1 mutations suppress the ct mutant phenotype. The results are discussed in terms

L. Melnikova; A. Kulikov; P. Georgiev

1996-01-01

209

Quantification of the paternal allele bias for new germline mutations in the retinoblastoma gene  

SciTech Connect

New germline mutations in the human retinoblastoma gene preferentially arise on a paternally derived allele. In nonhereditary retinoblastoma, the initial somatic mutation seems to have no such bias. The few previous reports of these phenomena included relatively few cases (less than a dozen new germline or initial somatic mutations), so that the magnitude of the paternal allele bias for new germline mutations is not known. Knowledge of the magnitude of the bias is valuable for genetic counseling, since, for example, patients with new germline mutations who reproduce transmit risk for retinoblastoma according to the risk that the transmitted allele has a germline mutation. We sought to quantitate the paternal allele bias and to determine whether paternal age is a factor possibly accounting for it. We studied 311 families with retinoblastoma (261 simplex, 50 multiplex) that underwent clinical genetic testing and 5 informative families recruited from earlier research. Using RFLPs and polymorphic microsatellites in the retinoblastoma gene, we could determine the parental origin of 45 new germline mutations and 44 probable initial somatic mutations. Thirty-seven of the 45 new germline mutations, or 82%, arose on a paternal allele while only 24 of the 44 initial somatic mutations (55%) did so. Increased paternal age does not appear to account for the excess of new paternal germline mutations, since the average age of fathers of children with new germline mutations (29.4 years, n=26, incomplete records on 11) was not significantly different from the average age of fathers of children with maternal germline mutations or somatic initial mutations (29.8 years, n=35, incomplete records on 17).

Morrow, J.F.; Rapaport, J.M.; Dryia, T.P. [Massachusetts Eye & Ear Infirmary, Boston, MA (United States)

1994-09-01

210

Repeated Evolution of Chimeric Fusion Genes in the ?-Globin Gene Family of Laurasiatherian Mammals  

PubMed Central

The evolutionary fate of chimeric fusion genes may be strongly influenced by their recombinational mode of origin and the nature of functional divergence between the parental genes. In the ?-globin gene family of placental mammals, the two postnatally expressed ?- and ?-globin genes (HBD and HBB, respectively) have a propensity for recombinational exchange via gene conversion and unequal crossing-over. In the latter case, there are good reasons to expect differences in retention rates for the reciprocal HBB/HBD and HBD/HBB fusion genes due to thalassemia pathologies associated with the HBD/HBB “Lepore” deletion mutant in humans. Here, we report a comparative genomic analysis of the mammalian ?-globin gene cluster, which revealed that chimeric HBB/HBD fusion genes originated independently in four separate lineages of laurasiatherian mammals: Eulipotyphlans (shrews, moles, and hedgehogs), carnivores, microchiropteran bats, and cetaceans. In cases where an independently derived “anti-Lepore” duplication mutant has become fixed, the parental HBD and/or HBB genes have typically been inactivated or deleted, so that the newly created HBB/HBD fusion gene is primarily responsible for synthesizing the ?-type subunits of adult and fetal hemoglobin (Hb). Contrary to conventional wisdom that the HBD gene is a vestigial relict that is typically inactivated or expressed at negligible levels, we show that HBD-like genes often encode a substantial fraction (20–100%) of ?-chain Hbs in laurasiatherian taxa. Our results indicate that the ascendancy or resuscitation of genes with HBD-like coding sequence requires the secondary acquisition of HBB-like promoter sequence via unequal crossing-over or interparalog gene conversion. PMID:24814285

Gaudry, Michael J.; Storz, Jay F.; Butts, Gary Tyler; Campbell, Kevin L.; Hoffmann, Federico G.

2014-01-01

211

Repeated evolution of chimeric fusion genes in the ?-globin gene family of laurasiatherian mammals.  

PubMed

The evolutionary fate of chimeric fusion genes may be strongly influenced by their recombinational mode of origin and the nature of functional divergence between the parental genes. In the ?-globin gene family of placental mammals, the two postnatally expressed ?- and ?-globin genes (HBD and HBB, respectively) have a propensity for recombinational exchange via gene conversion and unequal crossing-over. In the latter case, there are good reasons to expect differences in retention rates for the reciprocal HBB/HBD and HBD/HBB fusion genes due to thalassemia pathologies associated with the HBD/HBB "Lepore" deletion mutant in humans. Here, we report a comparative genomic analysis of the mammalian ?-globin gene cluster, which revealed that chimeric HBB/HBD fusion genes originated independently in four separate lineages of laurasiatherian mammals: Eulipotyphlans (shrews, moles, and hedgehogs), carnivores, microchiropteran bats, and cetaceans. In cases where an independently derived "anti-Lepore" duplication mutant has become fixed, the parental HBD and/or HBB genes have typically been inactivated or deleted, so that the newly created HBB/HBD fusion gene is primarily responsible for synthesizing the ?-type subunits of adult and fetal hemoglobin (Hb). Contrary to conventional wisdom that the HBD gene is a vestigial relict that is typically inactivated or expressed at negligible levels, we show that HBD-like genes often encode a substantial fraction (20-100%) of ?-chain Hbs in laurasiatherian taxa. Our results indicate that the ascendancy or resuscitation of genes with HBD-like coding sequence requires the secondary acquisition of HBB-like promoter sequence via unequal crossing-over or interparalog gene conversion. PMID:24814285

Gaudry, Michael J; Storz, Jay F; Butts, Gary Tyler; Campbell, Kevin L; Hoffmann, Federico G

2014-05-01

212

Identification of novel mutations in the KCNQ4 gene of patients with nonsyndromic deafness from Taiwan.  

PubMed

Ion channels play important roles in signal transduction and in the regulation of the ionic composition of intra- and extracellular fluids. Mutations in ion channels have long been thought to be responsible for some forms of hearing loss. Defects in KCNQ4, a voltage-gated potassium channel, are a cause of nonsyndromic sensorineural deafness type 2, an autosomal dominant form of progressive hearing loss. We present data of mutation analysis of KCNQ4 from 185 unrelated Taiwanese probands with nonsyndromic hearing loss. The analysis revealed three novel KCNQ4 mutations and many polymorphisms. The prevalence of KCNQ4 gene mutations in this study was 1.62% (3/185). The mutations include a missense mutation (F182L) and two silent mutations (R216R and T501T). The F182L missense mutation was located in the S3 domain of KCNQ4. The F182 residue of KCNQ4 is highly conserved in KCNQ4 among various species and is less conserved in all members of the KCNQ family. In addition, although R216R is a silent mutation and does not alter the content of amino acid residue, the neural network prediction system revealed that it can potentially create a novel splice donor site during transcription. This mutation might affect the protein structure of KCNQ4 and consequently the normal function of the K+ channel. Our data provide the first comprehensive analysis of the KCNQ4 gene in Taiwanese patients with nonsyndromic deafness. PMID:17033161

Su, Ching-Chyuan; Yang, Jiann-Jou; Shieh, Jia-Ching; Su, Mao-Chang; Li, Shuan-Yow

2007-01-01

213

UCSD scientists find gene mutation for aggressive form of pancreatic cancer  

Cancer.gov

Researchers at the University of California, San Diego School of Medicine have identified a mutated gene common to adenosquamous carcinoma tumors – the first known unique molecular signature for this rare, but particularly virulent, form of pancreatic cancer.

214

A novel mutation of coproporphyrinogen oxidase (CPO) gene in a Japanese family.  

PubMed

Hereditary coproporphyria (HCP) is an autosomal dominant disease characterized by a deficiency of coproporphyrinogen oxidase (CPO). Only 11 mutations of the gene have been reported to date as the mutations responsible for HCP. We report here a novel mutation of the gene responsible for the disease in a Japanese family. Analysis of the polymerase chain reaction (PCR) amplified DNA fragments of the gene by direct-sequencing and/or cloning-based sequencing methods revealed the gene abnormality responsible for the disease. The mutation found was a single base deletion of T at nt position 526, which results in frame shift and truncation of coded protein at amino acid position 204. Screening of pre-symptomatic cases seemed to be possible by PCR restriction analysis using restriction enzyme Xcm I. PMID:9747031

Susa, S; Daimon, M; Yamamori, I; Kondo, M; Yamatani, K; Sasaki, H; Kato, T

1998-01-01

215

1/9/09 2:14 PMResearchers Pinpoint Spontaneous Gene Mutations Responsible for 10 Percent of Non-Familial Cases of Schizophrenia Page 1 of 3http://cumc.columbia.edu/news/press_releases/gene-mutation-schizophrenia.html  

E-print Network

-Familial Cases of Schizophrenia Page 1 of 3http://cumc.columbia.edu/news/press_releases/gene-mutation-schizophrenia Gene Mutations Responsible for 10 Percent of Non-Familial Cases of Schizophrenia NEW YORK (May 30, 2008) ­ Scans of the genome of patients with schizophrenia have revealed rare spontaneous copy number mutations

216

The Mutator Gene Swi8 Effects Specific Mutations in the Mating-Type Region of Schizosaccharomyces Pombe  

PubMed Central

The swi8(+) gene of Schizosaccharomyces pombe appears to be involved in the termination step of copy synthesis during mating-type (MT) switching. Mutations in swi8 confer a general mutator phenotype and, in particular, generate specific mutations in the MT region. Sequencing of the MT cassettes of the h(90) swi8-137 mutant revealed three altered sites. One is situated at the switching (smt) signal adjacent to the H1 homology box of the expression locus mat1:1. It reduces the rate of MT switching. The alteration at the smt signal arose frequently in other h(90) swi8 strains and is probably caused by gene conversion in which the sequence adjacent to the H1 box of mat2:2 is used as template. This change might be generated during the process of MT switching when hybrid DNA formation is anomalously extended into the more heterologous region flanking the H1 homology box. In addition to the gene conversion at mat1:1, two mutations were found in the H3 homology boxes of the silent cassettes mat2:2 and mat3:3. PMID:7851760

Fleck, O.; Rudolph, C.; Albrecht, A.; Lorentz, A.; Schar, P.; Schmidt, H.

1994-01-01

217

Novel mutations in the TBX5 gene in patients with Holt-Oram Syndrome  

PubMed Central

The Holt-Oram syndrome (HOS) is an autosomal dominant condition characterized by upper limb and cardiac malformations. Mutations in the TBX5 gene cause HOS and have also been associated with isolated heart and arm defects. Interactions between the TBX5, GATA4 and NKX2.5 proteins have been reported in humans. We screened the TBX5, GATA4, and NKX2.5 genes for mutations, by direct sequencing, in 32 unrelated patients presenting classical (8) or atypical HOS (1), isolated congenital heart defects (16) or isolated upper-limb malformations (7). Pathogenic mutations in the TBX5 gene were found in four HOS patients, including two new mutations (c.374delG; c.678G > T) in typical patients, and the hotspot mutation c.835C > T in two patients, one of them with an atypical HOS phenotype involving lower-limb malformations. Two new mutations in the GATA4 gene were found in association with isolated upper-limb malformations, but their clinical significance remains to be established. A previously described possibly pathogenic mutation in the NKX2.5 gene (c.73C > 7) was detected in a patient with isolated heart malformations and also in his clinically normal father. PMID:21637475

2010-01-01

218

In silico analysis of single nucleotide polymorphism (SNPs) in human ?-globin gene.  

PubMed

Single amino acid substitutions in the globin chain are the most common forms of genetic variations that produce hemoglobinopathies--the most widespread inherited disorders worldwide. Several hemoglobinopathies result from homozygosity or compound heterozygosity to beta-globin (HBB) gene mutations, such as that producing sickle cell hemoglobin (HbS), HbC, HbD and HbE. Several of these mutations are deleterious and result in moderate to severe hemolytic anemia, with associated complications, requiring lifelong care and management. Even though many hemoglobinopathies result from single amino acid changes producing similar structural abnormalities, there are functional differences in the generated variants. Using in silico methods, we examined the genetic variations that can alter the expression and function of the HBB gene. Using a sequence homology-based Sorting Intolerant from Tolerant (SIFT) server we have searched for the SNPs, which showed that 200 (80%) non-synonymous polymorphism were found to be deleterious. The structure-based method via PolyPhen server indicated that 135 (40%) non-synonymous polymorphism may modify protein function and structure. The Pupa Suite software showed that the SNPs will have a phenotypic consequence on the structure and function of the altered protein. Structure analysis was performed on the key mutations that occur in the native protein coded by the HBB gene that causes hemoglobinopathies such as: HbC (E?K), HbD (E?Q), HbE (E?K) and HbS (E?V). Atomic Non-Local Environment Assessment (ANOLEA), Yet Another Scientific Artificial Reality Application (YASARA), CHARMM-GUI webserver for macromolecular dynamics and mechanics, and Normal Mode Analysis, Deformation and Refinement (NOMAD-Ref) of Gromacs server were used to perform molecular dynamics simulations and energy minimization calculations on ?-Chain residue of the HBB gene before and after mutation. Furthermore, in the native and altered protein models, amino acid residues were determined and secondary structures were observed for solvent accessibility to confirm the protein stability. The functional study in this investigation may be a good model for additional future studies. PMID:22028795

Alanazi, Mohammed; Abduljaleel, Zainularifeen; Khan, Wajahatullah; Warsy, Arjumand S; Elrobh, Mohamed; Khan, Zahid; Al Amri, Abdullah; Bazzi, Mohammad D

2011-01-01

219

Novel Gene Mutations in Patients With Left Ventricular Noncompaction or Barth Syndrome  

Microsoft Academic Search

Background—Mutations in the gene G4.5 result in a wide spectrum of severe infantile cardiomyopathic phenotypes, including isolated left ventricular noncompaction (LVNC), as well as Barth syndrome (BTHS) with dilated cardiomyopathy (DCM). The purpose of this study was to investigate patients with LVNC or BTHS for mutations in G4.5 or other novel genes. Methods and Results—DNA was isolated from 2 families

Fukiko Ichida; Shinichi Tsubata; Karla R. Bowles; Noriyuki Haneda; Keiichiro Uese; Toshio Miyawaki; W. Jeffrey Dreyer; John Messina; Hua Li; Neil E. Bowles; Jeffrey A. Towbin

2010-01-01

220

ISOLATION AND CHARACTERIZATION OF MUTATIONS IN THE @TUBULIN GENE OF SACCHAROMYCES CEREVISIAE  

Microsoft Academic Search

Of 173 mutants of Saccharomyces cerevisiae resistant to the antimitotic drug benomyl (BenR), six also conferred cold-sensitivity for growth and three others conferred temperature-sensitivity for growth in the absence of benomyl. All of the benR mutations tested, including the nine conditional-lethal mutations, were shown to be in the same gene. This gene, TUBP, has previously been molecu- larly cloned and

JAMES H. THOMAS; NORMA F. NEFF; DAVID BOTSTEIN

221

Mutations of the p53 Tumor Suppressor Gene Occur Infrequently in Wilms' Tumor  

Microsoft Academic Search

Mutations of the p53 tumor suppressor gene occur frequently in a variety ofadult-onset tumors, including colon, breast, lung, and brain, yet are infrequently identified In pediatric malignancies. Wilma' tumor, a common solid tumor ofchildhood, can be associated with mutations of the w'ri gene.Alterations of thep53genehavebeenshownto modulate the ability of WT1to transactivate its targets. Although positive p5.3 immu nostaining has been

David Malkin; Elizabeth Sexsmith; Herman Yeger; G. Williams; Max J. Coppes

222

A Novel Activating Mutation of the K- ras Gene in Human Primary Colon Adenocarcinoma  

Microsoft Academic Search

We identified a novel type of point mutation at the 22nd codon of the K-ras gene in a primary colon cancer. The mutation was C to A transversion substituting lysine (AAG) for normal glutamine (CAG) codon. Biological activity of this mutant K-ras gene was tested by expression of full-length cDNA clones in NIH3T3 cells. Most of the K-ras Lys22-transfected cells

Kazunori Tsukuda; Motohiko Tanino; Hiroyuki Soga; Nobuyoshi Shimizu; Kenji Shimizu

2000-01-01

223

Mutation to Herbicide Resistance Maps within the psbA Gene of Anacystis nidulans R2  

Microsoft Academic Search

A psbA gene encoding the target of photosystem II herbicide inhibition the 32,000-dalton thylakoid membrane protein, has cloned from a mutant of Anacystis nidulans R2, Which is resistant to 3-(3,4-dicholorophenyl)-1,1-dimethylurea-(diuron). A cloned DNA fragnebt from within the coding region of this gene transforms wild-type cells to herbicide resistance, proving that mutation within psbA is responsible for that phenotype. The mutation

Susan S. Golden; Robert Haselkorn

1985-01-01

224

Novel stop and frameshifting mutations in the autosomal dominant polycystic kidney disease 2 (PKD2) gene  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most frequent inherited disorders. The majority of cases\\u000a are due to mutation of the PKD1 gene, on 16p13.3, while in most of the remainder the disease maps to the PKD2 locus, at chromosome\\u000a 4q21-q23. Recently, the PKD2 gene has been positionally cloned and three nonsense mutations within the coding sequence

Miguel Viribay; Tomohito Hayashi; Dolores Tellería; Toshio Mochizuki; David M. Reynolds; Rafael Alonso; Xose M. Lens; Felipe Moreno; Peter C. Harris; Stefan Somlo; José L. San Millán

1997-01-01

225

Fanconi Anemia Gene Mutations Are Not Involved in Sporadic Wilms Tumor  

Microsoft Academic Search

Bi-allelic germline mutations of the Fancom anemia (FA) genes, PALB2\\/FANCN and BRCA2\\/FANCD1, have been reported in a few Wilms tumor (WT) patients with an atypical FA phenotype Therefore, we screened a random cohort of 47 Dutch WT cases for germline mutations in these two FA-genes by DNA sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA) Although several cases appeared to carry

Muriel A. Adank; Heidi Segers; Mil van S. E; Helsdingen van Y. M; Najim Ameziane; Ouweland van den A. M. W; Anja Wagner; Hanne Meijers-Heijboer; Marcel Kool; Jan de Kraker; Quinten Waisfisz; Marry M. van den Heuvel-Eibrink

2010-01-01

226

Whole exome sequencing reveals concomitant mutations of multiple FA genes in individual Fanconi anemia patients  

PubMed Central

Background Fanconi anemia (FA) is a rare inherited genetic syndrome with highly variable clinical manifestations. Fifteen genetic subtypes of FA have been identified. Traditional complementation tests for grouping studies have been used generally in FA patients and in stepwise methods to identify the FA type, which can result in incomplete genetic information from FA patients. Methods We diagnosed five pediatric patients with FA based on clinical manifestations, and we performed exome sequencing of peripheral blood specimens from these patients and their family members. The related sequencing data were then analyzed by bioinformatics, and the FANC gene mutations identified by exome sequencing were confirmed by PCR re-sequencing. Results Homozygous and compound heterozygous mutations of FANC genes were identified in all of the patients. The FA subtypes of the patients included FANCA, FANCM and FANCD2. Interestingly, four FA patients harbored multiple mutations in at least two FA genes, and some of these mutations have not been previously reported. These patients’ clinical manifestations were vastly different from each other, as were their treatment responses to androstanazol and prednisone. This finding suggests that heterozygous mutation(s) in FA genes could also have diverse biological and/or pathophysiological effects on FA patients or FA gene carriers. Interestingly, we were not able to identify de novo mutations in the genes implicated in DNA repair pathways when the sequencing data of patients were compared with those of their parents. Conclusions Our results indicate that Chinese FA patients and carriers might have higher and more complex mutation rates in FANC genes than have been conventionally recognized. Testing of the fifteen FANC genes in FA patients and their family members should be a regular clinical practice to determine the optimal care for the individual patient, to counsel the family and to obtain a better understanding of FA pathophysiology. PMID:24885126

2014-01-01

227

Non-existence of caveolin-1 gene mutations in human breast cancer.  

PubMed

Caveolin-1 is the principal constituent protein of caveolae, which are specialised plasma membrane invaginations with diverse biological roles. Caveolin-1 is suggested to have tumour suppressive functions and CAV1 gene mutations have been reported in 20% of breast cancers. The aim of the present study was to evaluate the frequency of CAV1 mutations in a large cohort of optimally accrued breast cancers. Two independent series of breast cancer samples were analysed: 82 fresh-frozen grade 3 and 158 formalin-fixed paraffin-embedded invasive ductal carcinomas of no special type were consecutively accrued and subjected to microdissection of neoplastic epithelial cells prior to DNA extraction. Thirty-nine human breast cancer cell lines were also included in this study. The trans-membrane region of CAV1 and adjacent sequences, where mutations are reported to cluster, were amplified by PCR, followed by direct sequencing and mutational analysis. None of the reported CAV1 gene mutations, including CAV1 (P132L), were identified in either clinical samples (95% CI: 0-1.5%) or human breast cancer cell lines analysed. One novel non-synonymous germline polymorphism was detected within a reported region of high mutational frequency. This study does not corroborate the reported frequent occurrence of CAV1 gene mutations, including CAV1 (P132L), in primary human breast carcinomas. Our findings demonstrate that if CAV1 mutations do exist, their overall mutational frequency is substantially lower than positive reports have suggested. Taken together with other studies, which have also failed to identify CAV1 mutations, our data call into question the existence and biological and clinical relevance of CAV1 gene mutations in human breast cancer. PMID:21909981

Patani, Neill; Lambros, Maryou B; Natrajan, Rachael; Dedes, Konstantin J; Geyer, Felipe C; Ward, Eric; Martin, Lesley-Ann; Dowsett, Mitch; Reis-Filho, Jorge S

2012-01-01

228

Gain-of-function mutations of platelet-derived growth factor receptor ? gene in gastrointestinal stromal tumors  

Microsoft Academic Search

Background & Aims: Most gastrointestinal stromal tumors (GISTs) have gain-of-function mutations of c-kit receptor tyrosine kinase (KIT) gene, but some GISTs do not. We investigated the cause of GISTs without KIT mutations. Because GISTs apparently expressed platelet-derived growth factor receptor (PDGFR) ?, we examined whether GISTs without KIT mutations had a mutation of PDGFR ?. Methods: Whole coding region of

Seiichi Hirota; Akiko Ohashi; Toshirou Nishida; Koji Isozaki; Kazuo Kinoshita; Yasuhisa Shinomura; Yukihiko Kitamura

2003-01-01

229

Immunohistochemical NF1 Analysis Does not Predict NF1 Gene Mutation Status in Pheochromocytoma.  

PubMed

Pheochromocytomas (PCCs) are tumors originating from the adrenal medulla displaying a diverse genetic background. While most PCCs are sporadic, about 40 % of the tumors have been associated with constitutional mutations in one of at least 14 known susceptibility genes. As 25 % of sporadic PCCs harbor somatic neurofibromin 1 gene (NF1) mutations, NF1 has been established as the most recurrently mutated gene in PCCs. To be able to pinpoint NF1-related pheochromocytoma (PCC) disease in clinical practice could facilitate the detection of familial cases, but the large size of the NF1 gene makes standard DNA sequencing methods cumbersome. The aim of this study was to examine whether mutations in the NF1 gene could be predicted by immunohistochemistry as a method to identify cases for further genetic characterization. Sixty-seven PCCs obtained from 67 unselected patients for which the somatic and constitutional mutational status of NF1 was known (49 NF1 wild type, 18 NF1 mutated) were investigated for NF1 protein immunoreactivity, and the results were correlated to clinical and genetic data. NF1 immunoreactivity was absent in the majority of the PCCs (44/67; 66 %), including 13 out of 18 cases (72 %) with a somatic or constitutional NF1 mutation. However, only a minority of the NF1 wild-type PCCs (18/49; 37 %) displayed retained NF1 immunoreactivity, thereby diminishing the specificity of the method. We conclude that NF1 immunohistochemistry alone is not a sufficient method to distinguish between NF1-mutated and non-mutated PCCs. In the clinical context, genetic screening therefore remains the most reliable tool to detect NF1-mutated PCCs. PMID:25403449

Stenman, Adam; Svahn, Fredrika; Welander, Jenny; Gustavson, Boel; Söderkvist, Peter; Gimm, Oliver; Juhlin, C Christofer

2014-11-18

230

[Mutation analysis of the pathogenic gene in a Chinese family with hereditary hemochromatosis].  

PubMed

Hereditary hemochromatosis (HHC) is a rare autosomal recessive disorder. We recruited a consanguineous Chinese family including the proband with HHC and other four members without HHC. Using whole-exome sequencing, we identified two homozygous mutations (c.G18C [p.Q6H] and c.GC962_963AA [p.C321X]) in the hemojuvelin gene (HJV) in the proband with HHC. No mutation was found in other four previously identified HHC related genes, HAMP, TFR2, FPN and HFE. The functional impact of p.Q6H mutation is weak whereas p.C321X, a premature termination mutation, results in a truncated HJV protein, which lacks the glycosylphosphatidylinositol (GPI) anchor domain. In addition to the mutations in HJV, other 12 homozygous mutations were identified in this patient. However, none of these mutations showed strong damaging impact and the mutated genes are not related to iron metabolism. Our in-house data further demonstrated that p.C321X is absent in the general Chinese population, suggesting that the homozygous mutation p.C321X in HJV is causative in the patient with HHC. Accordingly, all of the four members without HHC from the same family carried wild-type alleles or heterozygous mutations, but not the homozygous mutation in this site. Thus, we found for the first time that the homozygous mutation p.C321X in HJV can result in HHC, which will help genetic diagnosis and prenatal counseling for HHC. PMID:25567873

Yuanfeng, Li; Hongxing, Zhang; Haitao, Zhang; Xiaobo, Peng; Lili, Bai; Fuchu, He; Zewu, Qiu; Gangqiao, Zhou

2014-11-01

231

Dystrophin Gene Mutation Location and the Risk of Cognitive Impairment in Duchenne Muscular Dystrophy  

PubMed Central

Background A significant component of the variation in cognitive disability that is observed in Duchenne muscular dystrophy (DMD) is known to be under genetic regulation. In this study we report correlations between standardised measures of intelligence and mutational class, mutation size, mutation location and the involvement of dystrophin isoforms. Methods and Results Sixty two male subjects were recruited as part of a study of the cognitive spectrum in boys with DMD conducted at the Sydney Children's Hospital (SCH). All 62 children received neuropsychological testing from a single clinical psychologist and had a defined dystrophin gene (DMD) mutation; including DMD gene deletions, duplications and DNA point mutations. Full Scale Intelligence Quotients (FSIQ) in unrelated subjects with the same mutation were found to be highly correlated (r?=?0.83, p?=?0.0008), in contrast to results in previous publications. In 58 cases (94%) it was possible to definitively assign a mutation as affecting one or more dystrophin isoforms. A strong association between the risk of cognitive disability and the involvement of groups of DMD isoforms was found. In particular, improvements in the correlation of FSIQ with mutation location were identified when a new classification system for mutations affecting the Dp140 isoform was implemented. Significance These data represent one of the largest studies of FSIQ and mutational data in DMD patients and is among the first to report on a DMD cohort which has had both comprehensive mutational analysis and FSIQ testing through a single referral centre. The correlation between FSIQ results with the location of the dystrophin gene mutation suggests that the risk of cognitive deficit is a result of the cumulative loss of central nervous system (CNS) expressed dystrophin isoforms, and that correct classification of isoform involvement results in improved estimates of risk. PMID:20098710

Maroulis, Sarah; Gilissen, Christian; Pedersen, Robyn L.; Mowat, David R.; Johnston, Heather M.; Buckley, Michael F.

2010-01-01

232

Mutational Analysis of EGFR and Related Signaling Pathway Genes in Lung Adenocarcinomas Identifies a Novel Somatic Kinase Domain Mutation in FGFR4  

PubMed Central

Background Fifty percent of lung adenocarcinomas harbor somatic mutations in six genes that encode proteins in the EGFR signaling pathway, i.e., EGFR, HER2/ERBB2, HER4/ERBB4, PIK3CA, BRAF, and KRAS. We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other potential somatic mutations in genes of this signaling pathway that could contribute to lung tumorigenesis. Methodology/Principal Findings We analyzed genomic DNA from a total of 261 resected, clinically annotated non-small cell lung cancer (NSCLC) specimens. The coding sequences of 39 genes were screened for somatic mutations via high-throughput dideoxynucleotide sequencing of PCR-amplified gene products. Mutations were considered to be somatic only if they were found in an independent tumor-derived PCR product but not in matched normal tissue. Sequencing of 9MB of tumor sequence identified 239 putative genetic variants. We further examined 22 variants found in RAS family genes and 135 variants localized to exons encoding the kinase domain of respective proteins. We identified a total of 37 non-synonymous somatic mutations; 36 were found collectively in EGFR, KRAS, BRAF, and PIK3CA. One somatic mutation was a previously unreported mutation in the kinase domain (exon 16) of FGFR4 (Glu681Lys), identified in 1 of 158 tumors. The FGFR4 mutation is analogous to a reported tumor-specific somatic mutation in ERBB2 and is located in the same exon as a previously reported kinase domain mutation in FGFR4 (Pro712Thr) in a lung adenocarcinoma cell line. Conclusions/Significance This study is one of the first comprehensive mutational analyses of major genes in a specific signaling pathway in a sizeable cohort of lung adenocarcinomas. Our results suggest the majority of gain-of-function mutations within kinase genes in the EGFR signaling pathway have already been identified. Our findings also implicate FGFR4 in the pathogenesis of a subset of lung adenocarcinomas. PMID:17487277

Marks, Jenifer L.; McLellan, Michael D.; Zakowski, Maureen F.; Lash, Alex E.; Kasai, Yumi; Broderick, Stephen; Sarkaria, Inderpal S.; Pham, DuyKhanh; Singh, Bhuvanesh; Miner, Tracie L.; Fewell, Ginger A.; Fulton, Lucinda L.; Mardis, Elaine R.; Wilson, Richard K.; Kris, Mark G.; Rusch, Valerie W.; Varmus, Harold; Pao, William

2007-01-01

233

Identification of genes that protect the C. elegans genome against mutations by genome-wide RNAi.  

PubMed

An RNA interference (RNAi)-based genome-wide screen was performed to detect genes that contribute to genome stability in somatic cells of Caenorhabditis elegans. We identified 61 such genes; these also affect spontaneous mutagenesis in the germ line. Their sequence suggests a role in DNA repair and/or replication, in chromatin remodeling, or in cell cycle control; there are also many novel genes that are highly conserved from yeast to human. Because known mutator genes are causally involved in many hereditary and sporadic human cancers, it is likely that some of these new mutators are equally relevant in cancer etiology. PMID:12600937

Pothof, Joris; van Haaften, Gijs; Thijssen, Karen; Kamath, Ravi S; Fraser, Andrew G; Ahringer, Julie; Plasterk, Ronald H A; Tijsterman, Marcel

2003-02-15

234

Mutations in genes involved in nonsense mediated decay ameliorate the phenotype of sel-12 mutants with amber stop mutations in Caenorhabditis elegans  

Microsoft Academic Search

BACKGROUND: Presenilin proteins are part of a complex of proteins that can cleave many type I transmembrane proteins, including Notch Receptors and the Amyloid Precursor Protein, in the middle of the transmembrane domain. Dominant mutations in the human presenilin genes PS1 and PS2 lead to Familial Alzheimer's disease. Mutations in the Caenorhabditis elegans sel-12 presenilin gene cause a highly penetrant

Alisson M Gontijo; Sylvie Aubert; Ingele Roelens; Bernard Lakowski

2009-01-01

235

FGFR3 Mutations and the Skin: Report of a Patient with a FGFR3 Gene Mutation, Acanthosis Nigricans, Hypochondroplasia and Hyperinsulinemia and Review of the Literature  

Microsoft Academic Search

Fibroblast growth factor receptor 3 (FGFR3) gene mutations in the germline are well-known causes of skeletal syndromes. Somatic FGFR3 mutations have been found in malignant neoplasms and more recently in several cutaneous elements. We present a 14-year-old girl with mild hypochondroplasia who developed acanthosis nigricans. The report of a K650Q mutation in the FGFR3 gene in a similar case prompted

M. Blomberg; E. M. Jeppesen; F. Skovby; E. Benfeldt

2010-01-01

236

Comprehensive characterization of HNPCC-related colorectal cancers reveals striking molecular features in families with no germline mismatch repair gene mutations  

Microsoft Academic Search

A considerable fraction of families with HNPCC shows no germline mismatch repair (MMR) gene mutations. We previously detected ‘hidden’ MMR gene defects in 42% of such families, leaving the remaining 58% ‘truly’ mutation negative. Here, we characterized 50 colorectal carcinomas and five adenomas arising in HNPCC families; 24 truly MMR gene mutation negative and 31 MMR gene mutation positive. Among

Wael M Abdel-Rahman; Miina Ollikainen; Reetta Kariola; Heikki J Järvinen; Jukka-Pekka Mecklin; Minna Nyström-Lahti; Sakari Knuutila; Päivi Peltomäki

2005-01-01

237

Point Mutations Effects on Charge Transport Properties of the Tumor-Suppressor Gene p53  

E-print Network

We report on a theoretical study of point mutations effects on charge transfer properties in the DNA sequence of the tumor-suppressor p53 gene. On the basis of effective single-strand or double-strand tight-binding models which simulate hole propagation along the DNA, a statistical analysis of charge transmission modulations associated with all possible point mutations is performed. We find that in contrast to non-cancerous mutations, mutation hotspots tend to result in significantly weaker {\\em changes of transmission properties}. This suggests that charge transport could play a significant role for DNA-repairing deficiency yielding carcinogenesis.

Chi-Tin Shih; Stephan Roche; Rudolf A. Römer

2007-08-23

238

Constitutional RB1-gene mutations in patients with isolated unilateral retinoblastoma.  

PubMed Central

In most patients with isolated unilateral retinoblastoma, tumor development is initiated by somatic inactivation of both alleles of the RB1 gene. However, some of these patients can transmit retinoblastoma predisposition to their offspring. To determine the frequency and nature of constitutional RB1-gene mutations in patients with isolated unilateral retinoblastoma, we analyzed DNA from peripheral blood and from tumor tissue. The analysis of tumors from 54 (71%) of 76 informative patients showed loss of constitutional heterozygosity (LOH) at intragenic loci. Three of 13 uninformative patients had constitutional deletions. For 39 randomly selected tumors, SSCP, hetero-duplex analysis, sequencing, and Southern blot analysis were used to identify mutations. Mutations were detected in 21 (91%) of 23 tumors with LOH. In 6 (38%) of 16 tumors without LOH, one mutation was detected, and in 9 (56%) of the tumors without LOH, both mutations were found. Thus, a total of 45 mutations were identified in tumors of 36 patients. Thirty-nine of the mutations-including 34 small mutations, 2 large structural alterations, and hypermethylation in 3 tumors-were not detected in the corresponding peripheral blood DNA. In 6 (17%) of the 36 patients, a mutation was detected in constitutional DNA, and 1 of these mutations is known to be associated with reduced expressivity. The presence of a constitutional mutation was not associated with an early age at treatment. In 1 patient, somatic mosaicism was demonstrated by molecular analysis of DNA and RNA from peripheral blood. In 2 patients without a detectable mutation in peripheral blood, mosaicism was suggested because 1 of the patients showed multifocal tumors and the other later developed bilateral retinoblastoma. In conclusion, our results emphasize that the manifestation and transmissibility of retinoblastoma depend on the nature of the first mutation, its time in development, and the number and types of cells that are affected. Images Figure 2 Figure 3 Figure 4 PMID:9311732

Lohmann, D R; Gerick, M; Brandt, B; Oelschläger, U; Lorenz, B; Passarge, E; Horsthemke, B

1997-01-01

239

Genomic organization of SLC3A1, a transporter gene mutated in cystinuria  

SciTech Connect

The SLC3A1 gene encodes a transport protein for cystine and the dibasic amino acids. Recently mutations in this gene have been shown to cause cystinuria. We report the genomic structure and organization of SLC3A1, which is composed of 10 exons and spans nearly 45 kb. Until now screening for mutations in SLC3A1 has been based on RT-PCR amplification of illegitimate mRNA transcripts from white blood cells. In this report we provide primers for amplification of exons from genomic DNA, thus simplifying the process of screening for SLC3A1 mutations in cystinuria. 20 refs., 3 figs., 2 tabs.

Pras, E.; Sood, R.; Raben, N. [National Inst. of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD (United States)] [National Inst. of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD (United States)

1996-08-15

240

Bilateral transverse sinus thrombosis secondary to a homozygous C677T MTHFR gene mutation.  

PubMed

We describe the case of a previously healthy young man who presented with headache, diplopia, nausea, vomiting, and bilateral papilledema. Magnetic resonance venography of the brain revealed thrombosis of the right transverse sinus. Blood tests showed elevated homocysteine levels, and coagulation studies revealed a homozygous C677T mutation and a heterozygous A1298C mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. The patient had no other etiology for venous thrombosis. We recommend screening patients who present with sinus thrombosis for MTHFR gene mutations. PMID:18666857

Kanaan, Ziad M; Mahfouz, Rami; Taher, Ali; Sawaya, Raja A

2008-09-01

241

"20209C-T" a variant mutation of prothrombin gene mutation in a patient with recurrent pregnancy loss.  

PubMed

Recurrent pregnancy loss is considered when a female undergoes at least two consecutive, spontaneous abortions or more than two alternatively. This condition affects approximately 5% of women in reproductive age. Several causes of recurrent abortion have been established, but nevertheless, approximately half of all cases remain unexplained. Thrombophilic disorders have been suggested as a possible cause of recurrent miscarriage. A single 20210 G-A mutation of the 3'-untranslated region of (F2) has been reported as a cause of inherited thrombophilia. The F2 G-A mutation affects 1% to 4% of the US population, and its prevalence is higher among Caucasian women of Southern European descendants. Studies of G20210A polymorphism have also shown conflicting associations with recurrent abortions. In addition to G20210A polymorphism, other mutations affecting the F2 gene have been associated with thrombosis and/or pregnancy complications. PMID:25117109

Prat, Maria; Morales-Indiano, Cristian; Jimenez, Carme; Mas, Virgina; Besses, Carles; Checa, Miguel A; Carreras, Ramon

2014-01-01

242

[Detection of germline mutations in the APC gene with the protein truncation test].  

PubMed

The protein truncation test was established for analyzing mutations in the adenomatous polyposis coli (APC) gene which plays an important role in familial adenomatous polyposis (FAP). The sites of APC mutations and the clinic features of FAP patients were examined to find the relationship between them. Genomic DNA, which was extracted from peripheral blood lymphocytes of 22 FAP patients and the normal colon tissues of 43 sporadic colorectal cancers, were examined for mutations in exon15 of the APC gene by using PCR-TNT T7 Quick Coupled Tanscription/Translation System. The subsequent sequencing was used to confirm the mutation sites. Germline mutations were found in 5 of 22 FAP patients. All of the five mutations showed base pair deletions and led to produce truncated protein. No truncating germline mutation was found in normal tissues of 43 sporadic colorectal cancers. The protein truncation test is a sensitive and accurate technique to detect truncated mutations especially in the large exons of APC gene. It can be used as an routine method for assisting the early diagnosis of the FAP patients. PMID:16201232

Liu, Xiao-Rong; Shan, Xiang-Nian; Friedl, W; Uhlhaas, S; Li, Jin-Tian; Propping, P; Wang, Ya-Ping

2005-09-01

243

A mutational hot spot in the KCNQ4 gene responsible for autosomal dominant hearing impairment.  

PubMed

Several different mutations in the KCNQ4 K+ channel gene are responsible for autosomal dominant nonsyndromic hearing impairment (DFNA2). Here we describe two additional families originating from Europe and Japan with a KCNQ4 missense mutation (W276S) that was previously found in one European family. We compared the disease-associated haplotype of the three W276S-bearing families using closely linked microsatellite markers and intragenic single nucleotide polymorphisms. Differences between the haplotypes were found, excluding a single founder mutation for the families. Therefore, the W276S mutation has occurred three times independently, and most likely represents a hot spot for mutation in the KCNQ4 gene. PMID:12112653

Van Camp, Guy; Coucke, Paul J; Akita, Jiro; Fransen, Erik; Abe, Satoko; De Leenheer, Els M R; Huygen, Patrick L M; Cremers, Cor W R J; Usami, Shin-Ichi

2002-07-01

244

Characterization of six mutations in Exon 37 of neurofibromatosis type 1 gene  

SciTech Connect

Neurofibromatosis type 1 (NF1) is one of the most common inherited disorders, with an incidence of 1 in 3,000. We screened a total of 320 unrelated NF1 patients for mutations in exon 37 of the NF1 gene. Six independent mutations were identified, of which three are novel, and these include a recurrent nonsense mutation identified in 2 unrelated patients at codon 2281 (G2281X), a 1-bp insertion (6791 ins A) resulting in a change of TAG (tyrosine) to a TAA (stop codon), and a 3-bp deletion (6839 del TAC) which generated a frameshift. Another recurrent nonsense mutation, Y2264X, which was detected in 2 unrelated patients in this study, was also previously reported in 2 NF1 individuals. All the mutations were identified within a contiguous 49-bp sequence. Further studies are warranted to support the notion that this region of the gene contains highly mutable sequences. 17 refs., 2 figs., 1 tab.

Upadhyaya, M.; Osborn, M.; Maynard, J.; Harper, P. [Institute of Medical Genetics, Cardiff, Wales (United Kingdom)] [Institute of Medical Genetics, Cardiff, Wales (United Kingdom)

1996-07-26

245

A Mutation in the Mitochondrial Fission Gene Dnm1l Leads to Cardiomyopathy  

PubMed Central

Mutations in a number of genes have been linked to inherited dilated cardiomyopathy (DCM). However, such mutations account for only a small proportion of the clinical cases emphasising the need for alternative discovery approaches to uncovering novel pathogenic mutations in hitherto unidentified pathways. Accordingly, as part of a large-scale N-ethyl-N-nitrosourea mutagenesis screen, we identified a mouse mutant, Python, which develops DCM. We demonstrate that the Python phenotype is attributable to a dominant fully penetrant mutation in the dynamin-1-like (Dnm1l) gene, which has been shown to be critical for mitochondrial fission. The C452F mutation is in a highly conserved region of the M domain of Dnm1l that alters protein interactions in a yeast two-hybrid system, suggesting that the mutation might alter intramolecular interactions within the Dnm1l monomer. Heterozygous Python fibroblasts exhibit abnormal mitochondria and peroxisomes. Homozygosity for the mutation results in the death of embryos midway though gestation. Heterozygous Python hearts show reduced levels of mitochondria enzyme complexes and suffer from cardiac ATP depletion. The resulting energy deficiency may contribute to cardiomyopathy. This is the first demonstration that a defect in a gene involved in mitochondrial remodelling can result in cardiomyopathy, showing that the function of this gene is needed for the maintenance of normal cellular function in a relatively tissue-specific manner. This disease model attests to the importance of mitochondrial remodelling in the heart; similar defects might underlie human heart muscle disease. PMID:20585624

Ashrafian, Houman; Docherty, Louise; Leo, Vincenzo; Towlson, Christopher; Neilan, Monica; Steeples, Violetta; Lygate, Craig A.; Hough, Tertius; Townsend, Stuart; Williams, Debbie; Wells, Sara; Norris, Dominic; Glyn-Jones, Sarah; Land, John; Barbaric, Ivana; Lalanne, Zuzanne; Denny, Paul; Szumska, Dorota; Bhattacharya, Shoumo; Griffin, Julian L.; Hargreaves, Iain; Fernandez-Fuentes, Narcis; Cheeseman, Michael; Watkins, Hugh; Dear, T. Neil

2010-01-01

246

Iron overload and HFE gene mutations in Czech patients with chronic liver diseases.  

PubMed

The aim of the study was to identify the prevalence of HFE gene mutations in Czech patients with chronic liver diseases and the influence of the mutations on iron status. The presence of HFE gene mutations (C282Y, H63D, and S65C) analyzed by the PCR-RFLP method, presence of cirrhosis, and serum iron indices were compared among 454 patients with different chronic liver diseases (51 with chronic hepatitis B, 122 with chronic hepatitis C, 218 with alcoholic liver disease, and 63 patients with hemochromatosis). Chronic liver diseases patients other than hemochromatics did not have an increased frequency of HFE gene mutations compared to controls. Although 33.3% of patients with hepatitis B, 43% of patients with hepatitis C, and 73.2% of patients with alcoholic liver disease had elevated transferrin saturation or serum ferritin levels, the presence of HFE gene mutations was not significantly associated with iron overload in these patients. Additionally, patients with cirrhosis did not have frequencies of HFE mutations different from those without cirrhosis. This study emphasizes the importance, not only of C282Y, but also of the H63D homozygous genetic constellation in Czech hemochromatosis patients. Our findings show that increased iron indices are common in chronic liver diseases but {\\it HFE} mutations do not play an important role in the pathogenesis of chronic hepatitis B, chronic hepatitis C, and alcoholic liver disease. PMID:22297603

Dostalikova-Cimburova, Marketa; Kratka, Karolina; Stransky, Jaroslav; Putova, Ivana; Cieslarova, Blanka; Horak, Jiri

2012-01-01

247

Mutation Analysis of the APC Gene in a Chinese FAP Pedigree with Unusual Phenotype.  

PubMed

Background and Aim. Germline mutations of the adenomatous polyposis coli (APC) gene cause familial adenomatous polyposis (FAP), an autosomal dominant inherited disease mainly characterized by colorectal adenomatous polyposis. Genetic studies of FAP have shown that somatic APC mutations are dependent on the position of the germline APC mutation. However, the molecular mechanism underlying these genotype-phenotype associations for APC in Chinese remain largely unknown. Patients and Methods. In this study, we investigated the APC gene mutation in a Chinese FAP family by systematic screening with multiplex ligation-dependent probe amplification (MLPA), denaturing high-performance liquid chromatography (dHPLC), and DNA sequencing. Promoter methylation was detected by methylation-specific PCR. Results. The identical germline mutation c.1999 C>T (Q667X) of APC was identified in 5 affected members, among which 2 members carried somatic mutations of APC, one with promoter hypermethylation and the other with loss of wild-type allele in their adenomas. The somatic mutations were shown connected with the disease severity, demonstrating a unique genotype-phenotype association in this FAP pedigree. Conclusion. The study revealed the existence of novel pathogenic mutations in Chinese patients with FAP. Somatic mutations are of particular interest because of the unusual phenotypic features shown by patients. PMID:22164339

Chen, S; Zhou, J; Zhang, X; Zhou, X; Zhu, M; Zhang, Y; Ma, G; Li, J

2011-01-01

248

Investigation of mutations in Erg11 gene of fluconazole resistant Candida albicans isolates from Turkish hospitals.  

PubMed

Widespread use of fluconazole has resulted in resistance in strains of Candida. The aim of our study was to investigate Y132H and other mutations in the ERG11 gene in conferring fluconazole resistance to C. albicans isolates. Seven fluconazole-resistant (R)/susceptible dose-dependent (SDD)/trailing and 10 fluconazole-susceptible (S) isolates were included. Restriction enzyme analysis was performed on all isolates for Y132H mutation and sequence analysis was performed for other mutations in the ERG11 gene. None of our strains had Y132H mutation. One single mutation (D153E, E266D, D116E, V437I) was detected in isolates 348, 533, 644, 1453, 2157, while the others had more than one nucleotide change. D116E and E266D, which were two mutations found in fluconazole R/SDD/trailing isolates with the highest frequency, were also detected in azole S strains. K143R, G464S, G465S and V488I mutations were determined in three of the R/SDD isolates. S412T and R469K mutations were detected only in this group of strains by sequence analysis. Mutations such as K143R, G464S, G465S, V488I, S412T and R469K in the ERG11 gene were determined to be effective mechanisms in our fluconazole R/SDD C. albicans isolates. Other mechanisms of resistance, such as overexpression of ERG11 and efflux pumps and mutations in the ERG3 gene should also be investigated. PMID:19732347

Manast?r, Lerzan; Ergon, M Cem; Yücesoy, Mine

2011-03-01

249

Identification and in silico analysis of 14 novel GJB1, MPZ and PMP22 gene mutations  

PubMed Central

Duplication within the chromosome 17p11.2 (CMT1Adup), peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) and gap junction ?1-protein (GJB1) gene mutations are frequent causes of the Charcot-Marie-Tooth disease (CMT). A large number of mutations in these genes are listed in databases. Sequence variants identified in patients are frequently reported as mutations without further evaluation. We analyzed 250 consecutively recruited unrelated Austrian CMT patients for CMT1Adup by microsatellite marker typing, real-time PCR or MLPA, and found 79 duplications (31.6%). The coding regions of the PMP22, MPZ and GJB1 genes were analyzed by direct sequencing in the remaining patients; 28 patients showed mutations, 14 of which were novel. We scored the pathogenicity of novel missense mutations by segregation studies and by their exclusion in control samples. Our comprehensive literature study found that up to 60% of the reported mutations in these genes had not been evaluated regarding their pathogenicity, and the PANTHER bioinformatics tool was used to score novel and published missense variants. The PANTHER program scored known polymorphisms as such, but scored ?82–88% only of the published and novel mutations as most likely deleterious. Mutations associated with axonal CMT were less likely to be classified as deleterious, and the PMP22 S72L mutation repeatedly associated with severe CMT was classified as a polymorphism using default parameters. Our data suggest that this in silico analysis tool could be useful for assessing the functional impact of DNA variations only as a complementary approach. The CMT1Adup, GJB1, MPZ and PMP22 mutation frequencies were in the range of those described in other CMT patient collectives with different ethnical backgrounds. PMID:19259128

Miltenberger-Miltenyi, Gabriel; Schwarzbraun, Thomas; Löscher, Wolfgang N; Wanschitz, Julia; Windpassinger, Christian; Duba, Hans-Christoph; Seidl, Rainer; Albrecht, Gerhard; Weirich-Schwaiger, Helga; Zoller, Heinz; Utermann, Gerd; Auer-Grumbach, Michaela; Janecke, Andreas R

2009-01-01

250

Mutation spectrum in BBS genes guided by homozygosity mapping in an Indian cohort.  

PubMed

Bardet-Biedl syndrome (BBS), a ciliopathy disorder with pleiotropic effect manifests primarily as retinal degeneration along with renal insufficiency, polydactyly and obesity. In this study, we have performed homozygosity mapping using NspI 250K affymetrix gene chip followed by mutation screening of the candidate genes located in the homozygous blocks. These regions are prioritized based on the block length and candidature of the genes in BBS and other ciliopathies. Gene alterations in known BBS (22) and other ciliopathy genes such as ALMS1 (2) were seen in 24 of 30 families (80%). Mutations in BBS3 gene, inclusive of a novel recurrent mutation (p.I91T) accounted for 18% of the identified variations. Disease associated polymorphisms p.S70N (BBS2), rs1545 and rs1547 (BBS6) were also observed. This is the first study in Indian BBS patients and homozygosity mapping has proved to be an effective tool in prioritizing the candidate genes in consanguineous pedigrees. The study reveals a different mutation profile in the ciliopathy genes in Indian population and implication of novel loci/genes in 20% of the study group. PMID:24400638

Sathya Priya, C; Sen, P; Umashankar, V; Gupta, N; Kabra, M; Kumaramanickavel, G; Stoetzel, C; Dollfus, H; Sripriya, S

2015-02-01

251

A bacterial model for expression of mutations in the human ornithine transcarbamylase (OTC) gene  

SciTech Connect

OTC is a mitochondrial enzyme catalyzing the formation of citrulline from carbamyl phosphate and ornithine. X-linked deficiency of OTC is the most prevalent genetic defect of ureagenesis. Mutations and polymorphisms in the OTC gene identified in deficient patients have indicated the occurrence of many family-specific, unique alleles. Due to the low frequency of recurrent mutations, distinguishing between deleterious mutations and polymorphisms is difficult. Using a human OTC gene containing plasmid driven by a tac promoter, we have devised a simple and efficient method for expressing mutations in the mature human OTC enzyme. To demonstrate this method, PCR engineered site-directed mutagenesis was employed to generated cDNA fragments which contained either the R151Q or R277W known mutations found in patients with neonatal and late-onset OTC deficiency, respectively. The normal allele for each mutation was also generated by an identical PCR procedure. Digestion with Bgl II- and Sty I-generated mutant and normal replacement cassettes containing the respective mutant and wild type sequences. Upon transformation of JM109 E.coli cells, OTC enzymatic activity was measured at log and stationary phases of growth using a radiochromatographic method. The R141Q mutation abolished enzymatic activity (<0.02% of normal), whereas the R277W mutation expressed partial activity (2.3% of normal). In addition, a PCR-generated mutation, A280V, resulted in 73% loss of catalytic activity. This OTC expression system is clinically applicable for distinguishing between mutations and polymorphisms, and it can be used to investigate the effects of mutations on various domains of the OTC gene.

Tuchman, M.; McCann, M.T.; Qureshi, A.A. [Univ. of Minnesota, Mineapolis (United States)

1994-09-01

252

Insulin-like factor 3 gene mutations in testicular dysgenesis syndrome: clinical and functional characterization.  

PubMed

Insulin-like factor 3 (INSL3) plays a crucial role in testicular descent. Genetic ablation of Insl3 or its G protein-coupled receptor, leucine-rich repeat-containing G-protein-coupled receptor (Lgr8), causes cryptorchidism in mice. Mutation analyses of INSL3 in humans showed an association with cryptorchidism but led to non-conclusive data about a causative role. In this study, we explored the hypothesis that mutations in INSL3 may be associated with the signs of testicular dysgenesis syndrome (TDS). We screened for mutations in INSL3 gene in 967 subjects with a history of maldescended testes and/or infertility and/or testicular cancer and in 450 controls. Furthermore, we carried out in vitro functional analysis of three novel mutations by analysis of INSL3-dependent cAMP increase in cells expressing LGR8. We found six INSL3 mutations in 18 of 967 patients (1.9%) and no mutations in controls. Prevalence of mutations was similar in the different groups of patients (cryptorchidism and/or infertility and/testicular cancer). Three mutations were novel findings (R4H, W69R, and R72K); however, their analysis showed normal cAMP increase after the activation of LGR8 receptor. In conclusion, we found a significant association of INSL3 gene mutations in men presenting one or more signs of TDS syndrome. However, a causative role for some of these mutations is not clearly supported by functional analyses. Although a role for mutations of INSL3 and LGR8 genes in cryptorchidism is reasonable, additional studies are needed to establish an association between the disruption of INSL3 pathway and higher risk of infertility or testicular cancer. PMID:16687567

Ferlin, A; Bogatcheva, N V; Gianesello, L; Pepe, A; Vinanzi, C; Agoulnik, A I; Foresta, C

2006-06-01

253

Mutations of 3c and spike protein genes correlate with the occurrence of feline infectious peritonitis.  

PubMed

The genes encoding accessory proteins 3a, 3b, 3c, 7a and 7b, the S2 domain of the spike (S) protein gene and the membrane (M) protein gene of feline infectious peritonitis virus (FIPV) and feline enteric coronavirus (FECV) samples were amplified, cloned and sequenced. For this faeces and/or ascites samples from 19 cats suffering from feline infectious peritonitis (FIP) as well as from 20 FECV-infected healthy cats were used. Sequence comparisons revealed that 3c genes of animals with FIP were heavily affected by nucleotide deletions and point mutations compared to animals infected with FECV; these alterations resulted either in early termination or destruction of the translation initiation codon. Two ascites-derived samples of cats with FIP which displayed no alterations of ORF3c harboured mutations in the S2 domain of the S protein gene which resulted in amino acid exchanges or deletions. Moreover, changes in 3c were often accompanied by mutations in S2. In contrast, in samples obtained from faeces of healthy cats, the ORF3c was never affected by such mutations. Similarly ORF3c from faecal samples of the cats with FIP was mostly intact and showed only in a few cases the same mutations found in the respective ascites samples. The genes encoding 3a, 3b, 7a and 7b displayed no mutations linked to the feline coronavirus (FCoV) biotype. The M protein gene was found to be conserved between FECV and FIPV samples. Our findings suggest that mutations of 3c and spike protein genes correlate with the occurrence of FIP. PMID:25150756

Bank-Wolf, Barbara Regina; Stallkamp, Iris; Wiese, Svenja; Moritz, Andreas; Tekes, Gergely; Thiel, Heinz-Jürgen

2014-10-10

254

Mutational landscape of gingivo-buccal oral squamous cell carcinoma reveals new recurrently-mutated genes and molecular subgroups  

PubMed Central

Gingivo-buccal oral squamous cell carcinoma (OSCC-GB), an anatomical and clinical subtype of head and neck squamous cell carcinoma (HNSCC), is prevalent in regions where tobacco-chewing is common. Exome sequencing (n=50) and recurrence testing (n=60) reveals that some significantly and frequently altered genes are specific to OSCC-GB (USP9X, MLL4, ARID2, UNC13C and TRPM3), while some others are shared with HNSCC (for example, TP53, FAT1, CASP8, HRAS and NOTCH1). We also find new genes with recurrent amplifications (for example, DROSHA, YAP1) or homozygous deletions (for example, DDX3X) in OSCC-GB. We find a high proportion of C>G transversions among tobacco users with high numbers of mutations. Many pathways that are enriched for genomic alterations are specific to OSCC-GB. Our work reveals molecular subtypes with distinctive mutational profiles such as patients predominantly harbouring mutations in CASP8 with or without mutations in FAT1. Mean duration of disease-free survival is significantly elevated in some molecular subgroups. These findings open new avenues for biological characterization and exploration of therapies. PMID:24292195

Maitra, Arindam; Biswas, Nidhan K.; Amin, Kishore; Kowtal, Pradnya; Kumar, Shantanu; Das, Subrata; Sarin, Rajiv; Majumder, Partha P.; Bagchi, I; Bairagya, B. B.; Basu, A.; Bhan, M. K.; Chaturvedi, P.; Das, D.; D'Cruz, A.; Dhar, R.; Dutta, D.; Ganguli, D.; Gera, P.; Gupta, T.; Mahapatra, S.; Mujawar, M. H. K.; Mukherjee, S.; Nair, S.; Nikam, S.; Nobre, M.; Patil, A.; Patra, S.; Rama-Gowtham, M.; Rao, T. S.; Roy, B.; Roychowdhury, B.; Sarkar, D.; Sarkar, S.; Sarkar-Roy, N.; Sutradhar, D.

2013-01-01

255

A nonsense mutation in the LDL receptor gene leads to familial hypercholesterolemia in the Druze sect  

SciTech Connect

Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the LDL receptor gene. Here the authors characterize and LDL receptor mutation that is associated with a distinct haplotype and causes FH in the Druze, a small Middle Eastern Islamic sect with a high degree of inbreeding. The mutation was found in FH families from two distinct Druze villages from the Golan Heights (northern Israel). It was not found either in another Druze FH family residing in a different geographical area nor in eight Arab and four Jewish FH heterozygote index cases whose hypercholesterolemia cosegregates with an identical LDL receptor gene haplotype. The mutation, a single-base substitution, results in a termination codon in exon 4 of the LDL receptor gene that encodes for the fourth repeat of the binding domain of the mature receptor. It can be diagnosed by allele-specific oligonucleotide hybridization of PCR-amplified DNA from FH patients.

Landsberger, D.; Meiner, V.; Reshef, A.; Leitersdorf, E. (Hadassah University Hospital, Jerusalem (Israel)); Levy, Yishai (Rambam Medical Center and Faculty of Medicine, Haifa (Israel)); Westhytzen, D.R. van der; Coetzee, G.A. (University of Cape Town Medical School, (South Africa))

1992-02-01

256

[Detection of a gene mutation in familial adenomatous polyposis families by PCR-RFLP method].  

PubMed

A simple and rapid PCR-RFLP method was used to detect a mutation hotspot of adenomatous polyposis coli (APC) gene. Among seven familial adenomatous polyposis (FAP) families, we found individuals in family FD carrying a mutated APC gene or a mutated APC allele with AAAGA deletion in codon 1,309 region. Two young affected persons in twenties were detected by screening the family FD kindred with this PCR-RFLP method. The results are in good accordance with those of colonoscopic examination. The PCR-RFLP method we established proves to be a reliable and simple technique for early detection of some FAP patients. The results indicated the existence of same kind of APC gene mutations in Chinese FAP families as those in western countries. PMID:7994644

Gan, Y B; Zheng, S; Cai, X H

1994-06-01

257

A common FGFR3 gene mutation is present in achondroplasia but not in hypochondroplasia  

SciTech Connect

Achondroplasia is the most common type of genetic dwarfism. It is characterized by disproportionate short stature and other skeletal anomalies resulting from a defect in the maturation of the chondrocytes in the growth plate of the cartilage. Recent studies mapped the achondroplasia gene on chromosome region 4p16.3 and identified a common mutation in the gene encoding the fibroblast growth factor receptor 3 (FGFR3). In an analysis of 19 achondroplasia families from a variety of ethnic backgrounds we confirmed the presence of the G380R mutation in 21 of 23 achondroplasia chromosomes studied. In contrast, the G380R mutation was not found in any of the 8 hypochondroplasia chromosomes studied. Futhermore, linkage studies in a 3-generation family with hypochondroplasia show discordant segregation with markers in the 4p16.3 region suggesting that at least some cases of hypochondroplasia are caused by mutations in a gene other than FGFR3. 27 refs., 2 figs.

Stoilov, I.; Kilpatrick, M.W.; Tsipouras, P. [Univ. of Connecticut Health Center, Farmington, CT (United States)

1995-01-02

258

[Search for frequently encountered mutations in genes predisposing to breast cancer].  

PubMed

DNA of oncological patients, including Ashkenazi Jews and Slavs, living in St. Petersburg was collected, and the resultant collection was screened for three common mutations of genes BRCA1 and BRCA2 by means of heteroduplex analysis. The mutation 5382insC in exon 20 of the BRCA1 gene was found in four unrelated patients, including three Slavs and one Ashkenazi Jew, with a positive family history of breast cancer. The mutations 185delAG and 6174delT in the BRCA1 and BRCA2 genes, respectively, which are typical of Ashkenazi Jewish patients with breast cancer, were not found in the patients of either ethnicity living in St. Petersburg, although the 6174delT mutation was found in the control group of Ashkenazi Jews. A new 12-nucleotide duplication g.71741ins12nt found in intron 20 of the BRCA1 gene was described. The high frequency of the 5382insC mutation in the BRCA1 gene in patients with familial breast cancer in both St. Petersburg and Moscow indicates that Russian families with the history of breast cancer should be primarily tested for this mutation. PMID:11785296

Mandel'shtam, M Iu; Golubkov, V I; Lamber, E P; Shapiro, I M; Brezhneva, T V; Semiglazov, V F; Lipovetski?, B M; Hanson, K P; Ga?tskhoki, V S

2001-12-01

259

Frequent mutation of histone modifying genes in non-Hodgkin lymphoma  

PubMed Central

Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the two most common non-Hodgkin lymphomas (NHLs). To identify genes with mutations in B-cell NHL we sequenced tumour and matched normal DNA from 13 DLBCL cases and one FL case. We analysed RNA-seq data from these and another 113 NHLs to identify genes with candidate mutations, and then re-sequenced tumour and matched normal DNA from these cases to confirm 109 genes with multiple somatic mutations. Genes with roles in histone modification were frequent targets of somatic mutation. For example, 32% of DLBCL and 89% of FL cases had somatic mutations in MLL2, which encodes a histone methyltransferase. 11.4% of DLBCL and 13.4% of FL cases had somatic mutations in MEF2B, a calcium-regulated gene that cooperates with CREBBP and EP300 in acetylating histones. Our analysis thus suggests a previously unappreciated disruption of chromatin biology in lymphomagenesis. PMID:21796119

Morin, Ryan D.; Mendez-Lago, Maria; Mungall, Andrew J.; Goya, Rodrigo; Mungall, Karen L.; Corbett, Richard; Johnson, Nathalie A.; Severson, Tesa M.; Chiu, Readman; Field, Matthew; Jackman, Shaun; Krzywinski, Martin; Scott, David W.; Trinh, Diane L.; Tamura-Wells, Jessica; Li, Sa; Firme, Marlo; Rogic, Sanja; Griffith, Malachi; Chan, Susanna; Yakovenko, Oleksandr; Meyer, Irmtraud M.; Zhao, Eric Y.; Smailus, Duane; Moksa, Michelle; Chittaranjan, Suganthi; Rimsza, Lisa; Brooks-Wilson, Angela; Spinelli, John J.; Ben-Neriah, Susana; Meissner, Barbara; Woolcock, Bruce; Boyle, Merrill; McDonald, Helen; Tam, Angela; Zhao, Yongjun; Delaney, Allen; Zeng, Thomas; Tse, Kane; Butterfield, Yaron; Birol, Inanc; Holt, Rob; Schein, Jacqueline; Horsman, Douglas E.; Moore, Richard; Jones, Steven J.M.; Connors, Joseph M.; Hirst, Martin; Gascoyne, Randy D.; Marra, Marco A.

2011-01-01

260

Mutations of the tyrosinase gene in Indo-Pakistani patients with type I (tyrosinase-deficient) oculocutaneous albinsm (OCA)  

SciTech Connect

Oculocutaneous albinism (OCA) is a group of autosomal recessive disorders characterized by deficient synthesis of melanin pigment. Type I (tyrosinase-deficient) OCA results from mutations of the tyrosinase gene (TYR gene) encoding tyrosinase, the enzyme that catalyzes the first two steps of melanin biosynthesis. Mutations of the TYR gene have been identified in a large number of patients, most of Caucasian ethnic origin, with various forms of type I OCA. The authors present an analysis of the TYR gene in eight Indo-Pakistani patients with type I OCA. The authors describe four novel TYR gene mutations and a fifth mutation previously observed in a Caucasian patient. 16 refs., 6 figs.

Tripathi, R.K.; Droetto, S.; Strunk, K.M.; Holmes, S.A.; Spritz, R.A. (Univ. of Wisconsin, Madison, WI (United States)); Bundey, S.; Musarella, M.A.

1993-12-01

261

Five novel CNGB3 gene mutations in Polish patients with achromatopsia  

PubMed Central

Purpose To identify the genetic basis of achromatopsia (ACHM) in four patients from four unrelated Polish families. Methods In this study, we investigated probands with a clinical diagnosis of ACHM. Ophthalmologic examinations, including visual acuity testing, color vision testing, and full-field electroretinography (ERG), were performed in all patients (with the exception of patient p4, who had no ERG). Direct DNA sequencing encompassing the entire coding region of the CNGB3 gene, eight exons of the GNAT2 gene, and exons 5–7 of the CNGA3 gene was performed. Segregation analysis for the presence and independent inheritance of two mutant alleles was performed in the three families available for study. Results All patients showed typical achromatopsia signs and symptoms. Sequencing helped detect causative changes in the CNGB3 gene in all probands. Eight different mutations were detected in the CNGB3 gene, including five novel mutations: two splice site mutations (c.1579–1G>A and c.494–2A>T), one nonsense substitution (c.1194T>G), and two frame-shift mutations (c.393_394delGCinsTCCTGGTGA and c.1366delC). We also found three mutations: one splice site (c.1578+1G>A) and two frame-shift deletions that had been previously described (c.819_826del and c.1148delC). All respective parents were shown to be heterozygous carriers for the mutation detected in their children. Conclusions The present study reports five novel mutations in the CNGB3 gene, and thus broadens the spectrum of probably pathogenic mutations associated with ACHM. Together with molecular data, we provide a brief clinical description of the affected individuals.

Kohl, Susanne; Baumann, Britta; Walczak-Sztulpa, Joanna; Wicher, Katarzyna; Skorczyk-Werner, Anna; Krawczynski, Maciej R.

2014-01-01

262

Disruption Mutations of ADA2b and GCN5 Transcriptional Adaptor Genes Dramatically Affect Arabidopsis Growth, Development, and Gene Expression  

Microsoft Academic Search

We previously identified Arabidopsis genes homologous with the yeast ADA2 and GCN5 genes that encode components of the ADA and SAGA histone acetyltransferase complexes. In this report, we explore the biological roles of the Arabidopsis ADA2b and GCN5 genes. T-DNA insertion mutations in ADA2b and GCN5 were found to have pleiotropic effects on plant growth and development, including dwarf size,

Konstantinos E. Vlachonasios; Michael F. Thomashow; Steven J. Triezenberg

2003-01-01

263

Novel CFTR gene mutation in a patient with CBAVD  

Microsoft Academic Search

We report a novel mutation detected in a 33 year old Chinese man with congenital bilateral absence of the vas deferens (CBAVD), a past history of pulmonary meliodosis infection and a past history of bronchiolitis obliterans organising pneumonia.A novel splice site mutation in intron 6b (1001+5 G?A) in the homozygous state was identified, and was predicted to lead to inefficient

Denise L. M. Goh; Youyou Zhou; Samuel S. Chong; Nicola S. P. Ngiam; Daniel Y. T. Goh

2007-01-01

264

Mutation analysis of pre-mRNA splicing genes in Chinese families with retinitis pigmentosa  

PubMed Central

Purpose Seven genes involved in precursor mRNA (pre-mRNA) splicing have been implicated in autosomal dominant retinitis pigmentosa (adRP). We sought to detect mutations in all seven genes in Chinese families with RP, to characterize the relevant phenotypes, and to evaluate the prevalence of mutations in splicing genes in patients with adRP. Methods Six unrelated families from our adRP cohort (42 families) and two additional families with RP with uncertain inheritance mode were clinically characterized in the present study. Targeted sequence capture with next-generation massively parallel sequencing (NGS) was performed to screen mutations in 189 genes including all seven pre-mRNA splicing genes associated with adRP. Variants detected with NGS were filtered with bioinformatics analyses, validated with Sanger sequencing, and prioritized with pathogenicity analysis. Results Mutations in pre-mRNA splicing genes were identified in three individual families including one novel frameshift mutation in PRPF31 (p.Leu366fs*1) and two known mutations in SNRNP200 (p.Arg681His and p.Ser1087Leu). The patients carrying SNRNP200 p.R681H showed rapid disease progression, and the family carrying p.S1087L presented earlier onset ages and more severe phenotypes compared to another previously reported family with p.S1087L. In five other families, we identified mutations in other RP-related genes, including RP1 p. Ser781* (novel), RP2 p.Gln65* (novel) and p.Ile137del (novel), IMPDH1 p.Asp311Asn (recurrent), and RHO p.Pro347Leu (recurrent). Conclusions Mutations in splicing genes identified in the present and our previous study account for 9.5% in our adRP cohort, indicating the important role of pre-mRNA splicing deficiency in the etiology of adRP. Mutations in the same splicing gene, or even the same mutation, could correlate with different phenotypic severities, complicating the genotype–phenotype correlation and clinical prognosis. PMID:24940031

Pan, Xinyuan; Chen, Xue; Liu, Xiaoxing; Gao, Xiang; Kang, Xiaoli; Xu, Qihua; Chen, Xuejuan; Zhao, Kanxing; Zhang, Xiumei; Chu, Qiaomei; Wang, Xiuying

2014-01-01

265

Mutation survey of candidate genes in 40 Chinese patients with congenital ectopia lentis  

PubMed Central

Purpose To identify the spectrum and frequency of five candidate genes in Chinese patients with congenital ectopia lentis (EL). Methods Forty consecutive and unrelated congenital probands with EL were collected and underwent ocular, skeletal, and cardiovascular examinations. Sanger sequencing was used to analyze all of the coding and adjacent regions of five candidate genes: FBN1, ADAMTS10, ADAMTSL4, TGFBR2, and CBS. Mutation analysis was performed to evaluate the pathogenic variants and to identify the cause of congenital EL. Results The FBN1 gene screen revealed 25 pathogenic variants in 34 of the 40 families with congenital EL, including three novel (c.1955G>T, c.2222delA, and c.4381T>C) and 22 known mutations. The ADAMTSL10 gene screen revealed a compound heterozygous variant (c.1586G>A and c.2485T>A) in a family with Weill-Marchesani syndrome (WMS). In the remaining five probands, no pathogenic variant was detected in any of the five screened genes. Conclusions In this study, we identified three novel and 22 known mutations in FBN1 in 34 of 40 EL families. The results expand the mutation spectrum of the FBN1 gene and suggest that FBN1 mutations may be the major cause of congenital EL in Chinese patients. PMID:25053872

Li, Jie; Jia, Xiaoyun; Li, Shiqiang; Fang, Shaohua

2014-01-01

266

Mutation analysis of the APC gene in Taiwanese FAP families: low incidence of APC germline mutation in a distinct subgroup of FAP families.  

PubMed

Familial adenomatous polyposis (FAP) is an autosomal-dominant disease caused by germline mutations in the adenomatous polyposis coli (APC) gene. The affected individuals develop colorectal polyposis and show various extra-colonic manifestations. In this study, we aimed to investigate the genetic and clinical characteristics of FAP in Taiwanese families and analyze the genotype-phenotype correlations. Blood samples were obtained from 66 FAP patients registered in the hereditary colorectal cancer database. Then, germline mutations in the APC genes of these 66 polyposis patients from 47 unrelated FAP families were analyzed. The germline-mutation-negative cases were analyzed by performing multiplex ligation-dependent probe amplification (MLPA) and single-strand conformation polymorphism (SSCP) analysis of the MUTYH gene. Among the analyzed families, 79% (37/47) of the families showed 28 APC mutations, including 19 frameshift mutations, 4 nonsense mutations, 3 genomic deletion mutations, 1 missense mutation, and 1 splice-site mutation. In addition, we identified 15 novel mutations in 32% (15/47) of the families. The cases in which APC mutations were not identified showed significantly lower incidence of profuse polyposis (P = 0.034) and gastroduodenal polyps (P = 0.027). Furthermore, FAP families in which some affected individuals had less than 100 polyps showed significant association with low incidence of APC germline mutations (P = 0.002). We have added the APC germline-mutation data for Taiwanese FAP patients and indicated the presence of an FAP subgroup comprising affected individuals with nonadenomatous polyps or less than 100 adenomatous polyps; this form of FAP is less frequently caused by germline mutations of the APC gene. PMID:19768578

Chiang, J M; Chen, H W; Tang, R P; Chen, J S; Changchien, C R; Hsieh, P S; Wang, J Y

2010-06-01

267

Mutations in topoisomerase genes of fluoroquinolone-resistant salmonellae in Hong Kong.  

PubMed

A total of 88 salmonella isolates (72 clinical isolates for which the ciprofloxacin MIC was >0.06 microg/ml, 15 isolates for which the ciprofloxacin MIC was < or =0.06 microg/ml, and Salmonella enterica serotype Typhimurium ATCC 13311) were studied for the presence of genetic alterations in four quinolone resistance genes, gyrA, gyrB, parC, and parE, by multiplex PCR amplimer conformation analysis. The genetic alterations were confirmed by direct nucleotide sequencing. A considerable number of strains had a mutation in parC, the first to be reported in salmonellae. Seven of the isolates sensitive to 0.06 micro g of ciprofloxacin per ml had a novel mutation at codon 57 of parC (Tyr57-->Ser) which was also found in 29 isolates for which ciprofloxacin MICs were >0.06 micro g/ml. Thirty-two isolates had a single gyrA mutation (Ser83-->Phe, Ser83-->Tyr, Asp87-->Asn, Asp87-->Tyr, or Asp87-->Gly), 34 had both a gyrA mutation and a parC mutation (29 isolates with a parC mutation of Tyr57-->Ser and 5 isolates with a parC mutation of Ser80-->Arg). Six isolates which were isolated recently (from 1998 to 2001) were resistant to 4 micro g of ciprofloxacin per ml. Two of these isolates had double gyrA mutations (Ser83-->Phe and Asp87-->Asn) and a parC mutation (Ser80-->Arg) (MICs, 8 to 32 microg/ml), and four of these isolates had double gyrA mutations (Ser83-->Phe and Asp87-->Gly), one parC mutation (Ser80-->Arg), and one parE mutation (Ser458-->Pro) (MICs, 16 to 64 micro g/ml). All six of these isolates and those with a Ser80-->Arg parC mutation were S. enterica serotype Typhimurium. One S. enterica serotype Typhi isolate harbored a single gyrA mutation (Ser83-->Phe), and an S. enterica serotype Paratyphi A isolate harbored a gyrA mutation (Ser83-->Tyr) and a parC mutation (Tyr57-->Ser); both of these isolates had decreased susceptibilities to the fluoroquinolones. The MICs of ciprofloxacin, levofloxacin, and sparfloxacin were in general the lowest of those of the six fluoroquinolones tested. Isolates with a single gyrA mutation were less resistant to fluoroquinolones than those with an additional parC mutation (Tyr57-->Ser or Ser80-->Arg), while those with double gyrA mutations were more resistant. PMID:14576119

Ling, J M; Chan, E W; Lam, A W; Cheng, A F

2003-11-01

268

Variation in mutation rate and polymorphism among mitochondrial genes of Silene vulgaris.  

PubMed

The prevailing wisdom of the plant mitochondrial genome is that it has very low substitution rates, thus it is generally assumed that nucleotide diversity within species will also be low. However, recent evidence suggests plant mitochondrial genes may harbor variable and sometimes high levels of within-species polymorphism, a result attributed to variance in the influence of selection. However, insufficient attention has been paid to the effect of among-gene variation in mutation rate on varying levels of polymorphism across loci. We measured levels of polymorphism in seven mitochondrial gene regions across a geographically wide sample of the plant Silene vulgaris to investigate whether individual mitochondrial genes accumulate polymorphisms equally. We found that genes vary significantly in polymorphism. Tests based on coalescence theory show that the genes vary significantly in their scaled mutation rate, which, in the absence of differences among genes in effective population size, suggests these genes vary in their underlying mutation rate. Further evidence that among-gene variance in polymorphism is due to variation in the underlying mutation rate comes from a significant positive relationship between the number of segregating sites and silent site divergence from an outgroup. Contrary to recent studies, we found unconvincing evidence of recombination in the mitochondrial genome, and generally confirm the standard model of plant mitochondria characterized by low substitution rates and no recombination. We also show no evidence of significant variation in the strength or direction of selection among genes; this result may be expected if there is no recombination. The present study provides some of the most thorough data on plant mitochondrial polymorphism, and provides compelling evidence for mutation rate variation among genes. The study also demonstrates the difficulty in establishing a null model of mitochondrial genome polymorphism, and thus the difficulty, in the absence of a comparative approach, in testing the assumption that low substitution rates in plant mitochondria lead to low polymorphism. PMID:17533174

Barr, Camille M; Keller, Stephen R; Ingvarsson, Pär K; Sloan, Daniel B; Taylor, Douglas R

2007-08-01

269

Study on the Evolution of Genes Mutation Related With Gastrointestinal Stromal Tumors  

ClinicalTrials.gov

Full Gene Sequences of c-KIT?PDGFRA and DOG1 Are Analyzed With the Screening-sequencing Approach; Investigate the Characteristics and Variations Associated With the Different Gene Mutations of c-KIT?PDGFRA and DOG1 in GIST Patients

2012-01-05

270

Accumulation of slightly deleterious mutations in mitochondrial protein-coding genes of  

E-print Network

Accumulation of slightly deleterious mutations in mitochondrial protein-coding genes of large and can reach fixation. Here we investigate this phenomenon for a set of all 13 mitochondrial protein-coding genes from 110 mammalian species. By using body mass as a proxy for Ne, we show that large mammals (i

Sorenson, Michael

271

Mutations of the Tyrosinase gene in three Korean patients with Type I oculocutaneous albinism  

Microsoft Academic Search

Summary Oculocutaneous albinism (OCA) is an inherited disorder of the melanin pigmentary system, characterized by a decrease or an absence of melanin in the skin, hair, and eyes. Type I (tyrosinase-deficient) OCA results from mutations of thetyrosinase (TYR) gene encoding tyrosinase, the enzyme that catalyzes at least the first two steps of melanin biosynthesis. We have analyzed theTYR gene in

Kyoung Chan Park; Sang Kyu Park; Yong Suk Lee; Sang Woong Youn; Byung Soon Park; Kyu Han Kim; Seung Taek Lee

1996-01-01

272

Multiple Intestinal Neoplasia Caused by a Mutation in the Murine Homolog of the APC Gene  

Microsoft Academic Search

Germ-line mutations of the APC gene are responsible for familial adenomatous polyposis (FAP), an autosomal dominantly inherited disease in humans. Patients with FAP develop multiple benign colorectal tumors. Recently, a mouse lineage that exhibits an autosomal dominantly inherited predisposition to multiple intestinal neoplasia (Min) was described. Linkage analysis showed that the murine homolog of the APC gene (mApc) was tightly

Li-Kuo Su; Kenneth W. Kinzler; Bert Vogelstein; Antonette C. Preisinger; Amy Rapaich Moser; Cindy Luongo; Karen A. Gould; William F. Dove

1992-01-01

273

Mutation screening of the ARX gene in patients with autism Pauline Chaste  

E-print Network

spectrum of disorders, including nonsyndromic X-linked mental retardation, sometimes associated the ARX gene in 226 male patients with autism spectrum disorders and mental retardation; 42 that mutations in the ARX gene are very rare in autism. Key words: X chromosome, mental retardation, epilepsy

Paris-Sud XI, Université de

274

A common FGFR3 gene mutation is present in achondroplasia but not in hypochondroplasia  

Microsoft Academic Search

Achondroplasia is the most common type of genetic dwarfism. It is characterized by disproportionate short stature and other skeletal anomalies resulting from a defect in the maturation of the chondrocytes in the growth plate of the cartilage. Recent studies mapped the achondroplasia gene on chromosome region 4p16.3 and identified a common mutation in the gene encoding the fibroblast growth factor

Ivaylo Stoilov; Michael W. Kilpatrick; Petros Tsipouras

1995-01-01

275

Mutations in the GABRA1 and EFHC1 genes are rare in familial juvenile myoclonic epilepsy  

Microsoft Academic Search

Juvenile myoclonic epilepsy (JME), accounting for approximately 25% of idiopathic generalized epilepsies, is genetically heterogeneous. Mutations in the alpha-1 subunit of the GABAA receptor (GABRA1) and EFHC1 genes have been reported in a few families with autosomal dominant (AD) JME. We have investigated the contribution of these two genes to familial JME in our cohort of 54 JME Caucasian families.

Shaochun Ma; Marcia A. Blair; Bassel Abou-Khalil; Andre H. Lagrange; Christina A. Gurnett; Peter Hedera

2006-01-01

276

Targeted sequencing using a 47 gene multiple myeloma mutation panel (M3P) in -17p high risk disease  

PubMed Central

Summary We constructed a multiple myeloma (MM)-specific gene panel for targeted sequencing and investigated 72 untreated high-risk (del17p) MM patients. Mutations were identified in 78% of the patients. While the majority of studied genes were mutated at similar frequency to published literature, the prevalence of TP53 mutation was increased (28%) and no mutations were found in FAM46C. This study provides a comprehensive insight into the mutational landscape of del17p high-risk MM. Additionally, our work demonstrates the practical use of a customized sequencing panel, as an easy, cheap and fast approach to characterize the mutational profile of MM. PMID:25302557

Kortüm, Klaus M.; Langer, Christian; Monge, Jorge; Bruins, Laura; Egan, Jan B.; Zhu, Yuan X.; Shi, Chang Xin; Jedlowski, Patrick; Schmidt, Jessica; Ojha, Juhi; Bullinger, Lars; Liebisch, Peter; Kull, Miriam; Champion, Mia D.; Van Wier, Scott; Ahmann, Gregory; Rasche, Leo; Knop, Stefan; Fonseca, Rafael; Einsele, Hermann; Stewart, A Keith; Braggio, Esteban

2015-01-01

277

P53 gene mutations in breast cancers in Midwestern U.S. women: Null as well as missense-type mutations are associated with poor prognosis  

Microsoft Academic Search

Differences in patterns of p53 gene mutation in different types of cancers support the idea that analysis of acquired alterations in this gene will be useful as a {open_quotes}mutagen test{close_quotes}. We are studying the pattern of p53 gene mutation in sporadic breast carcinomas in high and low risk populations. All translated exons and adjacent splice regions have been analyzed in

H. Blaszyk; A. Hartmann; S. Saitoh

1994-01-01

278

Nemaline Myopathy Type 2 (NEM2): Two Novel Mutations in the Nebulin (NEB) Gene.  

PubMed

Nemaline myopathy is a type of the heterogeneous group of congenital myopathies. Generalized hypotonia, weakness, and delayed motor development are the main clinical features of the typical congenital form. Histopathology shows characteristic nemaline rods in the muscle biopsy. Mutations in at least 7 genes, including nebulin gene (NEB), proved to be responsible for this muscle disease. We present a boy with nemaline myopathy type 2 (NEM2) caused by compound heterozygosity for 2 novel mutations, a deletion and a duplication in the NEB gene. The deletion was inherited from the father and the duplication from the mother. Testing all family members supports genetic counseling. PMID:24056153

Gajda, Anna; Horváth, Emese; Hortobágyi, Tibor; Gergev, Gyurgyinka; Szabó, Hajnalka; Farkas, Katalin; Nagy, Nikoletta; Széll, Márta; Sztriha, László

2013-09-20

279

[Hereditary sensorineural hearing impairment and macrothrombocytopenia: a rare MYH9 gene mutation].  

PubMed

We report on a rare case of an exon 16 mutation of the MYH9 gene in a 23-year-old woman. This gene encodes for non-muscular myosin IIA, which acts as a cytoskeletal contractile protein in diverse cell types. This disorder led to sensorineural hearing loss, macrothrombocytopenia, and proteinuria. MYH9 gene mutation can lead to diverse organ manifestation like pre-senile cataract or renal failure which are progressive in course. Due to the current lack of causal treatment, diagnostic steps, advice for follow-up examinations and symptomatic therapy approaches are presented. PMID:23223919

Böttcher, A; Knecht, R; Busch, C-J; Lörincz, B B; Dalchow, C V

2013-02-01

280

Frequent mutations of Fas gene in nasal NK/T cell lymphoma.  

PubMed

Fas (Apo-1/CD95) is a cell-surface receptor involved in cell death signaling through binding of Fas ligand. Mutation of Fas gene in lymphoid cells results in accumulation of these cells, which might thus contribute to lymphomagenesis. We examined the open reading frame of Fas cDNA in 14 cases of nasal NK/T-cell lymphoma. Mutations of Fas gene were detected in seven (50%) of 14 cases which comprised four frameshift, two missense, and one silent mutations. Frameshift mutations were caused by insertion of 1 bp (A) at nucleotide 1095 in two cases and by deletion of 1 bp at nucleotide 597 and at 704, respectively, in one each. Mouse T-cell lymphoma cells transfected with two missense mutated genes and frameshift mutations caused by insertion of 1 bp (A) at nucleotide 1095 were resistant to apoptosis induced by the anti-Fas antibody. These findings suggested that accumulation of lymphoid cells with Fas mutations provides a basis for the development of nasal NK/T-cell lymphoma. PMID:12096347

Takakuwa, Tetsuya; Dong, Zhiming; Nakatsuka, Shinichi; Kojya, Shizuo; Harabuchi, Yasuaki; Yang, Woo-Ick; Nagata, Shigekazu; Aozasa, Katsuyuki

2002-07-11

281

Mutations in the MESP2 gene cause spondylothoracic dysostosis/Jarcho-Levin syndrome.  

PubMed

Spondylothoracic dysostosis (STD), also known as Jarcho-Levin syndrome (JLS), is an autosomal-recessive disorder characterized by abnormal vertebral segmentation and defects affecting spine formation, with complete bilateral fusion of the ribs at the costovertebral junction producing a "crab-like" configuration of the thorax. The shortened spine and trunk can severely affect respiratory function during early childhood. The condition is prevalent in the Puerto Rican population, although it is a panethnic disorder. By sequencing a set of candidate genes involved in mouse segmentation, we identified a recessive E103X nonsense mutation in the mesoderm posterior 2 homolog (MESP2) gene in a patient, of Puerto Rican origin and from the Boston area, who had been diagnosed with STD/JLS. We then analyzed 12 Puerto Rican families with STD probands for the MESP2 E103X mutation. Ten patients were homozygous for the E103X mutation, three patients were compound heterozygous for a second nonsense mutation, E230X, or a missense mutation, L125V, which affects a conserved leucine residue within the bHLH region. Thus, all affected probands harbored the E103X mutation. Our findings suggest a founder-effect mutation in the MESP2 gene as a major cause of the classical Puerto Rican form of STD/JLS. PMID:18485326

Cornier, Alberto S; Staehling-Hampton, Karen; Delventhal, Kym M; Saga, Yumiko; Caubet, Jean-Francois; Sasaki, Nobuo; Ellard, Sian; Young, Elizabeth; Ramirez, Norman; Carlo, Simon E; Torres, Jose; Emans, John B; Turnpenny, Peter D; Pourquié, Olivier

2008-06-01

282

Mutations in the MESP2 Gene Cause Spondylothoracic Dysostosis/Jarcho-Levin Syndrome  

PubMed Central

Spondylothoracic dysostosis (STD), also known as Jarcho-Levin syndrome (JLS), is an autosomal-recessive disorder characterized by abnormal vertebral segmentation and defects affecting spine formation, with complete bilateral fusion of the ribs at the costovertebral junction producing a “crab-like” configuration of the thorax. The shortened spine and trunk can severely affect respiratory function during early childhood. The condition is prevalent in the Puerto Rican population, although it is a panethnic disorder. By sequencing a set of candidate genes involved in mouse segmentation, we identified a recessive E103X nonsense mutation in the mesoderm posterior 2 homolog (MESP2) gene in a patient, of Puerto Rican origin and from the Boston area, who had been diagnosed with STD/JLS. We then analyzed 12 Puerto Rican families with STD probands for the MESP2 E103X mutation. Ten patients were homozygous for the E103X mutation, three patients were compound heterozygous for a second nonsense mutation, E230X, or a missense mutation, L125V, which affects a conserved leucine residue within the bHLH region. Thus, all affected probands harbored the E103X mutation. Our findings suggest a founder-effect mutation in the MESP2 gene as a major cause of the classical Puerto Rican form of STD/JLS. PMID:18485326

Cornier, Alberto S.; Staehling-Hampton, Karen; Delventhal, Kym M.; Saga, Yumiko; Caubet, Jean-Francois; Sasaki, Nobuo; Ellard, Sian; Young, Elizabeth; Ramirez, Norman; Carlo, Simon E.; Torres, Jose; Emans, John B.; Turnpenny, Peter D.; Pourquié, Olivier

2008-01-01

283

Identification of a novel FBN1 gene mutation in a large Pakistani family with Marfan syndrome  

PubMed Central

Purpose To describe a novel mutation in the fibrillin-1 (FBN1) gene in a large Pakistani family with autosomal dominant Marfan syndrome (MFS). Methods Blood samples were collected of 11 family members affected with Marfan syndrome, and DNA was isolated by phenol-extraction. The coding exons of FBN1 were analyzed by polymerase chain reaction (PCR) and direct sequencing. One hundred-thirty controls were screened for a mutation in the FBN1 gene that was identified in this family by restriction fragment length polymorphism (RFLP) analysis. Results A novel heterozygous missense mutation c.2368T>A; p.Cys790Ser was observed in exon 19. This mutation substitutes a highly conserved cysteine residue by serine in a calcium binding epidermal growth factor-like domain (cbEGF) of FBN1. This mutation was present in all affected members and absent from unaffected individuals of the family in addition to 130 healthy Pakistani controls. Interestingly all affected family members presented with ectopia lentis, myopia and glaucoma, but lacked the cardinal cardiovascular features of MFS. Conclusions This is a first report of a mutation in FBN1 in MFS patients of Pakistani origin. The identification of a FBN1 mutation in this family confirms the diagnosis of MFS patients and expands the worldwide spectrum of FBN1 mutations. PMID:22876116

Micheal, Shazia; Khan, Muhammad Imran; Akhtar, Farah; Weiss, Marjan M.; Islam, Farah; Ali, Mehmood; Qamar, Raheel; Maugeri, Alessandra

2012-01-01

284

Mutation analysis of the ferritin L-chain gene in age-related cataract  

PubMed Central

Purpose To investigate whether acquired somatic mutations in the iron response element of the ferritin L-chain gene account for the age-related cataract. Methods The 15 most prevalent point mutations causing hereditary hyperferritinemia cataract syndrome (HHCS) were screened in patients with age-related cataract using MALDI-TOF Mass Spectrometry. DNA samples were obtained from the lens capsules of patients following cataract surgery, and subjected to PCR amplification. Products were analyzed by a Sequenom® mass spectrometer, and classified as a mutation or wild type according to molecular weight. For a positive control, L-ferritin G32T mutation detected by direct sequencing in 3 members of an Israeli family known to be affected by HHCS was used. Results DNA samples were isolated from the lens capsules of 90 patients, mean age 73.86, and screened for L-ferritin mutations. While the G32T mutation was detected in all 3 positive control cases, all other patients were negative for the 15 mutations. Conclusions Somatic mutations in the iron response elements (IRE) of the L-ferritin gene are infrequent in the age-related cataract. The role of L-ferritin genetic variations in the pathogenesis of age-related cataract is yet to be explored. PMID:21139976

Assia, Nurit; Goldenberg-Cohen, Nitza; Rechavi, Gideon; Amariglio, Ninette

2010-01-01

285

A mutation in the MATP gene causes the cream coat colour in the horse  

PubMed Central

In horses, basic colours such as bay or chestnut may be partially diluted to buckskin and palomino, or extremely diluted to cream, a nearly white colour with pink skin and blue eyes. This dilution is expected to be controlled by one gene and we used both candidate gene and positional cloning strategies to identify the "cream mutation". A horse panel including reference colours was established and typed for different markers within or in the neighbourhood of two candidate genes. Our data suggest that the causal mutation, a G to A transition, is localised in exon 2 of the MATP gene leading to an aspartic acid to asparagine substitution in the encoded protein. This conserved mutation was also described in mice and humans, but not in medaka. PMID:12605854

Mariat, Denis; Taourit, Sead; Guérin, Gérard

2003-01-01

286

Recurrent Deep Intronic Mutations in the SLC12A3 Gene Responsible for Gitelman's Syndrome  

PubMed Central

Summary Background and objectives Gitelman's syndrome (GS) is an autosomal recessive renal tubular disorder caused by mutations in the SLC12A3 gene encoding the thiazide-sensitive Na+-Cl? cotransporter (NCC). Despite meticulous sequencing of genomic DNA, approximately one-third of GS patients are negative or heterozygotes for the known mutations. Design, Setting, Participants, & Measurements Because blood leukocytes express NCC mRNA, we evaluate whether deep intronic mutations contribute to GS patients with uniallelic or undetectable SLC12A3 mutations. Twenty-nine patients with GS (men/women = 16/13), including eight negative and 21 uniallelic SLC12A3 mutations from 19 unrelated families, and normal controls were enrolled in an academic medical center. Analysis of cDNA from blood leukocytes, sequencing of the corresponding introns of genomic DNA for abnormal transcript, and analysis of NCC protein expression from renal biopsy were performed. Results We identified nine Taiwan aboriginal patients carrying c.1670–191C?T mutations in intron 13 and 10 nonaboriginal patients carrying c.2548+253C?T mutations in intron 21 from 14 families (14/19). These two mutations undetected in 100 healthy subjects created pseudoexons containing new premature termination codons. Haplotype analysis with markers flanking SLC12A3 revealed that both mutations did not have founder effects. Apical NCC expression in the DCT of renal tissue was markedly diminished in two patients carrying deep intronic mutations. Conclusions Deep intronic mutations in SLC12A3 causing defective NCC expression can be identified with the RNA-based approach in patients with GS. c.1670–191C?T and c.2548+253C?T are hot spot mutations that can be screened in GS patients with uniallelic or negative SLC12A3 mutations. PMID:21051746

Lo, Yi-Fen; Nozu, Kandai; Iijima, Kazumoto; Morishita, Takahiro; Huang, Che-Chung; Yang, Sung-Sen; Sytwu, Huey-Kang; Fang, Yu-Wei; Tseng, Min-Hua

2011-01-01

287

Hb Manukau [?67(E11)Val???Gly; HBB: c.203T>G]: the role of genetic testing in the diagnosis of idiopathic hemolytic anemia.  

PubMed

The increasing availability of DNA sequencing of globin genes has improved our ability to detect conditions that were presumed to be extremely rare. These conditions may remain undiagnosed due to unfamiliarity with clinical presentation, relative unavailability of advanced diagnostic alternatives, or may defy detection by being electrophoretically silent or extreme instability rendering their presence to be below detection level. Genetic studies were pursued in a mother and daughter with severe hemolytic anemia as initial testing failed to be diagnostic. DNA sequence analysis of the ?-globin gene identified Hb Manukau [?67(E11)Val???Gly; HBB: c.203T?>?G], an extremely unstable hemoglobin (Hb) variant. This is the second family described with this condition (first in the western hemisphere). An astute clinician may benefit from being persistent and pursuing additional testing including molecular genetic characterization where clinical suspicion remains high. PMID:24611675

Kumar, Mudra Kohli; Judd, Courtney; Hoyer, James D; Swanson, Kenneth C; Nelson, Linda; Oliveira, Jennifer L

2014-01-01

288

Patterns of somatic mutations in VH genes reveal pathways of clonal transformation from MGUS to multiple myeloma  

Microsoft Academic Search

Monoclonal gammopathy of undeter- mined significance (MGUS) can trans- form to multiple myeloma (MM). In my- eloma, mutated VH genes with sequence homogeneity reveal a postfollicular ori- gin. Previously, some MGUS cases showed mutated VH genes with intra- clonal variation, indicating an earlier stage of arrest. We investigated progression from 2 of 2 MGUS to MM, in which VH genes

Niklas Zojer; Heinz Ludwig; Michael Fiegl; Freda K. Stevenson; Surinder S. Sahota

2003-01-01

289

UGT1A1 Gene Mutation due to Crigler-Najjar Syndrome in Iranian Patients: Identification of a Novel Mutation  

PubMed Central

Crigler-Najjar syndrome (CNS) type I and type II are inherited as autosomal recessive conditions that are caused by mutations in the UGT1A1 gene. We present the analysis of UGT1A1 gene in 12 individuals from three different families. This analysis allowed us to identify one novel mutation, which was not previously described. In this study, three families with clinically diagnosed CNS referred from Khuzestan province, southwest Iran, were screened. After signing the informed consent, peripheral blood samples from the patients and their parents were collected in EDTA-containing tube followed by DNA extraction using a routine phenol-chloroform method. All five coding exons and the flanking intronic regions of the bilirubin-UGT were amplified by polymerase chain reaction (PCR) followed by DNA sequencing by Sanger method. From the first family, a 9-month-old boy was homozygous for a deletion mutation of two adjacent nucleotides including one adenosine (A) and one glutamine (G) between nucleotides 238 and 239 in exon 1 (c.238_240 del AG). In the second family, there were two affected individuals, an 11-year-old girl and a fetus, found to be homozygous for the same mutation. The third family showed a mutation at nucleotide 479 in exon 1 (Val160Glu) that has been reported previously. Molecular analysis can significantly help confirm the diagnosis of CNS, without any need for the liver biopsy, and may help the therapeutic management by ruling out more harmful causes of hyperbilirubinemia. PMID:24286076

Mohammadi Asl, Javad; Tabatabaiefar, Mohammad Amin; Galehdari, Hamid; Riahi, Kourosh; Masbi, Mohammad Hosein; Zargar Shoshtari, Zohre; Rahim, Fakher

2013-01-01

290

Trypsinogen gene mutations in patients with chronic or recurrent acute pancreatitis.  

PubMed

Three-point mutations (R117H, N211, A16V) within the cationic trypsinogen gene have been identified in patients with hereditary pancreatitis (HP). A genetic background has also been discussed for idiopathic juvenile chronic pancreatitis (IJCP), which closely mimicks the clinical pattern of HP, and alcoholic chronic pancreatitis because only a small number of heavy drinkers develop pancreatitis. This prompted us to screen 104 patients in our well-defined pancreatitis cohort for the currently known cationic trypsinogen gene mutations. The R117H mutation was detected in seven patients (six patients of two clinically classified HP families, one patient with clinically classified IJCP) and the A16V mutation in one IJCP patient. No cationic trypsinogen gene mutations were found in the remaining 96 patients with chronic and recurrent acute pancreatitis of various etiologies. Our results demonstrate the need for genetic testing to exclude HP, particularly in the presence of an atypical or unknown family history. In addition, cationic trypsinogen gene mutations are no predisposing factor in patients with chronic and recurrent acute pancreatitis of different etiologies. PMID:11138965

Truninger, K; Köck, J; Wirth, H P; Muellhaupt, B; Arnold, C; von Weizsäcker, F; Seifert, B; Ammann, R W; Blum, H E

2001-01-01

291

Molecular analysis of mutations in the CSB (ERCC6) gene in patients with Cockayne syndrome.  

PubMed Central

Cockayne syndrome is a multisystem sun-sensitive genetic disorder associated with a specific defect in the ability to perform transcription-coupled repair of active genes after UV irradiation. Two complementation groups (CS-A and CS-B) have been identified, and 80% of patients have been assigned to the CS-B complementation group. We have analyzed the sites of the mutations in the CSB gene in 16 patients, to determine the spectrum of mutations in this gene and to see whether the nature of the mutation correlates with the type and severity of the clinical symptoms. In nine of the patients, the mutations resulted in truncated products in both alleles, whereas, in the other seven, at least one allele contained a single amino acid change. The latter mutations were confined to the C-terminal two-thirds of the protein and were shown to be inactivating by their failure to restore UV-irradiation resistance to hamster UV61 cells, which are known to be defective in the CSB gene. Neither the site nor the nature of the mutation correlated with the severity of the clinical features. Severe truncations were found in different patients with either classical or early-onset forms of the disease. PMID:9443879

Mallery, D L; Tanganelli, B; Colella, S; Steingrimsdottir, H; van Gool, A J; Troelstra, C; Stefanini, M; Lehmann, A R

1998-01-01

292

Mutations in the Human Ca2+-Sensing-Receptor Gene That Cause Familial Hypocalciuric Hypercalcemia  

PubMed Central

We report five novel mutations in the human Ca2+-sensing-receptor gene that cause familial hypocalciuric hypercalcemia (FHH) or neonatal severe hyperparathyroidism. Each gene defect is a missense mutation (228Arg?Gln, 139Thr?Met, 144Gly?Glu, 63Arg?Met, and 67Arg?Cys) that encodes a nonconservative amino acid alteration. These mutations are each predicted to be in the Ca2+-sensing receptor's large extracellular domain. In three families with FHH linked to the Ca2+-sensing-receptor gene on chromosome 3 and in unrelated individuals probands with FHH, mutations were not detected in protein-coding sequences. On the basis of these data and previous analyses, we suggest that there are a wide range of mutations that cause FHH. Mutations that perturb the structure and function of the extracellular or transmembrane domains of the receptor and those that affect noncoding sequences of the Ca2+-sensing-receptor gene can cause FHH. ImagesFigure 2 PMID:7726161

Chou, Yah-Huei Wu; Pollak, Martin R.; Brandi, Maria L.; Toss, Goran; Arnqvist, H.; Atkinson, A. Brew; Papapoulos, Socrates E.; Marx, Stephen; Brown, Edward M.; Seidman, J. G.; Seidman, Christine E.

1995-01-01

293

Mutation Survey of Known LCA Genes and Loci in the Saudi Arabian Population  

PubMed Central

Purpose The purpose of this study was to perform a comprehensive survey of all known Leber congenital amaurosis (LCA) genes and loci in a collection of 37 consanguineous LCA families from Saudi Arabia. Methods Direct PCR and sequencing were used to screen 13 known LCA genes (GUCY2D, CRX, RPE65, TULP1, AIPL1, CRB1, RPGRIP1, LRAT, RDH12, IMPDH1, CEP290, RD3, LCA5). In addition, families without mutations identified were further screened with STR markers around these 13 known LCA genes and two loci. Results Disease-causing mutations were identified in nine of the 37 families: five in TULP1, two in CRB1, one in RPE65, and one in GUCY2D. Mutations in known genes only accounted for 24% of the Saudi families—much less than what has been observed in the European population (65%). Phenotype-genotype analysis was carried out to investigate the LCA disease penetrance for all families whose mutations identified. All identified mutations were found to segregate perfectly with the disease phenotype. On the other hand, severity of the disease varies for different patients carrying the same mutation and even within the same family. Furthermore, based on homozygosity mapping with both STR and SNP markers, one family is likely to map to the LCA3 locus. Conclusions These results underscore the importance of studying LCA disease families from different ethnic backgrounds to identify additional novel LCA disease genes. Furthermore, perfect segregation between mutation and disease indicates that LCA is fully penetrant. However, phenotypic variations among patients carrying the same mutation suggest that at least some of the variations in the clinical phenotype is due to modification from the genetic background, environment, or other factors. PMID:18936139

Li, Yumei; Wang, Hui; Peng, Jianlan; Gibbs, Richard A.; Lewis, Richard Alan; Lupski, James R.; Mardon, Graeme; Chen, Rui

2009-01-01

294

VarWalker: Personalized Mutation Network Analysis of Putative Cancer Genes from Next-Generation Sequencing Data  

PubMed Central

A major challenge in interpreting the large volume of mutation data identified by next-generation sequencing (NGS) is to distinguish driver mutations from neutral passenger mutations to facilitate the identification of targetable genes and new drugs. Current approaches are primarily based on mutation frequencies of single-genes, which lack the power to detect infrequently mutated driver genes and ignore functional interconnection and regulation among cancer genes. We propose a novel mutation network method, VarWalker, to prioritize driver genes in large scale cancer mutation data. VarWalker fits generalized additive models for each sample based on sample-specific mutation profiles and builds on the joint frequency of both mutation genes and their close interactors. These interactors are selected and optimized using the Random Walk with Restart algorithm in a protein-protein interaction network. We applied the method in >300 tumor genomes in two large-scale NGS benchmark datasets: 183 lung adenocarcinoma samples and 121 melanoma samples. In each cancer, we derived a consensus mutation subnetwork containing significantly enriched consensus cancer genes and cancer-related functional pathways. These cancer-specific mutation networks were then validated using independent datasets for each cancer. Importantly, VarWalker prioritizes well-known, infrequently mutated genes, which are shown to interact with highly recurrently mutated genes yet have been ignored by conventional single-gene-based approaches. Utilizing VarWalker, we demonstrated that network-assisted approaches can be effectively adapted to facilitate the detection of cancer driver genes in NGS data. PMID:24516372

Jia, Peilin; Zhao, Zhongming

2014-01-01

295

VarWalker: personalized mutation network analysis of putative cancer genes from next-generation sequencing data.  

PubMed

A major challenge in interpreting the large volume of mutation data identified by next-generation sequencing (NGS) is to distinguish driver mutations from neutral passenger mutations to facilitate the identification of targetable genes and new drugs. Current approaches are primarily based on mutation frequencies of single-genes, which lack the power to detect infrequently mutated driver genes and ignore functional interconnection and regulation among cancer genes. We propose a novel mutation network method, VarWalker, to prioritize driver genes in large scale cancer mutation data. VarWalker fits generalized additive models for each sample based on sample-specific mutation profiles and builds on the joint frequency of both mutation genes and their close interactors. These interactors are selected and optimized using the Random Walk with Restart algorithm in a protein-protein interaction network. We applied the method in >300 tumor genomes in two large-scale NGS benchmark datasets: 183 lung adenocarcinoma samples and 121 melanoma samples. In each cancer, we derived a consensus mutation subnetwork containing significantly enriched consensus cancer genes and cancer-related functional pathways. These cancer-specific mutation networks were then validated using independent datasets for each cancer. Importantly, VarWalker prioritizes well-known, infrequently mutated genes, which are shown to interact with highly recurrently mutated genes yet have been ignored by conventional single-gene-based approaches. Utilizing VarWalker, we demonstrated that network-assisted approaches can be effectively adapted to facilitate the detection of cancer driver genes in NGS data. PMID:24516372

Jia, Peilin; Zhao, Zhongming

2014-02-01

296

Identification of recurrent mutations in the ARS (component B) gene encoding SLURP-1 in two families with mal de Meleda.  

PubMed

Mal de Meleda is a rare, autosomal recessive form of palmoplantar keratoderma. The disease has been mapped to chromosome 8qter, and in a recent study mutations in the ARS gene have been identified in families with this disorder. Here, we report two unrelated families with mal de Meleda, in which two different homozygous mutations in the ARS gene were identified. These findings support the notion that mutations in the ARS gene are pathogenic in mal de Meleda. PMID:12535203

Ward, Kimberley Morine; Yerebakan, Ozlem; Yilmaz, Ertan; Celebi, Jülide Tok

2003-01-01

297

Identification of two poorly prognosed ovarian carcinoma subtypes associated with CHEK2 germ-line mutation and non-CHEK2 somatic mutation gene signatures.  

PubMed

High-grade serous ovarian cancer (HG-SOC), a major histologic type of epithelial ovarian cancer (EOC), is a poorly-characterized, heterogeneous and lethal disease where somatic mutations of TP53 are common and inherited loss-of-function mutations in BRCA1/2 predispose to cancer in 9.5-13% of EOC patients. However, the overall burden of disease due to either inherited or sporadic mutations is not known. We performed bioinformatics analyses of mutational and clinical data of 334 HG-SOC tumor samples from The Cancer Genome Atlas to identify novel tumor-driving mutations, survival-significant patient subgroups and tumor subtypes potentially driven by either hereditary or sporadic factors. We identified a sub-cluster of high-frequency mutations in 22 patients and 58 genes associated with DNA damage repair, apoptosis and cell cycle. Mutations of CHEK2, observed with the highest intensity, were associated with poor therapy response and overall survival (OS) of these patients (P = 8.00e-05), possibly due to detrimental effect of mutations at the nuclear localization signal. A 21-gene mutational prognostic signature significantly stratifies patients into relatively low or high-risk subgroups with 5-y OS of 37% or 6%, respectively (P = 7.31e-08). Further analysis of these genes and high-risk subgroup revealed 2 distinct classes of tumors characterized by either germline mutations of genes such as CHEK2, RPS6KA2 and MLL4, or somatic mutations of other genes in the signature. Our results could provide improvement in prediction and clinical management of HG-SOC, facilitate our understanding of this complex disease, guide the design of targeted therapeutics and improve screening efforts to identify women at high-risk of hereditary ovarian cancers distinct from those associated with BRCA1/2 mutations. PMID:24879340

Ow, Ghim Siong; Ivshina, Anna V; Fuentes, Gloria; Kuznetsov, Vladimir A

2014-07-15

298

Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours  

PubMed Central

Mixed lineage kinase 3 (MLK3) is a serine/threonine kinase, regulating MAPkinase signalling, in which cancer-associated mutations have never been reported. In this study, 174 primary gastrointestinal cancers (48 hereditary and 126 sporadic forms) and 7 colorectal cancer cell lines were screened for MLK3 mutations. MLK3 mutations were significantly associated with MSI phenotype in primary tumours (P = 0.0005), occurring in 21% of the MSI carcinomas. Most MLK3 somatic mutations identified were of the missense type (62.5%) and more than 80% of them affected evolutionarily conserved residues. A predictive 3D model points to the functional relevance of MLK3 missense mutations, which cluster in the kinase domain. Further, the model shows that most of the altered residues in the kinase domain probably affect MLK3 scaffold properties, instead of its kinase activity. MLK3 missense mutations showed transforming capacity in vitro and cells expressing the mutant gene were able to develop locally invasive tumours, when subcutaneously injected in nude mice. Interestingly, in primary tumours, MLK3 mutations occurred in KRAS and/or BRAF wild-type carcinomas, although not being mutually exclusive genetic events. In conclusion, we have demonstrated for the first time the presence of MLK3 mutations in cancer and its association to mismatch repair deficiency. Further, we demonstrated that MLK3 missense mutations found in MSI gastrointestinal carcinomas are functionally relevant. PMID:19955118

Velho, Sérgia; Oliveira, Carla; Paredes, Joana; Sousa, Sónia; Leite, Marina; Matos, Paulo; Milanezi, Fernanda; Ribeiro, Ana Sofia; Mendes, Nuno; Licastro, Danilo; Karhu, Auli; Oliveira, Maria José; Ligtenberg, Marjolijn; Hamelin, Richard; Carneiro, Fátima; Lindblom, Annika; Peltomaki, Paivi; Castedo, Sérgio; Schwartz, Simó; Jordan, Peter; Aaltonen, Lauri A.; Hofstra, Robert M.W.; Suriano, Gianpaolo; Stupka, Elia; Fialho, Arsenio M.; Seruca, Raquel

2010-01-01

299

High prevalence of occult paragangliomas in asymptomatic carriers of SDHD and SDHB gene mutations.  

PubMed

Hereditary paraganglioma is a benign tumor syndrome with an age-dependent penetrance. Carriers of germline mutations in the SDHB or SDHD genes may develop parasympathetic paragangliomas in the head and neck region or sympathetic catecholamine-secreting abdominal and thoracic paragangliomas (pheochromocytomas). In this study, we aimed to establish paraganglioma risk in 101 asymptomatic germline mutation carriers and evaluate the results of our surveillance regimen. Asymptomatic carriers of an SDHD or SDHB mutation were included once disease status was established by MRI diagnosis. Clinical surveillance revealed a head and neck paraganglioma in 28 of the 47 (59.6%) asymptomatic SDHD mutation carriers. Risk of tumor development was significantly lower in SDHB mutation carriers: 2/17 (11.8%, P=0.001). Sympathetic paragangliomas were encountered in two SDHD mutation carriers and in one SDHB mutation carrier. In conclusion, asymptomatic carriers of an SDHD mutation are at a high risk for occult parasympathetic paraganglioma. SDHB carrier risk is considerably lower, consistent with lower penetrance of SDHB mutations. For both syndromes, the risk of symptomless sympathetic paragangliomas is small. PMID:22948026

Heesterman, Berdine L; Bayley, Jean Pierre; Tops, Carli M; Hes, Frederik J; van Brussel, Bernadette T J; Corssmit, Eleonora P M; Hamming, Jaap F; van der Mey, Andel G L; Jansen, Jeroen C

2013-04-01

300

Frequency of mutations and polymorphisms in borderline ovarian tumors of known cancer genes.  

PubMed

Borderline ovarian tumors represent an understudied subset of ovarian tumors. Most studies investigating aberrations in borderline tumors have focused on KRAS/BRAF mutations. In this study, we conducted an extensive analysis of mutations and single-nucleotide polymorphisms (SNPs) in borderline ovarian tumors. Using the Sequenom MassArray platform, we investigated 160 mutations/polymorphisms in 33 genes involved in cell signaling, apoptosis, angiogenesis, cell cycle regulation and cellular senescence. Of 52 tumors analyzed, 33 were serous, 18 mucinous and 1 endometrioid. KRAS c.35G>A p.Gly12Asp mutations were detected in eight tumors (six serous and two mucinous), BRAF V600E mutations in two serous tumors, and PIK3CA H1047Y and PIK3CA E542K mutations in a serous and an endometrioid BOT, respectively. CTNNB1 mutation was detected in a serous tumor. Potentially functional polymorphisms were found in vascular endothelial growth factor (VEGF), ABCB1, FGFR2 and PHLPP2. VEGF polymorphisms were the most common and detected at four loci. PHLPP2 polymorphisms were more frequent in mucinous as compared with serous tumors (P=0.04), with allelic imbalance in one case. This study represents the largest and most comprehensive analysis of mutations and functional SNPs in borderline ovarian tumors to date. At least 25% of borderline ovarian tumors harbor somatic mutations associated with potential response to targeted therapeutics. PMID:23174937

Stemke-Hale, Katherine; Shipman, Kristy; Kitsou-Mylona, Isidora; de Castro, David G; Hird, Vicky; Brown, Robert; Flanagan, James; Gabra, Hani; Mills, Gordon B; Agarwal, Roshan; El-Bahrawy, Mona

2013-04-01

301

Identification of a germ-line mutation in the p53 gene in a patient with an intracranial ependymoma  

SciTech Connect

The authors detected a germ-line mutation of the p53 gene in a patient with a malignant ependymoma of the posterior fossa. This mutation, which was found at codon 242, resulted in an amino acid substitution in a highly conserved site of exon 7 of the p53 gene; the same mutation was found in both the germ-line and tumor tissue. This is the most common region of previously described somatic p53 mutations in tumor specimens and of the germ-line p53 mutations in patients with the Li-Fraumeni cancer syndrome. Evaluation of the patient's family revealed several direct maternal and paternal relatives who had died at a young age from different types of cancer. The association of a germ-line p53 mutation with an intracranial malignancy and a strong family history of cancer suggests that p53 gene mutations predispose a person to malignancy and, like retinoblastoma mutations, may be inherited.

Metzger, A.K.; Duyk, G.; Daneshvar, L.; Edwards, M.S.B.; Cogen, P.H. (Univ. of California, San Francisco (United States)); Sheffield, V.C. (Univ. of Iowa, Iowa City (United States))

1991-09-01

302

GeneChip{sup {trademark}} screening assay for cystic fibrosis mutations  

SciTech Connect

GeneChip{sup {trademark}} assays are based on high density, carefully designed arrays of short oligonucleotide probes (13-16 bases) built directly on derivatized silica substrates. DNA target sequence analysis is achieved by hybridizing fluorescently labeled amplification products to these arrays. Fluorescent hybridization signals located within the probe array are translated into target sequence information using the known probe sequence at each array feature. The mutation screening assay for cystic fibrosis includes sets of oligonucleotide probes designed to detect numerous different mutations that have been described in 14 exons and one intron of the CFTR gene. Each mutation site is addressed by a sub-array of at least 40 probe sequences, half designed to detect the wild type gene sequence and half designed to detect the reported mutant sequence. Hybridization with homozygous mutant, homozygous wild type or heterozygous targets results in distinctive hybridization patterns within a sub-array, permitting specific discrimination of each mutation. The GeneChip probe arrays are very small (approximately 1 cm{sup 2}). There miniature size coupled with their high information content make GeneChip probe arrays a useful and practical means for providing CF mutation analysis in a clinical setting.

Cronn, M.T.; Miyada, C.G.; Fucini, R.V. [Affymetrix, Santa Clara, CA (United States)] [and others

1994-09-01

303

Mutations That Alter the Timing and Pattern of Cubitus Interruptus Gene Expression in Drosophila Melanogaster  

PubMed Central

The cubitus interruptus (ci) gene is a member of the Drosophila segment polarity gene family and encodes a protein with a zinc finger domain homologous to the vertebrate Gli genes and the nematode tra-1 gene. Three classes of existing mutations in the ci locus alter the regulation of ci expression and can be used to examine ci function during development. The first class of ci mutations causes interruptions in wing veins four and five due to inappropriate expression of the ci product in the posterior compartment of imaginal discs. The second class of mutations eliminates ci protein early in embryogenesis and causes the deletion of structures that are derived from the region including and adjacent to the engrailed expressing cells. The third class of mutations eliminates ci protein later in embryogenesis and blocks the formation of the ventral naked cuticle. The loss of ci expression at these two different stages in embryonic development correlates with the subsequent elimination of wingless expression. Adults heterozygous for the unique ci(Ce) mutation have deletions between wing veins three and four. A similar wing defect is present in animals mutant for the segment polarity gene fused that encodes a putative serine/threonine kinase. In ci(Ce)/+ and fused mutants, the deletions between wing veins three and four correlate with increased ci protein levels in the anterior compartment. Thus, proper regulation of both the ci mRNA and protein appears to be critical for normal Drosophila development. PMID:7705626

Slusarski, D. C.; Motzny, C. K.; Holmgren, R.

1995-01-01

304

Mutations that alter the timing and pattern of cubitus interruptus gene expression in Drosophila melanogaster.  

PubMed

The cubitus interruptus (ci) gene is a member of the Drosophila segment polarity gene family and encodes a protein with a zinc finger domain homologous to the vertebrate Gli genes and the nematode tra-1 gene. Three classes of existing mutations in the ci locus alter the regulation of ci expression and can be used to examine ci function during development. The first class of ci mutations causes interruptions in wing veins four and five due to inappropriate expression of the ci product in the posterior compartment of imaginal discs. The second class of mutations eliminates ci protein early in embryogenesis and causes the deletion of structures that are derived from the region including and adjacent to the engrailed expressing cells. The third class of mutations eliminates ci protein later in embryogenesis and blocks the formation of the ventral naked cuticle. The loss of ci expression at these two different stages in embryonic development correlates with the subsequent elimination of wingless expression. Adults heterozygous for the unique ciCe mutation have deletions between wing veins three and four. A similar wing defect is present in animals mutant for the segment polarity gene fused that encodes a putative serine/threonine kinase. In ciCe/+ and fused mutants, the deletions between wing veins three and four correlate with increased ci protein levels in the anterior compartment. Thus, proper regulation of both the ci mRNA and protein appears to be critical for normal Drosophila development. PMID:7705626

Slusarski, D C; Motzny, C K; Holmgren, R

1995-01-01

305

The original shaker-with-syndactylism mutation (sy) is a contiguous gene deletion syndrome.  

PubMed

Tests for allelism among mice with four different mutant alleles at the shaker-with-syndactylism locus on mouse Chromosome (Chr) 18 provide evidence that the original radiation-induced mutation, sy, is a deletion including at least two genes associated with distinct phenotypes. Mice homozygous for sy have syndactylous feet and other skeletal malformations, are deaf, and exhibit abnormal behavior characteristic of vestibular dysfunction. Two less severe spontaneous mutations, shown to be allelic with sy, cause syndactylism when homozygous (hence named fused phalanges, sy(fp) and sy(fp-2J)), but do not affect hearing and behavior. Here we describe a third spontaneous mutation allelic with sy that does not affect foot morphology (hence named no syndactylism, sy(ns)), but that does cause deafness and balance defects when homozygous. Complementation test results indicate that sy(fp) and sy(fp-2J) are alleles of the same gene, but that sy(ns) is an allele of a different gene. The original sy mutation, therefore, includes both of the genes defined by these three spontaneous mutations. Typing of DNA markers in sy/sy mice revealed a deletion of approximately 1 cM in the sy region of Chr 18, including D18Mit52, D18Mit124, D18Mit181, and D18Mit205. The genetic relationships described here will aid in positional cloning efforts to identify the genes responsible for the disparate phenotypes associated with the sy locus. PMID:9799839

Johnson, K R; Cook, S A; Zheng, Q Y

1998-11-01

306

Release of Epigenetic Gene Silencing by Trans-Acting Mutations in Arabidopsis  

Microsoft Academic Search

Gene silencing in plants inactivates transgenes introduced into plants and\\/or endogenous homologous genes. This stable but potentially reversible loss of gene activity resembles epigenetic changes that occur in normal development. The stability of silencing implies the involvement of trans-acting components, although none of them have been identified so far. Here we report the finding of second-site mutations interfering with maintenance

Ortrun Mittelsten Scheid; Karin Afsar; Jerzy Paszkowski

1998-01-01

307

A mutation in a dog gene opens new research into the defensin protein  

NSDL National Science Digital Library

Researchers who were trying to find the mutated gene that controls coat color in dogs now report that they found the gene, and have also discovered that it has an unexpected additional role. The gene also sends a signal to a member of a protein family that is responsible for defending the body against infection. The proteins are called defensins, because their job is to defend the body.

American Association for the Advancement of Science (AAAS;)

2007-10-18

308

The stop mutation R553X in the CFTR gene results in exon skipping  

SciTech Connect

Stop or nonsense mutations are known to disrupt gene function in a number of different ways. The authors have studied the effects of the stop mutation R553X in exon 11 of the CFTR gene by analyzing mRNA extracted from nasal epithelial cells harvested from patients with cystic fibrosis. Four patients who were compound heterozygotes for the R553X mutation were studied. Ten non-CF control subjects were also studied. In all four patients, full-length CFTR mRNA was identified, but only a very small proportion of this was derived from the R553X allele. A smaller transcript, lacking exon 11, was also seen in the R553X patients but not in the controls. Most of this transcript was derived from the R553X allele. These results suggest that the R553X mutation results in skipping of the exon in which it is located. 14 refs., 3 figs.

Hull, J.; Shackleton, S.; Harris, A. (Institute of Molecular Medicine, Oxford (United Kingdom))

1994-01-15

309

The interplay of mutations and electronic properties in disease-related genes  

E-print Network

Electronic properties of DNA are believed to play a crucial role in many phenomena in living organisms, for example the location of DNA lesions by base excision repair (BER) glycosylases and the regulation of tumor-suppressor genes such as p53 by detection of oxidative damage. However, the reproducible measurement and modelling of charge migration through DNA molecules at the nanometer scale remains a challenging and controversial subject even after more than a decade of intense efforts. Here we show, by analysing 162 disease-related genes from a variety of medical databases with a total of almost 20,000 observed pathogenic mutations, a significant difference in the electronic properties of the population of observed mutations compared to the set of all possible mutations. Our results have implications for the role of the electronic properties of DNA in cellular processes, and hint at the possibility of prediction, early diagnosis and detection of mutation hotspots.

Shih, Chi-Tin; Hsu, Ching-Ling; Cheng, Yun-Yin; Römer, Rudolf A

2011-01-01

310

The interplay of mutations and electronic properties in disease-related genes  

NASA Astrophysics Data System (ADS)

Electronic properties of DNA are believed to play a crucial role in many phenomena in living organisms, for example the location of DNA lesions by base excision repair (BER) glycosylases and the regulation of tumor-suppressor genes such as p53 by detection of oxidative damage. However, the reproducible measurement and modelling of charge migration through DNA molecules at the nanometer scale remains a challenging and controversial subject even after more than a decade of intense efforts. Here we show, by analysing 162 disease-related genes from a variety of medical databases with a total of almost 20,000 observed pathogenic mutations, a significant difference in the electronic properties of the population of observed mutations compared to the set of all possible mutations. Our results have implications for the role of the electronic properties of DNA in cellular processes, and hint at the possibility of prediction, early diagnosis and detection of mutation hotspots.

Shih, Chi-Tin; Wells, Stephen A.; Hsu, Ching-Ling; Cheng, Yun-Yin; Römer, Rudolf A.

2012-02-01

311

Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice.  

PubMed

Calcifications in the basal ganglia are a common incidental finding and are sometimes inherited as an autosomal dominant trait (idiopathic basal ganglia calcification (IBGC)). Recently, mutations in the PDGFRB gene coding for the platelet-derived growth factor receptor ? (PDGF-R?) were linked to IBGC. Here we identify six families of different ancestry with nonsense and missense mutations in the gene encoding PDGF-B, the main ligand for PDGF-R?. We also show that mice carrying hypomorphic Pdgfb alleles develop brain calcifications that show age-related expansion. The occurrence of these calcium depositions depends on the loss of endothelial PDGF-B and correlates with the degree of pericyte and blood-brain barrier deficiency. Thus, our data present a clear link between Pdgfb mutations and brain calcifications in mice, as well as between PDGFB mutations and IBGC in humans. PMID:23913003

Keller, Annika; Westenberger, Ana; Sobrido, Maria J; García-Murias, Maria; Domingo, Aloysius; Sears, Renee L; Lemos, Roberta R; Ordoñez-Ugalde, Andres; Nicolas, Gael; da Cunha, José E Gomes; Rushing, Elisabeth J; Hugelshofer, Michael; Wurnig, Moritz C; Kaech, Andres; Reimann, Regina; Lohmann, Katja; Dobri?i?, Valerija; Carracedo, Angel; Petrovi?, Igor; Miyasaki, Janis M; Abakumova, Irina; Mäe, Maarja Andaloussi; Raschperger, Elisabeth; Zatz, Mayana; Zschiedrich, Katja; Klepper, Jörg; Spiteri, Elizabeth; Prieto, Jose M; Navas, Inmaculada; Preuss, Michael; Dering, Carmen; Jankovi?, Milena; Paucar, Martin; Svenningsson, Per; Saliminejad, Kioomars; Khorshid, Hamid R K; Novakovi?, Ivana; Aguzzi, Adriano; Boss, Andreas; Le Ber, Isabelle; Defer, Gilles; Hannequin, Didier; Kosti?, Vladimir S; Campion, Dominique; Geschwind, Daniel H; Coppola, Giovanni; Betsholtz, Christer; Klein, Christine; Oliveira, Joao R M

2013-09-01

312

A novel nonsense mutation of the KAL1 gene (p.Trp204*) in Kallmann syndrome  

PubMed Central

Objective To describe a novel KAL1 mutation in patients affected by Kallmann syndrome. Setting Endocrinology Clinic of the João de Barros Barreto University Hospital – Federal University of Pará, Brazil. Methods Clinical examination, hormone assays and sequencing of exons 5, 6 and 9 of the KAL1 gene in four Brazilian brothers with Kallmann syndrome. Results Detected a novel KAL1 mutation, c.612G.A/p.Trp204*, in four hemizygous brothers with Kallmann syndrome, and five heterozygous female family members. Conclusion The novel p.Trp204* mutation of the KAL1 gene results in the production of a truncated anosmin-1 enzyme in patients with Kallmann syndrome. This finding broadens the spectrum of pathogenic mutations for this disease. PMID:25328414

El Husny, Antonette Souto; Raiol-Moraes, Milene; Fernandes-Caldato, Milena Coelho; Ribeiro-dos-Santos, Ândrea

2014-01-01

313

Germline mutations in the PAF1 complex gene CTR9 predispose to Wilms tumour.  

PubMed

Wilms tumour is a childhood kidney cancer. Here we identify inactivating CTR9 mutations in 3 of 35 Wilms tumour families, through exome and Sanger sequencing. By contrast, no similar mutations are present in 1,000 population controls (P<0.0001). Each mutation segregates with Wilms tumour in the family and a second mutational event is present in available tumours. CTR9 is a key component of the polymerase-associated factor 1 complex which has multiple roles in RNA polymerase II regulation and is implicated in embryonic organogenesis and maintenance of embryonic stem cell pluripotency. These data establish CTR9 as a Wilms tumour predisposition gene and suggest it acts as a tumour suppressor gene. PMID:25099282

Hanks, Sandra; Perdeaux, Elizabeth R; Seal, Sheila; Ruark, Elise; Mahamdallie, Shazia S; Murray, Anne; Ramsay, Emma; Del Vecchio Duarte, Silvana; Zachariou, Anna; de Souza, Bianca; Warren-Perry, Margaret; Elliott, Anna; Davidson, Alan; Price, Helen; Stiller, Charles; Pritchard-Jones, Kathy; Rahman, Nazneen

2014-01-01

314

Germline mutations in the PAF1 complex gene CTR9 predispose to Wilms tumour  

PubMed Central

Wilms tumour is a childhood kidney cancer. Here we identify inactivating CTR9 mutations in 3 of 35 Wilms tumour families, through exome and Sanger sequencing. By contrast, no similar mutations are present in 1,000 population controls (P<0.0001). Each mutation segregates with Wilms tumour in the family and a second mutational event is present in available tumours. CTR9 is a key component of the polymerase-associated factor 1 complex which has multiple roles in RNA polymerase II regulation and is implicated in embryonic organogenesis and maintenance of embryonic stem cell pluripotency. These data establish CTR9 as a Wilms tumour predisposition gene and suggest it acts as a tumour suppressor gene. PMID:25099282

Hanks, Sandra; Perdeaux, Elizabeth R.; Seal, Sheila; Ruark, Elise; Mahamdallie, Shazia S.; Murray, Anne; Ramsay, Emma; Del Vecchio Duarte, Silvana; Zachariou, Anna; de Souza, Bianca; Warren-Perry, Margaret; Elliott, Anna; Davidson, Alan; Price, Helen; Stiller, Charles; Pritchard-Jones, Kathy; Rahman, Nazneen

2014-01-01

315

SETX gene mutation in a family diagnosed autosomal dominant proximal spinal muscular atrophy.  

PubMed

Autosomal dominant proximal spinal muscular atrophy (ADSMA) is a rare disorder with unknown gene defects in the majority of families. Here we describe a family where the diagnosis of juvenile and adult onset ADSMA was made in three individuals. Because of retained tendon reflexes an atypical course of juvenile amyotrophic lateral sclerosis (ALS4) was considered. SETX gene sequencing revealed the previously reported heterozygous missense mutation c.1166Tmutation of unknown function V891A in trans. Altogether these results expand the phenotype associated with SETX mutations supporting the notion that patients with ADSMA should be investigated for SETX mutations. PMID:22088787

Rudnik-Schöneborn, Sabine; Arning, Larissa; Epplen, Jörg T; Zerres, Klaus

2012-03-01

316

A Nonsense Mutation in the Acid ?-Glucosidase Gene Causes Pompe Disease in Finnish and Swedish Lapphunds  

PubMed Central

Pompe disease is a recessively inherited and often fatal disorder caused by the deficiency of acid ?-glucosidase, an enzyme encoded by the GAA gene and needed to break down glycogen in lysosomes. This glycogen storage disease type II has been reported also in Swedish Lapphund dogs. Here we describe the genetic defect in canine Pompe disease and show that three related breeds from Scandinavia carry the same mutation. The affected dogs are homozygous for the GAA c.2237G>A mutation leading to a premature stop codon at amino acid position 746. The corresponding mutation has previously been reported in humans and causes infantile Pompe disease in combination with a second fully deleterious mutation. The affected dogs from both the Finnish as well as the Swedish breed mimic infantile-onset Pompe disease genetically, but also clinico-pathologically. Therefore this canine model provides a valuable tool for preclinical studies aimed at the development of gene therapy in Pompe disease. PMID:23457621

Seppälä, Eija H.; Reuser, Arnold J. J.; Lohi, Hannes

2013-01-01

317

Germ-line mutations in the first 14 exons of the adenomatous polyposis coli (APC) gene.  

PubMed Central

The first 14 exons of the APC gene have been screened by the denaturation gradient gel electrophoresis method in 160 unrelated patients with familial adenomatous polyposis coli (APC) syndrome. Four polymorphic variants corresponding to silent mutations not associated with the disease phenotype were observed. Mutations predicted to alter the coding property of the APC gene were observed in 26 patients. All these mutations are expected to lead either to aberrant splicing, to synthesis of a truncated APC protein because of the emergence of a stop codon, or to a change in the translation reading frame. Single-base-pair substitutions were observed on 21 occasions. The most frequent mutation (eight cases) was a C-to-T change which exclusively occurred on the nontranscribed strand within a CG dinucleotide. Images Figure 1 Figure 2 PMID:8381580

Olschwang, S; Laurent-Puig, P; Groden, J; White, R; Thomas, G

1993-01-01

318

Increase in hypoxanthine-guanine phosphoribosyl transferase gene mutations by exposure to electric field.  

PubMed

Previously, we reported that exposure to extremely low frequency magnetic field (400 mT) increased in hypoxanthine-guanine phosphoribosyl transferase (HPRT) gene mutations. However, it is unclear these mutations were induced by magnetic field (MF), electric field (EF), or both. To explore this question, a new exposure apparatus for EF was manufactured. We observed an increase in HPRT gene mutations in Chinese hamster ovary (CHO) cells after exposure to EF (10 V/m, 60 Hz) for 10 h. The mutant frequency by EF-exposure was an approximate 2-fold of that by sham-exposure. Our data suggest that the mutations induced by exposure of cells to the variable magnetic field at 400 mT may be, in part, due to the induced EF. PMID:11212867

Ding, G R; Wake, K; Taki, M; Miyakoshi, J

2001-01-19

319

Mutation Profile of the CDH23 Gene in 56 Probands with Usher Syndrome Type I  

PubMed Central

Mutations in the human gene encoding cadherin 23 (CDH23) cause Usher syndrome type 1D (USH1D) and nonsyndromic hearing loss. Individuals with Usher syndrome type I have profound congenital deafness, vestibular areflexia and usually begin to exhibit signs of RP in early adolescence. In the present study, we carried out the mutation analysis in all 69 exons of the CDH23 gene in 56 Usher type 1 probands already screened for mutations in MYO7A. A total of 18 of 56 subjects (32.1%) were observed to have one or two CDH23 variants that are presumed to be pathologic. Twenty one different pathologic genome variants were observed of which 15 were novel. Out of a total of 112 alleles, 31 (27.7%) were considered pathologic. Based on our results it is estimated that about 20% of patients with Usher syndrome type I have CDH23 mutations. PMID:18429043

Oshima, A.; Jaijo, T.; Aller, E.; Millan, J.M.; Carney, C.; Usami, S.; Moller, C.; Kimberling, W.J.

2008-01-01

320

Significance of sarcomere gene mutations analysis in the end-stage phase of hypertrophic cardiomyopathy.  

PubMed

End-stage hypertrophic cardiomyopathy (ES-HC) has an ominous prognosis. Whether genotype can influence ES-HC occurrence is unresolved. We assessed the spectrum and clinical correlates of HC-associated mutations in a large multicenter cohort with end-stage ES-HC. Sequencing analysis of 8 sarcomere genes (MYH7, MYBPC3, TNNI3, TNNT2, TPM1, MYL2, MYL3, and ACTC1) and 2 metabolic genes (PRKAG2 and LAMP2) was performed in 156 ES-HC patients with left ventricular (LV) ejection fraction (EF) <50%. A comparison among mutated and negative ES-HC patients and a reference cohort of 181 HC patients with preserved LVEF was performed. Overall, 131 mutations (36 novel) were identified in 104 ES-HC patients (67%) predominantly affecting MYH7 and MYBPC3 (80%). Complex genotypes with double or triple mutations were present in 13% compared with 5% of the reference cohort (p = 0.013). The distribution of mutations was otherwise indistinguishable in the 2 groups. Among ES-HC patients, those presenting at first evaluation before the age of 20 had a 30% prevalence of complex genotypes compared with 19% and 21% in the subgroups aged 20 to 59 and ?60 years (p = 0.003). MYBPC3 mutation carriers with ES-HC were older than patients with MYH7, other single mutations, or multiple mutations (median 41 vs 16, 26, and 28 years, p ?0.001). Outcome of ES-HC patients was severe irrespective of genotype. In conclusion, the ES phase of HC is associated with a variable genetic substrate, not distinguishable from that of patients with HC and preserved EF, except for a higher frequency of complex genotypes with double or triple mutations of sarcomere genes. PMID:25037680

Biagini, Elena; Olivotto, Iacopo; Iascone, Maria; Parodi, Maria I; Girolami, Francesca; Frisso, Giulia; Autore, Camillo; Limongelli, Giuseppe; Cecconi, Massimiliano; Maron, Barry J; Maron, Martin S; Rosmini, Stefania; Formisano, Francesco; Musumeci, Beatrice; Cecchi, Franco; Iacovoni, Attilio; Haas, Tammy S; Bacchi Reggiani, Maria L; Ferrazzi, Paolo; Salvatore, Francesco; Spirito, Paolo; Rapezzi, Claudio

2014-09-01

321

G388R mutation of the FGFR4 gene is not relevant to breast cancer prognosis  

Microsoft Academic Search

This study screened large cohorts of node-positive and node-negative breast cancer patients to determine whether the G388R mutation of the FGFR4 gene is a useful prognostic marker for breast cancer as reported by Bange et al in 2002. Node-positive (n=139) and node-negative (n=95) breast cancer cohorts selected for mutation screening were followed up for median periods of 89 and 87

P Jézéquel; L Campion; M-P Joalland; M Millour; F Dravet; J-M Classe; V Delecroix; R Deporte; P Fumoleau; G Ricolleau

2004-01-01

322

C1824T mutation in the LMNA gene has no association with senile cataract  

Microsoft Academic Search

Mutations in the LMNA gene encoding lamins A\\/C are responsible for Hutchinson-Gilford syndrome (HGS), a disorder of premature aging. Cataract is 1 of the main manifestations. The most prevalent mutation in Hutchinson-Gilford syndrome is C1824T, which activates a cryptic splice donor site to produce an abnormal lamin A protein. The purpose of this study was to investigate a possible association

Tamilla Sadikov; Amos J. Simon; Bat-Chen R. Avraham-Lubin; Olga Dratviman-Storobinsky; Yoram Cohen; Nitza Goldenberg-Cohen

323

HIF gene mutation found in tumor cells offers new clues about cancer metabolism  

Cancer.gov

For the first time, a mutation in HIF2?, a specific group of genes known as transcription factors that is involved in red blood cell production and cell metabolism, has been identified in cancer tumor cells. Researchers from Huntsman Cancer Institute (HCI) at the University of Utah and the National Institutes of Health found the mutation in tumor cells of two patients with the rare cancers paraganglioma/pheochromocytoma and somatostatinoma.

324

A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2  

Microsoft Academic Search

Amyotrophic lateral sclerosis 2 (ALS2) is an autosomal recessive form of juvenile ALS and has been mapped to human chromosome 2q33. Here we report the identification of two independent deletion mutations linked to ALS2 in the coding exons of the new gene ALS2. These deletion mutations result in frameshifts that generate premature stop codons. ALS2 is expressed in various tissues

Shinji Hadano; Collette K. Hand; Hitoshi Osuga; Yoshiko Yanagisawa; Asako Otomo; Rebecca S. Devon; Natsuki Miyamoto; Junko Showguchi-Miyata; Yoshinori Okada; Roshni Singaraja; Denise A. Figlewicz; Thomas Kwiatkowski; Betsy A. Hosler; Tally Sagie; Jennifer Skaug; Jamal Nasir; Robert H. Brown; Stephen W. Scherer; Guy A. Rouleau; Michael R. Hayden; Joh-E Ikeda

2001-01-01

325

Six Novel P Gene Mutations and Oculocutaneous Albinism Type 2 Frequency in Japanese Albino Patients  

Microsoft Academic Search

Type 2 oculocutaneous albinism (OCA2) is an autosomal recessive disorder that results from mutations in the P gene that codes one of the melanosomal proteins, the function of which remains unknown. In this paper, we report the frequency of OCA2, 8%, among the Japanese albino population, six novel mutations containing four missense substitutions (P198L, P211L, R10W, M398I), and two splice

Tamio Suzuki; Yoshinori Miyamura; Jun Matsunaga; Hiroshi Shimizu; Yasuhiro Kawachi; Naoko Ohyama; Osamu Ishikawa; Tomoyuki Ishikawa; Hiroshi Terao; Yasushi Tomita

2003-01-01

326

Novel Mutations in the ABCC6 Gene of German Patients with Pseudoxanthoma Elasticum  

Microsoft Academic Search

Pseudoxanthoma elasticum (PXE) is a heritable disorder of the connective tissue affecting the skin, eyes, and cardiovascular system. Recently, the PXE candidate gene ABCC6 was identified and a limited number of ABCC6 mutations were observed in different PXE cohorts. To identify novel PXE-causing ABCC6 mutations in German patients with PXE, we investigated a cohort of 54 German PXE patients and

Veronika Schulz; Hendig. Doris; Christiane Szliska; Christian Gotting; Knut Kleesiek

2005-01-01

327

Mutational analysis of podocyte genes in children with sporadic steroid-resistant nephrotic syndrome.  

PubMed

Recent studies have demonstrated that mutations in 4 podocyte genes, NPHS1, NPHS2, CD2AP, and WT1, are associated with the pathogenesis of steroid-resistant nephrotic syndrome (SRNS). Systematic investigation of all 4 genes for sporadic SRNS in China has not been performed. We examined 10 Chinese children with sporadic SRNS who showed no response to immunosuppressive agents and 20 SRNS controls who exhibited a response to prolonged steroid or immunosuppressive treatment and achieved complete remission. We analyzed mutations in the 4 podocyte genes, NPHS1, NPHS2, CD2AP, and WT1. Mutational analysis was performed using polymerase chain reaction and direct sequencing. Of the 10 SRNS children who showed no response to immunosuppressive agents, the compound heterozygous NPHS1 mutations 2677A>G (T893A) and *142T>C were identified in 1 patient, while a heterozygous mutation in WT1, 1180C>T (R394W), was found in another patient. Of the 20 SRNS children showing complete remission who responded to prolonged steroid therapy or immunosuppressive agents, 4 heterozygous NPHS1 mutations, 928G>A, IVS8+30C>T, IVS21+14G>A, and IVS25-23C>T, were identified in 4 patients and a heterozygous CD2AP mutation, IVS7-135G>A, was identified in 1 patient. Our results indicate the necessity of genetic examination for mutations in podocyte genes in Chinese SRNS children who show no response to immunosuppressive agents. PMID:25501161

Feng, D N; Yang, Y H; Wang, D J; Meng, D C; Fu, R; Wang, J J; Yu, Z H

2014-01-01

328

Mutation analysis of GJB2 and GJB6 genes in Southeastern Brazilians with hereditary nonsyndromic deafness  

Microsoft Academic Search

In developed countries deafness has a genetic cause in over 60% of the cases. Contrastingly, in Brazil, it is estimated that\\u000a only 16% of all deafnesses are caused by genetic factors. Among hereditary hearing deficiencies, approximately half is caused\\u000a by mutations in the Gap Junction Protein Beta-2 (GJB2) gene, which encodes the protein Connexin 26 (Cx26). There are four mutations

Melissa de Freitas Cordeiro-Silva; Andressa Barbosa; Marília Santiago; Mariana Provetti; Raquel Spinassé Dettogni; Thais Tristão Tovar; Eliete Rabbi-Bortolini; Iúri Drumond Louro

2011-01-01

329

Mutations in the gene for X-linked adrenoleukodystrophy in patients with different clinical phenotypes  

SciTech Connect

Recently, the gene for the most common peroxisomal disorder, X-linked adrenoleukodystrophy (X-ALD), has been described encoding a peroxisomal membrane transporter protein. We analyzed the entire protein-coding sequence of this gene by reverse-transcription PCR, SSCP, and DNA sequencing in five patients with different clinical expressions were cerebral childhood ALD, adrenomyecloneuropathy (AMN), and {open_quotes}Addison disease only{close_quotes} (AD) phenotype. In the three patients exhibiting the classical picture of severe childhood ALD we identified in the 5{prime} portion of the X-ALD gene a 38-bp deletion that causes a frameshift mutation, a 3-bp deletion leading to a deletion of an amino acid in the ATP-binding domain of the ALD protein, and a missense mutation. In the patient with the clinical phenotype of AMN, a nonsense mutation in codon 212, along with a second site mutation at codon 178, was observed. Analysis of the patient with the ADO phenotype revealed a further missense mutation at a highly conserved position in the ALDP/PMP70 comparison. The disruptive nature of two mutations (i.e., the frameshift and the nonsense mutation) in patients with biochemically proved childhood ALD and AMN further strongly supports the hypothesis that alterations in this gene play a crucial role in the pathogenesis of X-ALD. Since the current biochemical techniques for X-ALD carrier detection in affected families lack sufficient reliability, our procedure described for systematic mutation scanning is also capable of improving genetic counseling and prenatal diagnosis. 19 refs., 6 figs., 3 tabs.

Braun, A.; Ambach, H.; Kammerer, S.; Rolinski, B.; Roscher, A.; Rabl, W. [Univ. of Munich (Germany); Stoeckler, S. [Univ. of Graz (Germany); Gaertner, J. [Univ. of Duesseldorf (Germany); Zierz, S. [Univ. of Bonn (Germany)

1995-04-01

330

Rippling muscle disease and cardiomyopathy associated with a mutation in the CAV3 gene  

Microsoft Academic Search

Caveolin-3, the myocyte-specific isoform of caveolins, is preferentially expressed in skeletal, cardiac and smooth muscles. Mutations in the CAV3 gene cause clinically heterogeneous neuromuscular disorders, including rippling muscle disease, or cardiopathies. The same mutation may lead to different phenotypes, but cardiac and muscle involvement rarely coexists suggesting that the molecular network acting with caveolin-3 in skeletal muscle and heart may

Michela Catteruccia; Tommaso Sanna; Filippo Maria Santorelli; Alessandra Tessa; Raffaella Di Giacopo; Donato Sauchelli; Alessandro Verbo; Mauro Lo Monaco; Serenella Servidei

2009-01-01

331

Mutations at amino-acid 482 in the ABCG2 gene affect substrate and antagonist specificity  

Microsoft Academic Search

Recent studies have shown that mutations at amino-acid 482 in the ABCG2 gene affect the substrate specificity of the protein. To delineate the effects of these mutations clearly, human embryonic kidney cells (HEK-293) were stably transfected with wild-type 482R or mutant 482G and 482T ABCG2. By flow cytometry, mitoxantrone, BODIPY-prazosin, and Hoechst 33342 were found to be substrates of all

R W Robey; Y Honjo; K Morisaki; T A Nadjem; S Runge; M Risbood; M S Poruchynsky; S E Bates

2003-01-01

332

Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies  

Microsoft Academic Search

Noonan syndrome is an autosomal dominant disease characterized by dysmorphic features, webbed neck, cardiac anomalies, short stature and cryptorchidism. It shows phenotypic overlap with Costello syndrome and cardio-facio-cutaneous (CFC) syndrome. Noonan syndrome and related disorders are caused by germline mutations in genes encoding molecules in the RAS\\/MAPK pathway. Recently, a gain-of-function mutation in SHOC2, p.S2G, has been identified as causative

Shoko Komatsuzaki; Yoko Aoki; Tetsuya Niihori; Nobuhiko Okamoto; Raoul C M Hennekam; Saskia Hopman; Hirofumi Ohashi; Seiji Mizuno; Yoriko Watanabe; Hotaka Kamasaki; Ikuko Kondo; Nobuko Moriyama; Kenji Kurosawa; Hiroshi Kawame; Ryuhei Okuyama; Masue Imaizumi; Takeshi Rikiishi; Shigeru Tsuchiya; Shigeo Kure; Yoichi Matsubara

2010-01-01

333

Periventricular nodular heterotopia in patients with filamin-1 gene mutations: neuroimaging findings  

Microsoft Academic Search

Background. The filamin-1 (FLN-1) gene is responsible for periventricular nodular heterotopia (PNH), which is an X-linked dominant neuronal\\u000a migration disorder. Objective. To review the clinical and imaging findings in a series of patients with documented filamin-1 mutations.¶Materials and methods. A retrospective review of the medical records and MR studies of a series of patients with PNH and confirmed FLN-1 mutations

T. Y. Poussaint; J. W. Fox; W. B. Dobyns; R. Radtke; I. E. Scheffer; S. F. Berkovic; P. D. Barnes; P. R. Huttenlocher; C. A. Walsh

2000-01-01

334

Spontaneous reversion of novel Lesch-Nyhan mutation by HPRT gene rearrangement  

Microsoft Academic Search

Molecular analysis of an unusual patient with the Lesch-Nyhan syndrome has suggested that the mutation is due to a partial HPRTgene duplication. We now report the cloning and sequencing of the mutant HPRTcDNA which shows the precise duplication of exons 2 and 3. This mutation is the result of an internal duplication of 16–20 kilobases of the gene. The structure

Thomas P. Yang; John T. Stout; David S. Konecki; Pragna I. Patel; Raye L. Alford; C. Thomas Caskey

1988-01-01

335

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Gene Mutations and Risk for Pancreatic Adenocarcinoma  

PubMed Central

Background Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are common in white persons and are associated with pancreatic disease. The purpose of this case-control study was to determine whether CFTR mutations confer a higher risk of pancreatic cancer. Methods In a case-control study, we compared the rates of 39 common cystic fibrosis–associated CFTR mutations between 949 white patients with pancreatic adenocarcinoma and 13,340 white controls from a clinical laboratory database for prenatal testing for CFTR mutations. The main outcome measure was the CFTR mutation frequency in patients and controls. Results Overall, 50 (5.3%) of 949 patients with pancreatic cancer carried a common CFTR mutation versus 510 (3.8%) of 13,340 controls (odds ratio, 1.40; 95% confidence interval, 1.04–1.89; P=.027). Among patients who were younger when their disease was diagnosed (<60 years), the carrier frequency was higher than in controls (odds ratio, 1.82; 95% CI, 1.14–2.94; P=.011). In patient-only analyses, the presence of a mutation was associated with younger age (median 62 vs 67 years; P=.034). In subgroups, the difference was seen only among ever-smokers, (60 vs 65 years, p=.028). Subsequent sequencing analysis of the CFTR gene detected 8 (16%) compound heterozygotes among the 50 patients initially detected to have 1 mutation. Conclusions Carrying a disease-associated mutation in CFTR is associated with a modest increase in risk for pancreatic cancer. Those affected appear to be diagnosed at a younger age, especially among smokers. Clinical evidence of antecedent pancreatitis was uncommon among both carriers and noncarriers of CFTR mutations. PMID:19885835

McWilliams, Robert R.; Petersen, Gloria M.; Rabe, Kari G.; Holtegaard, Leonard M.; Lynch, Pamela J.; Bishop, Michele D.; Highsmith, W. Edward

2009-01-01

336

Two common mutations in the CLN2 gene underlie late infantile neuronal ceroid lipofuscinosis.  

PubMed

Late infantile neuronal ceroid lipofuscinosis (LINCL) is one of the most common pediatric neuronal degenerative disorders. A candidate gene underlying this disease, designated CLN2, was recently cloned and the gene product was characterized as a lysosomal pepstatin-insensitive carboxypeptidase (LPIC). Four mutations were identified in CLN2 from three unrelated LINCL individuals. To investigate further the mutation frequency in LINCL, we screened 16 LINCL probands for these four mutations. The previously reported intronic mutation, T523-1 G-->C. was found in 56% (9/16) of the cases, of which two were homozygous and accounted for 34% (11/32) of LINCL chromosomes. The previously reported nonsense mutation, 636 C-->T leading to R208stop, was found in 31% (5/16) of the cases, including one homozygote and accounted for 19% (6/32) of LINCL chromosomes. Two previously described missense mutations, 1107 T-->C and 1108 G-->A, were not detected in any of these 16 probands. In total, the two observed mutations, T523-1 G-->C and 636 C-->T, accounted for 53% (17/32) of LINCL alleles. Thus, one or both mutations were seen in 11 (69%) cases and no mutation has yet been identified in five. Our finding that these two mutations are common in LINCL cases adds further evidence in support of the idea that dysfunction of LPIC underlies LINCL. Positive molecular testing can now complement clinical diagnosis of LPIC and will allow for pre-natal diagnosis for subsequent pregnancies. PMID:9788728

Zhong, N; Wisniewski, K E; Hartikainen, J; Ju, W; Moroziewicz, D N; McLendon, L; Sklower Brooks, S S; Brown, W T

1998-09-01

337

Glucokinase Gene Mutations: Structural and Genotype-Phenotype Analyses in MODY Children from South Italy  

PubMed Central

Background Maturity onset diabetes of the young type 2 (or GCK MODY) is a genetic form of diabetes mellitus provoked by mutations in the glucokinase gene (GCK). Methodology/Principal Findings We screened the GCK gene by direct sequencing in 30 patients from South Italy with suspected MODY. The mutation-induced structural alterations in the protein were analyzed by molecular modeling. The patients' biochemical, clinical and anamnestic data were obtained. Mutations were detected in 16/30 patients (53%); 9 of the 12 mutations identified were novel (p.Glu70Asp, p.Phe123Leu, p.Asp132Asn, p.His137Asp, p.Gly162Asp, p.Thr168Ala, p.Arg392Ser, p.Glu290X, p.Gln106_Met107delinsLeu) and are in regions involved in structural rearrangements required for catalysis. The prevalence of mutation sites was higher in the small domain (7/12: ?59%) than in the large (4/12: 33%) domain or in the connection (1/12: 8%) region of the protein. Mild diabetic phenotypes were detected in almost all patients [mean (SD) OGTT?=?7.8 mMol/L (1.8)] and mean triglyceride levels were lower in mutated than in unmutated GCK patients (p?=?0.04). Conclusions The prevalence of GCK MODY is high in southern Italy, and the GCK small domain is a hot spot for MODY mutations. Both the severity of the GCK mutation and the genetic background seem to play a relevant role in the GCK MODY phenotype. Indeed, a partial genotype-phenotype correlation was identified in related patients (3 pairs of siblings) but not in two unrelated children bearing the same mutation. Thus, the molecular approach allows the physician to confirm the diagnosis and to predict severity of the mutation. PMID:18382660

Capuano, Marina; De Simone, Alfonso; Capobianco, Valentina; Daniele, Gerardo; Giugliano, Michela; Spadaro, Raffaella; Franzese, Adriana; Sacchetti, Lucia

2008-01-01

338

The Berkeley Drosophila Genome Project gene disruption project: Single P-element insertions mutating 25% of vital Drosophila genes.  

PubMed Central

A fundamental goal of genetics and functional genomics is to identify and mutate every gene in model organisms such as Drosophila melanogaster. The Berkeley Drosophila Genome Project (BDGP) gene disruption project generates single P-element insertion strains that each mutate unique genomic open reading frames. Such strains strongly facilitate further genetic and molecular studies of the disrupted loci, but it has remained unclear if P elements can be used to mutate all Drosophila genes. We now report that the primary collection has grown to contain 1045 strains that disrupt more than 25% of the estimated 3600 Drosophila genes that are essential for adult viability. Of these P insertions, 67% have been verified by genetic tests to cause the associated recessive mutant phenotypes, and the validity of most of the remaining lines is predicted on statistical grounds. Sequences flanking >920 insertions have been determined to exactly position them in the genome and to identify 376 potentially affected transcripts from collections of EST sequences. Strains in the BDGP collection are available from the Bloomington Stock Center and have already assisted the research community in characterizing >250 Drosophila genes. The likely identity of 131 additional genes in the collection is reported here. Our results show that Drosophila genes have a wide range of sensitivity to inactivation by P elements, and provide a rationale for greatly expanding the BDGP primary collection based entirely on insertion site sequencing. We predict that this approach can bring >85% of all Drosophila open reading frames under experimental control. PMID:10471706

Spradling, A C; Stern, D; Beaton, A; Rhem, E J; Laverty, T; Mozden, N; Misra, S; Rubin, G M

1999-01-01

339

Imperfect Genes, Fisherian Mutation and the Evolution of Sex  

PubMed Central

In this paper we present a mathematical model of mutation and selection that allows for the coexistence of multiple alleles at a locus with very small selective differences between alleles. The model also allows for the determination of fitness by multiple loci. Models of this sort are biologically plausible. However, some previous attempts to construct similar models have assumed that all mutations produce a decrease in fitness, and this has led to a tendency for the average fitness of population members to decline when population numbers are finite. In our model we incorporate some of the ideas of R. A. FISHER, so that both deleterious and beneficial mutations are possible. As a result, average fitness tends to approach a stationary distribution. We have used computer simulation methods to apply the Fisherian mutation model to the problem of the evolution of sex and recombination. The results suggest that sex and recombination can provide very large benefits in terms of average fitness. The results also suggest that obligately sexual species will win ecological competitions with species that produce a substantial fraction of their offspring asexually, so long as the number of sites under selection within the genomes of the competing species is not too small and the population sizes are not too large. Our model focuses on fertility selection in an hermaphroditic plant. However, the results are likely to generalize to a wide variety of other situations as well. PMID:9093868

Peck, J. R.; Barreau, G.; Heath, S. C.

1997-01-01

340

A large-scale gene-trap screen for insertional mutations in developmentally regulated genes in mice  

SciTech Connect

We have used a gene-trap vector and mouse embryonic stem (ES) cells to screen for insertional mutations in genes developmentally regulated at 8.5 days of embryogenesis (dpc). From 38,730 cell lines with vector insertions, 393 clonal integrations had disrupted active transcription units, as assayed by {beta}-galactosidase reporter gene expression. From these lines, 290 clones were recovered and injected into blastocysts to assay for reporter gene expression in 8.5-dpc chimeric mouse embryos. Of these, 279 clones provided a sufficient number of chimeric embryos for analysis. Thirty-six (13%) showed restricted patterns of reporter-gene expression, 88 (32%) showed widespread expression and 155 (55%) failed to show detectable levels of expression. Further analysis showed that approximately one-third of the clones that did not express detectable levels of the reporter gene at 8.5 dpc displayed reporter gene activity at 12.5 dpc. Thus, a large proportion of the genes that are expressed in ES cells are either temporally or spatially regulated during embryogenesis. These results indicate that gene-trap mutageneses in embryonic stem cells provide an effective approach for isolating mutations in a large number of developmentally regulated genes. 40 refs., 5 figs., 4 tabs.

Wurst, W.; Rossant, J.; Prideaux, V.; Kownacka, M.; Hill, D.P.; Guillemot, F.; Auerbach, A.; Cado, D.; Ang, S.L. [Mount Sinai Hospital, Toronto, Ontario (Canada); and others

1995-02-01

341

Two novel NIPBL gene mutations in Chinese patients with Cornelia de Lange syndrome.  

PubMed

Cornelia de Lange syndrome (CdLS) is a dominantly inherited developmental disorder characterized by distinctive facial features, mental retardation, and upper limb defects, with the involvement of multiple organs and systems. To date, mutations have been identified in five genes responsible for CdLS: NIPBL, SMC1A, SMC3, RAD21, and HDAC8. Here, we present a clinical and molecular characterization of five unrelated Chinese patients whose clinical presentation is consistent with that of CdLS. There were no chromosomal abnormalities in the five children. In three patients, DNA sequencing revealed a previously reported frameshift mutation c.2479delA (p.Arg827GlyfsX20), and two novel mutations including a heterozygous mutation c.6272 G>T (p.Cys2091Phe) and a frameshift mutation c.1672delA (p.Thr558LeufsX7) in NIPBL. For the remaining patients, large deletions and/or duplications within the NIPBL gene were excluded as playing a role in the pathogenesis, by Multiplex Ligation-dependent Probe Amplification (MLPA) analysis. These findings broaden the mutation spectrum of NIPBL and further our understanding of the diverse and variable effects of NIPBL mutations on CdLS. PMID:25447906

Mei, Libin; Liang, Desheng; Huang, Yanru; Pan, Qian; Wu, Lingqian

2015-01-25

342

Novel IL31RA gene mutation and ancestral OSMR mutant allele in familial primary cutaneous amyloidosis  

PubMed Central

Primary cutaneous amyloidosis (PCA) is an itchy skin disorder associated with amyloid deposits in the superficial dermis. The disease is relatively common in Southeast Asia and South America. Autosomal dominant PCA has been mapped earlier to 5p13.1–q11.2 and two pathogenic missense mutations in the OSMR gene, which encodes the interleukin-6 family cytokine receptor oncostatin M receptor beta (OSMR?), were reported. Here, we investigated 29 Taiwanese pedigrees with PCA and found that 10 had heterozygous missense mutations in OSMR: p.D647V (one family), p.P694L (six families), and p.K697T (three families). The mutation p.P694L was associated with the same haplotype in five of six families and also detected in two sporadic cases of PCA. Of the other 19 pedigrees that lacked OSMR pathology, 8 mapped to the same locus on chromosome 5, which also contains the genes for 3 other interleukin-6 family cytokine receptors, including interleukin-31 receptor A (IL31RA), which can form a heterodimeric receptor with OSMR? through interleukin-31 signaling. In one family, we identified a point mutation in the IL31RA gene, c.1562C>T that results in a missense mutation, p.S521F, which is also sited within a fibronectin type III-like repeat domain as observed in the OSMR mutations. PCA is a genetically heterogeneous disorder but our study shows that it can be caused by mutations in two biologically associated cytokine receptor genes located on chromosome 5. The identification of OSMR and IL31RA gene pathology provides an explanation of the high prevalence of PCA in Taiwan as well as new insight into disease pathophysiology. PMID:19690585

Lin, Ming-Wei; Lee, Ding-Dar; Liu, Tze-Tze; Lin, Yong-Feng; Chen, Shang-Yi; Huang, Chih-Cheng; Weng, Hui-Ying; Liu, Yu-Fen; Tanaka, Akio; Arita, Ken; Lai-Cheong, Joey; Palisson, Francis; Chang, Yun-Ting; Wong, Chu-Kwan; Matsuura, Isao; McGrath, John A; Tsai, Shih-Feng

2010-01-01

343

Mutational Analysis of Androgen Receptor (AR) Gene in 46,XY Patients with Ambiguous Genitalia and Normal Testosterone Secretion: Endocrinological Characteristics of Three Patients with AR Gene Mutations  

PubMed Central

The prevalence of abnormalities in androgen receptor gene (AR) among patients with ambiguous genitalia is unknown. Moreover, endocrinological data from prepubertal patients with AR mutation are very limited. Thus, the aim of this study was to examine the prevalence of abnormalities in AR among patients with both ambiguous genitalia, which was defined as a combination of two or more genital abnormalities (i.e. hypospadias, microphallus (penile length < 25 mm), hypoplastic scrotum, bifid scrotum, undescended testis) in this study, and normal to elevated T levels. We also compared the endocrinological data of prepubertal patients with AR mutation and ambiguous genitalia with that of those without the AR mutation. We screened 26 Japanese prepubertal 46,XY patients (five from three families were included) with both ambiguous genitalia and normal to elevated T levels. Mutations in AR were found in three (two of the three were related). Among the 23 patients without mutation in AR, the steroid 5-alpha-reductase 2 gene (SRD5A2) was also examined in eight patients with elevated T/dehydrotestosterone ratio after the hCG (>10) or with undervirilized family members. No mutation in SRD5A2 was found. Characteristics of the three patients with mutation in AR were compared with the 23 patients without mutation. In two patients, basal T levels (0.3, 0.2 ng/ml) and peak T levels after the hCG tests (8.3, 8.5 ng/ml) tended to be higher, and the peak LH/ peak FSH ratios after the GnRH tests (4.6, 4.0) were higher than in patients without mutation, at the ages of 1 yr and 9 mo and 3 yr and 8 mo, respectively. In conclusion, an abnormality in either AR or SRD5A2 was not common among patients with ambiguous genitalia and normal testosterone secretion. Elevated peak LH/peak FSH ratio (?4) after the GnRH test in addition to detectable basal T levels and elevated peak T levels after the hCG test may infer AR abnormality in prepubertal patients with ambiguous genitalia at the age of one and over, although further study is needed, because our data were limited. PMID:24790336

Miyamoto, Junko; Asanuma, Hiroshi; Nakai, Hideo; Hasegawa, Tomonobu; Nawata, Hajime; Hasegawa, Yukihiro

2006-01-01

344

A genetic pedigree analysis to identify gene mutations involved in femoral head necrosis.  

PubMed

The present study presents results from a linkage and mutation screening analysis aiming to identify the causative gene of femoral head necrosis, also known as osteonecrosis of femoral head (ONFH), in a Chinese pedigree. We collected clinical data on the osteonecrosis pedigree, and extracted blood and genomic DNA from the family members. Polymerase chain reaction (PCR) and direct sequencing allowed to identify a mutation in the COL2A1 gene of the proband; the clinical manifestations of the proband meet the criteria for osteonecrosis. The exons of COL2A1 were amplified by polymerase chain reaction and mutation screening was conducted by direct sequencing in all the family members. The locus was also sequenced in 50 unrelated healthy controls. The c.3665G>A heterozygous mutation was detected in patients of the pedigree, but not in healthy individuals. We conclude that a mutation in the COL2A1 gene is the causative agent of ONFH in this family. Therefore, this mutation may be associated with osteonecrosis in Chinese populations. PMID:25050885

Wang, Lin; Pan, Hehai; Zhu, Zhen-An

2014-10-01

345

Limited clinical relevance of mitochondrial DNA mutation and gene expression analyses in ovarian cancer  

PubMed Central

Background In recent years, numerous studies have investigated somatic mutations in mitochondrial DNA in various tumours. The observed high mutation rates might reflect mitochondrial deregulation; consequently, mutation analyses could be clinically relevant. The purpose of this study was to determine if mutations in the mitochondrial D-loop region and/or the level of mitochondrial gene expression could influence the clinical course of human ovarian carcinomas. Methods We sequenced a 1320-base-pair DNA fragment of the mitochondrial genome (position 16,000-750) in 54 cancer samples and in 44 corresponding germline control samples. In addition, six transcripts (MT-ATP6, MT-CO1, MT-CYB, MT-ND1, MT-ND6, and MT-RNR1) were quantified in 62 cancer tissues by real-time RT-PCR. Results Somatic mutations in the D-loop sequence were found in 57% of ovarian cancers. Univariate analysis showed no association between mitochondrial DNA mutation status or mitochondrial gene expression and any of the examined clinicopathologic parameters. A multivariate logistic regression model revealed that the expression of the mitochondrial gene RNR1 might be used as a predictor of tumour sensitivity to chemotherapy. Conclusion In contrast to many previously published papers, our study indicates rather limited clinical relevance of mitochondrial molecular analyses in ovarian carcinomas. These discrepancies in the clinical utility of mitochondrial molecular tests in ovarian cancer require additional large, well-designed validation studies. PMID:18842121

Bragoszewski, Piotr; Kupryjanczyk, Jolanta; Bartnik, Ewa; Rachinger, Andrea; Ostrowski, Jerzy

2008-01-01

346

An association study of HFE gene mutation with idiopathic male infertility in the Chinese Han population  

PubMed Central

Mutations in the haemochromatosis gene (HFE) influence iron status in the general population of Northern Europe, and excess iron is associated with the impairment of spermatogenesis. The aim of this study is to investigate the association between three mutations (C282Y, H63D and S65C) in the HFE gene with idiopathic male infertility in the Chinese Han population. Two groups of Chinese men were recruited: 444 infertile men (including 169 with idiopathic azoospermia) and 423 controls with proven fertility. The HFE gene was detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The experimental results demonstrated that no C282Y or S65C mutations were detected. Idiopathic male infertility was not significantly associated with heterozygous H63D mutation (odds ratio=0.801, 95% confidence interval=0.452–1.421, ?2=0.577, P=0.448). The H63D mutation frequency did not correlate significantly with the serum luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone (T) levels in infertile men (P=0.896, P=0.404 and P=0.05, respectively). Our data suggest that the HFE H63D mutation is not associated with idiopathic male reproductive dysfunction. PMID:22504868

Yu, Xiao-Ying; Wang, Bin-Bin; Xin, Zhong-Cheng; Liu, Tao; Ma, Ke; Jiang, Jian; Fang, Xiang; Yu, Li-Hua; Peng, Yi-Feng; Ma, Xu

2012-01-01

347

An association study of HFE gene mutation with idiopathic male infertility in the Chinese Han population.  

PubMed

Mutations in the haemochromatosis gene (HFE) influence iron status in the general population of Northern Europe, and excess iron is associated with the impairment of spermatogenesis. The aim of this study is to investigate the association between three mutations (C282Y, H63D and S65C) in the HFE gene with idiopathic male infertility in the Chinese Han population. Two groups of Chinese men were recruited: 444 infertile men (including 169 with idiopathic azoospermia) and 423 controls with proven fertility. The HFE gene was detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The experimental results demonstrated that no C282Y or S65C mutations were detected. Idiopathic male infertility was not significantly associated with heterozygous H63D mutation (odds ratio=0.801, 95% confidence interval=0.452-1.421, ?(2)=0.577, P=0.448). The H63D mutation frequency did not correlate significantly with the serum luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone (T) levels in infertile men (P=0.896, P=0.404 and P=0.05, respectively). Our data suggest that the HFE H63D mutation is not associated with idiopathic male reproductive dysfunction. PMID:22504868

Yu, Xiao-Ying; Wang, Bin-Bin; Xin, Zhong-Cheng; Liu, Tao; Ma, Ke; Jiang, Jian; Fang, Xiang; Yu, Li-Hua; Peng, Yi-Feng; Ma, Xu

2012-07-01

348

Insulin-like 3/relaxin-like factor gene mutations are associated with cryptorchidism.  

PubMed

Cryptorchidism is a common anomaly of male sexual differentiation. Two phases of testicular descent are recognized, transabdominal and inguinoscrotal. With evidence that androgens and Müllerian inhibitory hormone were not completely responsible for testicular descent, the existence of a third testicular hormone mediating testicular descent was postulated. Insulin-like 3 (INSL3) [also known as relaxin-like factor (RLF) and Leydig insulin-like protein (LEY I-L)] is a member of the insulin/relaxin hormone superfamily that is highly expressed in Leydig cells. The phenotype of transgenic mice with targeted deletion of the Insl3 gene was bilateral cryptorchidism with morphological evidence of abnormal gubernacular development. With this implicit evidence that Insl3 mediates testicular descent in mice, we performed mutation detection analysis of the coding regions of the 2 exon INSL3 gene in genomic DNA samples obtained from 145 formerly cryptorchid patients and 36 adult male controls. Single-strand conformational polymorphism analysis was used for the mutation detection studies. Two mutations, R49X and P69L, and several polymorphisms were identified. Both mutations were located in the connecting peptide region of the protein. The frequency of INSL3/RLF gene mutations as a cause of cryptorchidism is low, because only 2 of 145 (1.4%) formerly cryptorchid patients were found to have mutations. PMID:11095425

Tomboc, M; Lee, P A; Mitwally, M F; Schneck, F X; Bellinger, M; Witchel, S F

2000-11-01

349

A novel mutation of the insulin-like 3 gene in patients with cryptorchidism.  

PubMed

Two independent studies demonstrated that transgenic mice with a targeted deletion of the insulin-like 3 ( INSL3) gene presented bilateral cryptorchidism. Studies in humans have investigated the possibility that mutations in the INSL3 gene are the cause of cryptorchidism. In the present study, genomic DNA was obtained from 150 patients with idiopathic cryptorchidism. DNA was amplified and the polymerase chain reaction products of both exons were sequenced. A previously unidentified missense mutation was found in only one of the patients studied. In exon 2, a heterozygous C/G substitution at nucleotide 2560, which turned asparagine into lysine at codon 86, was documented. The familial study revealed that the mother was a heterozygous carrier of the mutation and the father was a homozygote wild type. We also found three polymorphic changes, previously reported in exon 1. The Asn-into-Lys change is likely deleterious because it leads to a nonconservative amino acid substitution, changing a highly conserved residue. This mutation, located in the A-chain of the INSL3 protein, is the first mutation reported in this region. This finding provides new evidence that INSL3 is involved in testicular descent in humans; however, mutations of this gene are not a frequent cause of cryptorchidism. PMID:12601553

Canto, Patricia; Escudero, Irineo; Söderlund, Daniela; Nishimura, Elisa; Carranza-Lira, Sebastian; Gutierrez, Jesus; Nava, Andres; Mendez, Juan Pablo

2003-01-01

350

[Mutational analysis of the connexin26 gene in sporadic cases of moderate to profound deafness].  

PubMed

Non-syndromic neurosensory recessive deafness (NSRD) is one of the most common human sensory disorders. Mutations in the connexin 26 gene have been established as a major cause of inherited and sporadic non-syndromic deafness in different populations. The CX26 gene encodes the gap junction protein connexin 26 (beta-2, GJB2), whose expression was shown in several tissues and in the cochlea. The 30delG mutation is the most frequent mutation in the CX26 gene. It represents a deletion of guanosine (G) in a sequence of six Gs extending from position 30 to 35 of the CX26 cDNA. The deletion creates a frameshift resulting in a premature stop codon and a non-functional intracellular domain in the protein. The 30delG mutation can be detected at the molecular level using PCR followed by BsiYI digestion. We screened 164 mainly German patients with non-syndromic sporadic deafness for this mutation to determine its distribution in the German population. The frequency of the mutation in our analyzed patients was lower than in other studies and therefore indicates its dependency on geographically distinct populations. PMID:11056855

Kupka, S; Mirghomizadeh, F; Haug, T; Braun, S; Leistenschneider, P; Schmitz-Salue, C; Arold, R; Blin, N; Zenner, H P; Pfister, M

2000-09-01

351

Missense mutation of the cholecystokinin B receptor gene: Lack of association with panic disorder  

SciTech Connect

Cholecystokinin tetrapeptide (CCK{sub 4}) is known to induce panic attacks in patients with panic disorder at a lower dose than in normal controls. Therefore, the cholecystokinin B (CCK{sub B}) receptor gene is a candidate gene for panic disorder. We searched for mutations in the CCK{sub B} gene in 22 probands of panic disorder pedigrees, using single-strand conformation polymorphism (SSCP) analysis. Two polymorphisms were detected. A polymorphism in an intron (2491 C{yields}A) between exons 4 and 5 was observed in 10 of 22 probands. A missense mutation in the extracellular loop of exon 2 (1550 G{yields}A, Val{sup 125}{yields}Ile) was found in only one proband. This mutation was also examined in additional 34 unrelated patients with panic disorder and 112 controls. The prevalence rate of this mutation was 8.8% in patients with panic disorder (3/34) and 4.4% in controls (5/112). The mutation did not segregate with panic disorder in two families where this could be tested. These results suggest no pathophysiological significance of this mutation in panic disorder. 21 refs., 4 figs., 1 tab.

Kato, Tadafumi; Wang, Zhe Wu; Crowe, R.R. [Univ. of Iowa College of Medicine, Iowa City, IA (United States)] [Univ. of Iowa College of Medicine, Iowa City, IA (United States); Zoega, T. [National Univ. Hospital, Reykjavik (Iceland)] [National Univ. Hospital, Reykjavik (Iceland)

1996-07-26

352

Novel Hypoxanthine Guanine Phosphoribosyltransferase Gene Mutations in Saudi Arabian Hyperuricemia Patients  

PubMed Central

Over the past decade, a steady increase in the incidence of HPRT-related hyperuricemia (HRH) has been observed in Saudi Arabia. We examined all the nine exons of HPRT gene for mutations in ten biochemically confirmed hyperuricemia patients, including one female and three normal controls. In all, we identified 13 novel mutations in Saudi Arabian HPRT-related hyperuricemia patients manifesting different levels of uric acid. The Lys103Met alteration was highly recurrent and was observed in 50% of the cases, while Ala160Thr and Lys158Asn substitutions were found in two patients. Moreover, in 70% of the patients ?2 mutations were detected concurrently in the HPRT gene. Interestingly, one of the patients that harbored Lys103Met substitution along with two frameshift mutations at codons 85 and 160 resulting in shortened protein demonstrated unusually high serum uric acid level of 738??mol/L. Two of the seven point mutations that resulted in amino acid change (Lys103Met and Val160Gly) were predicted to be damaging by SIFT and Polyphen and were further analyzed for their protein stability and function by molecular dynamics simulation. The identified novel mutations in the HPRT gene may prove useful in the prenatal diagnosis and genetic counseling. PMID:25136576

Alanazi, Mohammed; Al-Arfaj, Abdulrahman Saud; Abduljaleel, Zainularifeen; Fahad Al-Arfaj, Hussein; Reddy Parine, Narasimha; Purusottapatnam Shaik, Jilani; Khan, Zahid; Ali Khan Pathan, Akbar

2014-01-01

353

The 2588G-->C mutation in the ABCR gene is a mild frequent founder mutation in the Western European population and allows the classification of ABCR mutations in patients with Stargardt disease.  

PubMed Central

In 40 western European patients with Stargardt disease (STGD), we found 19 novel mutations in the retina-specific ATP-binding cassette transporter (ABCR) gene, illustrating STGD's high allelic heterogeneity. One mutation, 2588G-->C, identified in 15 (37.5%) patients, shows linkage disequilibrium with a rare polymorphism (2828G-->A) in exon 19, suggesting a founder effect. The guanine at position 2588 is part of the 3' splice site of exon 17. Analysis of the lymphoblastoid cell mRNA of two STGD patients with the 2588G-->C mutation shows that the resulting mutant ABCR proteins either lack Gly863 or contain the missense mutation Gly863Ala. We hypothesize that the 2588G-->C alteration is a mild mutation that causes STGD only in combination with a severe ABCR mutation. This is supported in that the accompanying ABCR mutations in at least five of eight STGD patients are null (severe) and that a combination of two mild mutations has not been observed among 68 STGD patients. The 2588G-->C mutation is present in 1 of every 35 western Europeans, a rate higher than that of the most frequent severe autosomal recessive mutation, the cystic fibrosis conductance regulator gene mutation DeltaPhe508. Given an STGD incidence of 1/10,000, homozygosity for the 2588G-->C mutation or compound heterozygosity for this and other mild ABCR mutations probably does not result in an STGD phenotype. PMID:10090887

Maugeri, A; van Driel, M A; van de Pol, D J; Klevering, B J; van Haren, F J; Tijmes, N; Bergen, A A; Rohrschneider, K; Blankenagel, A; Pinckers, A J; Dahl, N; Brunner, H G; Deutman, A F; Hoyng, C B; Cremers, F P

1999-01-01

354

A Novel WASP Gene Mutation in a Chinese Boy with Wiskott-Aldrich Syndrome.  

PubMed

Wiskott-Aldrich syndrome (WAS) is a rare inherited X-linked recessive immunodeficiency disease characterized by eczema, thrombocytopenia, immune deficiency, and bloody diarrhea and is caused by WASP gene mutations. This study reports a case of WAS with a novel mutation. A newborn Chinese infant was admitted to the hospital because of intermittent bloody stools, recurrent infections, and persistent thrombocytopenia. Genetic analysis of the coding sequences and flanking splice sites of the WASP gene showed a novel WASP gene deletion mutation (1144delA) at exon 10. Family history showed that both his mother and aunt had a heterozygous genotype of the WASP gene. The infant died at the age of 4 months due to persistent thrombocytopenia and severe pneumonia. A novel WASP gene deletion (1144delA) at exon 10 was identified in a Chinese infant with WAS. This base deletion results in a frame-shift mutation of the gene for an early stop codon at amino acid 444. PMID:25332617

Wu, Hui; Hu, Cheng; Dang, Dan; Guo, Ying-Jie

2014-09-01

355

Molecular basis of variegate porphyria: a missense mutation in the protoporphyrinogen oxidase gene.  

PubMed Central

Variegate porphyria (VP) is an autosomal dominant disorder characterised by a partial defect in the activity of protoporphyrinogen oxidase (PPO), and has recently been genetically linked to the PPO gene on chromosome 1q22-23 (Z=6.62). In this study, we identified a mutation in the PPO gene in a patient with VP and two unaffected family members. The mutation consisted of a previously unreported T to C transition in exon 13 of the PPO gene, resulting in the substitution of a polar serine by a non-polar proline (S450P). This serine residue is evolutionarily highly conserved in man, mouse, and Bacillus subtilis, attesting to the importance of this residue. Interestingly, the gene for Gardner's syndrome (FAP) also segregates in this family, independently of the VP mutation. Gardner's syndrome or familial adenomatous polyposis (FAP) is also an autosomal dominantly inherited genodermatosis, and typically presents with colorectal cancer in early adult life secondary to extensive adenomatous polyps of the colon. The specific gene on chromosome 5 that is the site of the mutation in this disorder is known as APC (adenomatous polyposis coli), and the gene has been genetically linked to the region of 5q22. Images PMID:9541112

Frank, J; Lam, H; Zaider, E; Poh-Fitzpatrick, M; Christiano, A M

1998-01-01

356

Plasmodium falciparum:Mutation Pattern in the Dihydrofolate Reductase–Thymidylate Synthase Genes of Vietnamese Isolates, a Novel Mutation, and Coexistence of Two Clones in a Thai Patient  

Microsoft Academic Search

ZINDROU, S., DUNG, N. P., SY, N. D., SKÖLD, O., and SWEDBERG, G. 1996.Plasmodium falciparum:Mutation pattern in the dihydrofolate reductase–thymidylate synthase genes of Vietnamese isolates, a novel mutation, and coexistence of two clones in a Thai patient.Experimental Parasitology84,56–64. Pyrimethamine and cycloguanil resistance ofPlasmodium falciparumhas been linked to mutations in the dihydrofolate reductase (dhfr) portion of thedhfr-tsgene. In this paper, the

Sherwan Zindrou; Nguyen Phuong Dung; Nguyen Duy Sy; Ola Sköld; Göte Swedberg

1996-01-01

357

Mutation of the prion protein gene at codon 208 in familial Creutzfeldt-Jakob disease.  

PubMed

Four point mutations and one insertion within the prion protein (PrP) gene have been tightly linked to the development of inherited prion disease. We developed a denaturing gradient gel electrophoresis system that allowed us to screen the entire open reading frame of the PrP gene. Using this system, we found a new mutation of the PrP gene in a patient with pathologically confirmed Creutzfeldt-Jakob disease and a negative family history for dementia. DNA sequencing revealed an adenine substitution for guanine at the second position of codon 208, which results in the nonconservative substitution of histidine for arginine. The same PrP mutation was identified in another younger member of the pedigree but was not present in more than 200 alleles tested. Such findings suggest that the frequency of inherited prion disease might be higher than ascertained by clinical history alone. PMID:8909447

Mastrianni, J A; Iannicola, C; Myers, R M; DeArmond, S; Prusiner, S B

1996-11-01

358

Mutation in the Prothrombin Gene G20210A as a Cause of Cerebral Venous Thrombosis  

PubMed Central

Introduction. Cerebral venous sinus thrombosis (CVST) is a rare form of cerebrovascular disease, which may manifest clinically by a wide variety of signs and symptoms. It has been associated with multiple risk factors including genetic or acquired blood disorders, infections, and trauma. Case Report. Man of 17 years who presented with 10 days of intense global headache with nausea and vomiting and subsequent onset of mild hemiparesis and hypoesthesia in right hemibody. Studies show venous thrombosis of the superior longitudinal sinus. It was identified a gene mutation in prothrombin G20210A as a probable cause of the thrombosis. Conclusions. Substitution of guanine for adenine at nucleotide 20210 in the coding region of the prothrombin gene is the second most common primary thrombophilia. Multiple cases of CVST have been associated with this mutation. In the presence of CVST must be considered the primary studies for thrombophilia gene mutations, including prothrombin G20210A. PMID:22645618

Arroyave, Jorge A.; Quiñones, Jairo

2012-01-01

359

Mutation in the Prothrombin Gene G20210A as a Cause of Cerebral Venous Thrombosis.  

PubMed

Introduction. Cerebral venous sinus thrombosis (CVST) is a rare form of cerebrovascular disease, which may manifest clinically by a wide variety of signs and symptoms. It has been associated with multiple risk factors including genetic or acquired blood disorders, infections, and trauma. Case Report. Man of 17 years who presented with 10 days of intense global headache with nausea and vomiting and subsequent onset of mild hemiparesis and hypoesthesia in right hemibody. Studies show venous thrombosis of the superior longitudinal sinus. It was identified a gene mutation in prothrombin G20210A as a probable cause of the thrombosis. Conclusions. Substitution of guanine for adenine at nucleotide 20210 in the coding region of the prothrombin gene is the second most common primary thrombophilia. Multiple cases of CVST have been associated with this mutation. In the presence of CVST must be considered the primary studies for thrombophilia gene mutations, including prothrombin G20210A. PMID:22645618

Arroyave, Jorge A; Quiñones, Jairo

2012-01-01

360

Mutations in Niemann Pick type C gene are risk factor for Alzheimer's disease.  

PubMed

Alzheimer's disease (AD) is the most common form of dementia characterized by deterioration of memory and other cognitive domains which leads to death in 3-9years after diagnosis. In addition to mutations in APP, PSEN1 and PSEN2 genes, that cause early onset autosomal dominant AD, several genetic risk factors for late onset AD are now known. There is another distinctive neurodegenerative lysosomal storage disorder - Niemann-Pick type C (NPC) that is sometimes referred to as "Childhood Alzheimer's". NPC is autosomal recessive disease caused by mutations in the NPC1 or NPC2 genes. NPC and AD share some biochemical and pathological similarities which are discussed in this paper. On the other hand, there is a well documented connection between other autosomal recessive lysosomal storage disorder - Gaucher's disease (GD) and neurodegenerative disorder - Parkinson's disease (PD). It has been shown that GD patients have 20-fold increased life-time risk of developing PD. Surprisingly, even heterozygous carriers of mutations in glucocerebrosidase gene (GBA) have increased risk for developing PD. Having in mind above mentioned correlations, we hypothesized that heterozygous mutations in the NPC gene may act as an independent risk factor for Alzheimer's disease. If true, this would expand link between lysosomal disorders and neurodegenerative diseases. Also, if heterozygous NPC1/2 mutation carriers develop AD we assume it would be worth trying with miglustat-specific therapy recommended for NPC disease. PMID:25220527

Kresojevi?, Nikola; Dobri?i?, Valerija; Svetel, Marina; Kosti?, Vladimir

2014-11-01

361

Association of mutations in mannose binding protein gene with childhood infection in consecutive hospital series.  

PubMed Central

OBJECTIVE: To determine the extent to which mutations in the mannose binding protein gene predispose to childhood infection. DESIGN: Clinical details and genotype of mannose binding protein determined in consecutive children attending a paediatric department. SETTING: Inner city hospital paediatric service in London. SUBJECTS: 617 children attending hospital between October 1993 and August 1995. MAIN OUTCOME MEASURE: Infection as the cause for attendance or admission in relation to mutations in the mannose binding protein gene. RESULTS: The prevalence of mutations in the mannose binding protein gene in children with infection (146/345) was about twice that in children without infection (64/272) (P < 0.0001). Increased susceptibility to infection was found in both heterozygotic and homozygotic children. 13 out of 17 children homozygotic for variant alleles presented with strikingly severe infections, including 6 with septicaemia. CONCLUSIONS: The findings suggest that mutations in the mannose binding protein gene are an important risk factor for infections in children. Screening for such mutations should be included in the investigation of severe or frequent infections. PMID:9154025

Summerfield, J. A.; Sumiya, M.; Levin, M.; Turner, M. W.

1997-01-01

362

A Novel HSF4 Gene Mutation Causes Autosomal-Dominant Cataracts in a Chinese Family  

PubMed Central

Congenital cataracts are a significant cause of visual impairment or blindness in children. One-third of cases estimated to have a genetic cause. We carried out gene analysis and bioinformatics analysis to map the locus and to identify the underlying genetic defect in a 12-member, four-generation Chinese family affected with bilateral congenital cataracts. We screened individuals of the family and discovered a distinct missense mutation in HSF4 (a gene at this locus that encodes teat-shock transcription factor 4). Bioinformatics analysis was used to determine possible changes in the protein structure that could affect the phenotype. Sequencing of the candidate genes showed a heterozygous c.69 G?T change in the heat shock transcription factor 4 (HSF4) gene, which resulted in the substitution of a lysine with an asparagine (p. K23N). This mutation cosegregated with all affected individuals and was not observed in unaffected family members. Bioinformatics analysis indicated that the p. K23N mutation was predicted to be disease causing. This is the first report of the novel missense mutation, c.69 G?T (p. K23N), in exon 3 of the HSF4 locus on 16q21-q22 associated with bilateral congenital cataracts in a Chinese family. This novel mutation could enable propergenetic diagnostics and counseling in affected families and could lead to a better understanding of the structure and function of HSF4 in health and disease. PMID:24637349

Lv, Huibin; Huang, Chen; Zhang, Jing; Liu, Ziyuan; Zhang, Zhike; Xu, Haining; You, Yuchen; Hu, Jinping; Li, Xuemin; Wang, Wei

2014-01-01

363

Mutation screening of the RYR1 gene in malignant hyperthermia: Detection of a novel Tyr to ser mutation in a pedigree with associated centrl cores  

SciTech Connect

The ryanodine receptor gene (RYR1) has been shown to be mutated in a small number of malignant hyperthermia (MH) predigrees. Missense mutations in this gene have also been identified in two families with central core disease (CCD), a rare myopathy closely associated with MH. In an effort to identify other RYR1 mutations responsible for MH and CCD, we used a SSCP approach to screen the RYR1 gene for mutations in a family exhibiting susceptibility to MH (MHS) where some of the MHS individuals display core regions in their muscle. Sequence analysis of a unique aberrant SSCP has allowed us to identify a point mutation cosegregating with MHS in the described family. The mutation changes a conserved tyrosine residue at position 522 to a serine residue. This mutation is positioned relatively close to five of the six MHS/CCD mutations known to date and provides further evidence that MHS/CCD mutations may cluster in the amino terminal region of the RYR1 protein.

Quane, K.A.; Keating, K.E.; Healy, J.M.S. [University College, Cork (United Kingdom)] [and others] [University College, Cork (United Kingdom); and others

1994-09-01

364

Two Desmin Gene Mutations Associated with Myofibrillar Myopathies in Polish Families  

PubMed Central

Desmin is a muscle-specific intermediate filament protein which forms a network connecting the sarcomere, T tubules, sarcolemma, nuclear membrane, mitochondria and other organelles. Mutations in the gene coding for desmin (DES) cause skeletal myopathies often combined with cardiomyopathy, or isolated cardiomyopathies. The molecular pathomechanisms of the disease remain ambiguous. Here, we describe and comprehensively characterize two DES mutations found in Polish patients with a clinical diagnosis of desminopathy. The study group comprised 16 individuals representing three families. Two mutations were identified: a novel missense mutation (Q348P) and a small deletion of nine nucleotides (A357_E359del), previously described by us in the Polish population. A common ancestry of all the families bearing the A357_E359del mutation was confirmed. Both mutations were predicted to be pathogenic using a bioinformatics approach, including molecular dynamics simulations which helped to rationalize abnormal behavior at molecular level. To test the impact of the mutations on DES expression and the intracellular distribution of desmin muscle biopsies were investigated. Elevated desmin levels as well as its atypical localization in muscle fibers were observed. Additional staining for M-cadherin, ?-actinin, and myosin heavy chains confirmed severe disruption of myofibrill organization. The abnormalities were more prominent in the Q348P muscle, where both small atrophic fibers as well large fibers with centrally localized nuclei were observed. We propose that the mutations affect desmin structure and cause its aberrant folding and subsequent aggregation, triggering disruption of myofibrils organization. PMID:25541946

Berdynski, Mariusz; Sikorska, Agata; Filipek, Slawomir; Redowicz, Maria Jolanta; Kaminska, Anna; Zekanowski, Cezary

2014-01-01

365

Recurrent mutations of NOTCH genes in follicular lymphoma identify a distinctive subset of tumours.  

PubMed

Follicular lymphoma (FL) is one of the most common malignant lymphomas. The t(14;18)(q32;q21) translocation is found in about 80% of cases and plays an important role in lymphomagenesis. However, the molecular mechanisms involved in the development and transformation of this lymphoma are not fully understood. Gain-of-function mutations of NOTCH1 or NOTCH2 have recently been reported in several B cell lymphoid neoplasms but the role of these mutations in FL is not known. In this study we investigated the mutational status of these genes in 112 FLs. NOTCH1 and NOTCH2 mutations were identified in five and two cases, respectively (total 7/112, 6.3%). All mutations predicted for truncated protein in the PEST domain and were identical to those identified in other B cell lymphoid neoplasms. NOTCH-mutated FL cases were characterized by lower frequency of t(14;18) (14% versus 69%, p = 0.01), higher incidence of splenic involvement (71% versus 25%, p = 0.02) and female predominance (100% versus 55%, p = 0.04). A diffuse large B cell lymphoma (DLBCL) component was more frequently identified in NOTCH-mutated FL than in wild-type cases (57% versus 18%, p = 0.03). These results indicate that NOTCH mutations are uncommon in FL but may occur in a subset of cases with distinctive, characteristic, clinicopathological features. PMID:25141821

Karube, Kennosuke; Martínez, Daniel; Royo, Cristina; Navarro, Alba; Pinyol, Magda; Cazorla, Maite; Castillo, Paola; Valera, Alexandra; Carrió, Anna; Costa, Dolors; Colomer, Dolors; Rosenwald, Andreas; Ott, German; Esteban, Daniel; Giné, Eva; López-Guillermo, Armando; Campo, Elias

2014-11-01

366

Epidermal Growth Factor Receptor (EGFR) mutation analysis, gene expression profiling and EGFR protein expression in primary prostate cancer  

Microsoft Academic Search

BACKGROUND: Activating mutations of the epidermal growth factor receptor (EGFR) confer sensitivity to the tyrosine kinase inhibitors (TKi), gefitinib and erlotinib. We analysed EGFR expression, EGFR mutation status and gene expression profiles of prostate cancer (PC) to supply a rationale for EGFR targeted therapies in this disease. METHODS: Mutational analysis of EGFR TK domain (exons from 18 to 21) and

Caterina Peraldo-Neia; Giorgia Migliardi; Maurizia Mello-Grand; Filippo Montemurro; Raffaella Segir; Ymera Pignochino; Giuliana Cavalloni; Bruno Torchio; Luciano Mosso; Giovanna Chiorino; Massimo Aglietta

2011-01-01

367

Detection of mutations in human genes by a new rapid method: cleavage fragment length polymorphism analysis (CFLPA)  

Microsoft Academic Search

Cleavage fragment length polymorphism analysis with silver staining visualization (CFLPA-SS) was used for the detection of mutations previously detected by single strand conformation (SSCA) or heteroduplex analyses (HA), in order to assess this new method for mutation screening. The analysed mutations include single nucleotide transitions, transversions, a deletion and a duplication in the following genes: CFTR (cystic fibrosis transmembrane conductance

S. Rossetti; S. Englisch; E. Bresin; P. F. Pignatti; A. E. Turco

1997-01-01

368

Human Genetic Disorders Caused by Mutations in Genes Encoding Biosynthetic Enzymes for Sulfated Glycosaminoglycans*  

PubMed Central

A number of genetic disorders are caused by mutations in the genes encoding glycosyltransferases and sulfotransferases, enzymes responsible for the synthesis of sulfated glycosaminoglycan (GAG) side chains of proteoglycans, including chondroitin sulfate, dermatan sulfate, and heparan sulfate. The phenotypes of these genetic disorders reflect disturbances in crucial biological functions of GAGs in human. Recent studies have revealed that mutations in genes encoding chondroitin sulfate and dermatan sulfate biosynthetic enzymes cause various disorders of connective tissues. This minireview focuses on growing glycobiological studies of recently described genetic diseases caused by disturbances in biosynthetic enzymes for sulfated GAGs. PMID:23457301

Mizumoto, Shuji; Ikegawa, Shiro; Sugahara, Kazuyuki

2013-01-01

369

Reversion mutation in dark variants of luminous bacteria and its application in gene toxicant monitoring  

NASA Astrophysics Data System (ADS)

The luminous intensity of dark variant separated form photobacterium phosphoreum is 1/10000 less than that of wild-type. Ethidium Bromide (EB), Mytomycin C(MC), 2-amino fluorine can all strongly induce reversion mutation for S1 within 24h and increase reversion ratio significantly. The results of experiments indicated that these revertants have stable genetic character and the mutation may take place at gene levels. The mutagenesis to S1 caused by EB, MC and 2-AF was detected and it may be a new rapid, simple and sensitive method of gene toxicant monitoring.

Sun, Yaliang; Guo, Jianli

2001-09-01

370

Cancer variation associated with the position of the mutation in the BRCA2 gene.  

PubMed

Inherited mutations of the BRCA2 gene give rise to a multi-site cancer phenotype which includes breast cancer (in female and males), ovarian, pancreatic and prostate cancer, ocular and other melanomas, laryngeal, colon and stomach cancers. Interpretation of test results and risk assessment is therefore complex. It has been proposed that families with mutations in the ovarian cancer cluster region (OCCR) of exon 11 (nucleotides 3035-6629) express a higher ratio of ovarian to breast cancer, than families with mutations elsewhere in the BRCA2 gene. In this study we have investigated the presence of 7 types of cancer (ovary, male breast, pancreas, prostate, colon, stomach and melanoma) in first- and second-degree relatives of mutation-positive individuals in 440 families with a BRCA2 mutation. We reviewed histories of cancer in relatives among families with mutations distributed throughout the gene. Families with ovarian cancer were more likely to harbour mutations in the OCCR (nucleotides 3035-6629) than elsewhere in the gene (OR = 2.21; P = 0.0002). We also compared cancer risks according to ethnic group. Ashkenazi Jewish families with the 6174delT founder mutation were more likely to have a family member with ovarian cancer (OR = 1.58; P = 0.002) and less likely to have a family member with prostate cancer (OR = 0.62; P = 0.04) than were non-Jewish families. In contrast, a reduced presence of ovarian cancer was found in families of French-Canadian ancestry, compared to other ancestries (OR = 0.37; P = 0.0026). A high risk of male breast cancer was observed with the 6503delTT mutation (OR = 15.7; P = 0.023). Families of Polish ancestry had a reduced frequency of pancreatic cancer (OR = 0.0; P = 0.03) compared to families of other ethnic origins. In conclusion, both the position of mutation and the ethnic background of the family appear to contribute to the phenotypic variation observed in families with BRCA2 mutations. PMID:15131399

Lubinski, Jan; Phelan, Catherine M; Ghadirian, Parviz; Lynch, Henry T; Garber, Judy; Weber, Barbara; Tung, Nadine; Horsman, Douglas; Isaacs, Claudine; Monteiro, Alvaro N A; Sun, Ping; Narod, Steven A

2004-01-01

371

Coexistence of two ?-globin gene deletions in a Chinese girl with ?-thalassemia minor.  

PubMed

This study reports a rare case of ?(41/42,Cap)/?(A) genotype in a girl with ?-thalassemia (?-thal) minor. The 13-month-old Chinese proband suffered anemia, diarrhea, stunted growth and emaciation. The routine polymerase chain reaction-reverse dot-blot (PCR-RDB) test result for ?-thal mutations indicated that she was a compound heterozygote for ?(41/42) and ?(Cap). However, the complete blood cell (CBC) test gave the following results: mean corpuscular volume (MCV) 79.8 fL, mean corpuscular hemoglobin (MCH) 19.9 pg, with a Hb A2 value of 5.66%, suggesting that the proband also was ?-thal minor. The proband's father showed typical microcytic hypochromic anemia characteristics with a decreased MCV and MCH (63.1 fL and 20.9 pg, respectively) and an increased level of Hb A2 (5.60%), while the proband's mother had normal levels of MCV, MCH and Hb A2. The PCR-RDB test result showed her father was also a compound heterozygote for the ?(41/42) (HBB: c.126_129delCTTT) and ?(Cap) (HBB: c.-11_-8delAAAC) mutations and her mother was normal. Finally, DNA sequencing identified that the ?(41/42) and ?(Cap) mutations of the proband were inherited from her father and located on one ?-globin gene, suggesting that the proband's genotype is ?(41/42,Cap)/?(A). PMID:24200214

Huang, Ge; Li, Ping; Li, Yun-Xiong; Ye, Lian-Zhen

2014-01-01

372

Numerous BAF complex genes are mutated in Coffin-Siris syndrome.  

PubMed

Coffin-Siris syndrome (CSS; OMIM#135900) is a rare congenital anomaly syndrome characterized by intellectual disability, coarse face, hypertrichosis, and absence/hypoplasia of the fifth digits' nails. As the majority of patients are sporadic, an autosomal dominant inheritance model has been postulated. Recently, whole exome sequencing (WES) emerged as a comprehensive analytical method for rare variants. We applied WES on five CSS patients and found two de novo mutations in SMARCB1. SMARCB1 was completely sequenced in 23 CSS patients and the mutations were found in two more patients. As SMARCB1 encodes a subunit of the BAF complex functioning as a chromatin remodeling factor, mutations in 15 other subunit genes may cause CSS and thus were analyzed in 23 CSS patients. We identified heterozygous mutations in either of six genes (SMARCA4, SMARCB1, SMARCA2, SMARCE1, ARID1A, and ARID1B) in 20 out of 23 CSS patients. The patient with a SMARCA2 mutation was re-evaluated and identified as having Nicolaides-Baraitser syndrome (OMIM#601358), which is similar to but different from CSS. Additionally, 49 more CSS patients were analyzed as a second cohort. Together with the first cohort, 37 out of 71 (22 plus 49) patients were found to have a mutation in either one of five BAF complex genes. Furthermore, two CSS patients were reported to have a PHF6 abnormality, which can also cause Borjeson-Forssman-Lehmann syndrome (OMIM#301900), an X-linked intellectual disability syndrome with epilepsy and endocrine abnormalities. The current list of mutated genes in CSS is far from being complete and analysis of more patients is required. PMID:25081545

Miyake, Noriko; Tsurusaki, Yoshinori; Matsumoto, Naomichi

2014-09-01

373

De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies.  

PubMed

Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic landscape. Through a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), we analyzed exome-sequencing data of 356 trios with the "classical" epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. In this expanded cohort, we find 429 de novo mutations, including de novo mutations in DNM1 in five individuals and de novo mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de novo mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p = 8.2 × 10(-4)), supporting a prominent role for de novo mutations in epileptic encephalopathies. We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have an identifiable causal de novo mutation. Strikingly, 75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de novo mutations in genes in this pathway in the entire cohort as well. These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies, above and beyond that caused by ion channel dysfunction. PMID:25262651

2014-10-01

374

Gene Mutation in MicroRNA Target Sites of CFTR Gene: A Novel Pathogenetic Mechanism in Cystic Fibrosis?  

PubMed Central

Cystic fibrosis (CF) is the most frequent lethal genetic disorder among Caucasians. It depends on alterations of a chloride channel expressed by most epithelial cells and encoded by CFTR gene. Also using scanning techniques to analyze the whole coding regions of CFTR gene, mutations are not identified in up to 10% of CF alleles, and such figure increases in CFTR-related disorders (CFTR-RD). Other gene regions may be the site of causing-disease mutations. We searched for genetic variants in the 1500 bp of CFTR 3? untranslated region, typical target of microRNA (miRNA) posttranscriptional gene regulation, in either CF patients with the F508del homozygous genotype and different clinical expression (n?=?20), CF (n?=?32) and CFTR-RD (n?=?43) patients with one or none mutation after CFTR scanning and in controls (n?=?50). We identified three SNPs, one of which, the c.*1043A>C, was located in a region predicted to bind miR-433 and miR-509-3p. Such mutation was peculiar of a CFTR-RD patient that had Congenital Bilateral Absence of Vas Deferens (CBAVD), diffuse bronchiectasis, a borderline sweat chloride test and the heterozygous severe F508del mutation on the other allele. The expression analysis demonstrated that the c.*1043A>C increases the affinity for miR-509-3p and slightly decreases that for the miR-433. Both miRNAs cause in vitro a reduced expression of CFTR protein. Thus, the c.*1043A>C may act as a mild CFTR mutation enhancing the affinity for inhibitory miRNAs as a novel pathogenetic mechanism in CF. PMID:23555973

Amato, Felice; Seia, Manuela; Giordano, Sonia; Elce, Ausilia; Zarrilli, Federica; Castaldo, Giuseppe; Tomaiuolo, Rossella

2013-01-01

375

Hb Youngstown [?101(G3)Glu???Ala; HBB: c.305A > C]: An unstable hemoglobin variant causing severe hemolytic anemia.  

PubMed

Hb Youngstown is a rare hemoglobin (Hb) variant caused by substitution of glutamic acid with alanine at amino acid residue 101 of the ?-globin chain as a result of an A > C transversion on the ?-globin gene nucleotide sequences [?101(G3)Glu???Ala; HBB: c.305A > C]. We now report three patients from two different families, one from South Africa and the other from Costa Rica, who are heterozygous for this Hb variant. All three carriers had marked hemolysis, consistent with Hb Youngstown being a highly unstable variant. The substitution of glutamic acid, a large and negatively charged amino acid, with alanine, a small and non polar amino acid, in the interface of the ?1- and ?2-globin subunits might interfere with the transition between the oxy- and deoxyHb, and lead to Hb instability and hemolytic anemia. PMID:25347256

Edward, Heather L; Pisani, Louis Almero Du; Rodriguez-Romero, Walter E; Chaves-Villalobos, Jorge; Garcia-Quesada, Jonielle; Harris, Neil S; Luo, Hong-Yuan; Steinberg, Martin H; Forget, Bernard G; Chui, David H K

2014-01-01

376

Genechip-detecting mutations in exon 8 in cTnI gene associated with FHCM  

NASA Astrophysics Data System (ADS)

As the rate of gene discovery accelerates, more efficient methods are needed to analyze genes in human tissues. Genechip, a kind of new device, is composed of DNA probes immobilized on a solid substrate. With the advantage of the high throughput information, genechip has become one of the best solutions to detect and analyse the mutations in genes. Hypertrophic cardiomyopathy (HCM), the most common cause of the sudden death in the young, is one of the diseases damaging people health most badly. It is an autosomal dominant disease. More than 55% of the HCM patients are genetic. The mutations of exon 8 in the Cardiac troponin I (cTnI) gene are closely associated with Family Hypertrophic Cardiomyopathy (FHCM). Our purpose is to perform the assay of the mutations in exon 8 in cTnI gene based on the genechip theory and technology. Special probes were designed to fabricate the genechip to detect the mutations in cTnI gene simultaneously. We designed two oligonucleotide sequences 5"-end labeled with fluorescein, one simulating wild-type and the other simulating mutant. We mixed oligonucleotide I and II together to simulate heterozygote. After optimizing the hybridization protocols, the fabricated genechip can detect the mutations in exon 8 in cTnI gene with relative high sensitivity and specificity. When applying the fabricated genechip to detect the target DNA sequence, we found that the fully complementary probe gave a fluorescent signal almost 50% stronger than that of the one base mismatched one, which is in accordance with the result from theoretic estimate. It is believed that an applicable special genechip can be developed for investigating and diagnosing FHCM after further improvement.

Zhang, Yuanying; He, Nongyue; Guo, Huishi; Yang, Di; Wan, Wenhui; Bian, Zhiping; Zhang, Jinan

2005-01-01

377

A novel small deletion mutation in RUNX2 gene in one Chinese family with cleidocranial dysplasia  

PubMed Central

Cleidocranial dysplasia (CCD) is a skeletal dysplasia with autosomal-dominant inheritance. The runt related transcription factor 2 (RUNX2) gene is the only gene in which mutations are known to cause CCD. We report identification of a novel small deletions mutation in the RUNX2 gene in a Chinese family with CCD. A 29-year-old female was diagnosed as proband of CCD based on the clinical findings, which show delayed closure of the fontanels, hypoplastic or aplastic clavicles and dental anomalies. Similar dental and skeletal symptoms were also observed in the other three affected individuals. We prepared genomic DNA from all four affected individuals, unaffected individual from her family members, as well as 100 unrelated healthy controls. PCR was conducted using the above genomic DNA as template and the RUNX2 gene-specific primers. The PCR product was subjected to direct sequencing and the sequence was compared to that of RUNX2 gene within the NCBI database. We detected a small deletion CCTA from nucleotide 635 to nucleotide 638 in exon 3 of RUNX2 gene of the proband. This will lead to the introduction of a translational stop codon at codon 220, resulting in a truncated RUNX2 protein, and therefore within the runt domain of the RUNX2 protein. We detected the same mutation in the the other three affected individuals, and did not detect any mutation in the unaffected family members or the 100 unrelated healthy controls, demonstrating that this is a novel missense mutation in RUNX2 gene and therefore, contributes to the molecular diagnosis of CCD. PMID:24966961

Chen, Ting; Hou, Jin; Hu, Ling-Ling; Gao, Jie; Wu, Bu-Ling

2014-01-01

378

CRISPR-mediated direct mutation of cancer genes in the mouse liver.  

PubMed

The study of cancer genes in mouse models has traditionally relied on genetically-engineered strains made via transgenesis or gene targeting in embryonic stem cells. Here we describe a new method of cancer model generation using the CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins) system in vivo in wild-type mice. We used hydrodynamic injection to deliver a CRISPR plasmid DNA expressing Cas9 and single guide RNAs (sgRNAs) to the liver that directly target the tumour suppressor genes Pten (ref. 5) and p53 (also known as TP53 and Trp53) (ref. 6), alone and in combination. CRISPR-mediated Pten mutation led to elevated Akt phosphorylation and lipid accumulation in hepatocytes, phenocopying the effects of deletion of the gene using Cre-LoxP technology. Simultaneous targeting of Pten and p53 induced liver tumours that mimicked those caused by Cre-loxP-mediated deletion of Pten and p53. DNA sequencing of liver and tumour tissue revealed insertion or deletion mutations of the tumour suppressor genes, including bi-allelic mutations of both Pten and p53 in tumours. Furthermore, co-injection of Cas9 plasmids harbouring sgRNAs targeting the ?-catenin gene and a single-stranded DNA oligonucleotide donor carrying activating point mutations led to the generation of hepatocytes with nuclear localization of ?-catenin. This study demonstrates the feasibility of direct mutation of tumour suppressor genes and oncogenes in the liver using the CRISPR/Cas system, which presents a new avenue for rapid development of liver cancer models and functional genomics. PMID:25119044

Xue, Wen; Chen, Sidi; Yin, Hao; Tammela, Tuomas; Papagiannakopoulos, Thales; Joshi, Nikhil S; Cai, Wenxin; Yang, Gillian; Bronson, Roderick; Crowley, Denise G; Zhang, Feng; Anderson, Daniel G; Sharp, Phillip A; Jacks, Tyler

2014-10-16

379

A homozygous missense mutation in the ciliary gene TTC21B causes familial FSGS.  

PubMed

Several genes, mainly involved in podocyte cytoskeleton regulation, have been implicated in familial forms of primary FSGS. We identified a homozygous missense mutation (p.P209L) in the TTC21B gene in seven families with FSGS. Mutations in this ciliary gene were previously reported to cause nephronophthisis, a chronic tubulointerstitial nephropathy. Notably, tubular basement membrane thickening reminiscent of that observed in nephronophthisis was present in patients with FSGS and the p.P209L mutation. We demonstrated that the TTC21B gene product IFT139, an intraflagellar transport-A component, mainly localizes at the base of the primary cilium in developing podocytes from human fetal tissue and in undifferentiated cultured podocytes. In contrast, in nonciliated adult podocytes and differentiated cultured cells, IFT139 relocalized along the extended microtubule network. We further showed that knockdown of IFT139 in podocytes leads to primary cilia defects, abnormal cell migration, and cytoskeleton alterations, which can be partially rescued by p.P209L overexpression, indicating its hypomorphic effect. Our results demonstrate the involvement of a ciliary gene in a glomerular disorder and point to a critical function of IFT139 in podocytes. Altogether, these data suggest that this homozygous TTC21B p.P209L mutation leads to a novel hereditary kidney disorder with both glomerular and tubulointerstitial damages. PMID:24876116

Cong, Evelyne Huynh; Bizet, Albane A; Boyer, Olivia; Woerner, Stéphanie; Gribouval, Olivier; Filhol, Emilie; Arrondel, Christelle; Thomas, Sophie; Silbermann, Flora; Canaud, Guillaume; Hachicha, Jamil; Ben Dhia, Nasr; Peraldi, Marie-Noëlle; Harzallah, Kais; Iftene, Daouia; Daniel, Laurent; Willems, Marjolaine; Noel, Laure-Hélène; Bole-Feysot, Christine; Nitschké, Patrick; Gubler, Marie-Claire; Mollet, Géraldine; Saunier, Sophie; Antignac, Corinne

2014-11-01

380

Novel mutations in the amyloid precursor protein gene within Moroccan patients with Alzheimer's disease.  

PubMed

In Morocco, Alzheimer's disease (AD) affects almost 30,000 individuals, and this number could increase to 75,000 by 2020. To our knowledge, the genes predisposing individuals to AD and predicting disease incidence remain elusive. In this study, we aimed to evaluate the genetic contribution of mutations in the amyloid precursor protein (APP) gene exons 16 and 17 to familial and sporadic AD cases. Seventeen sporadic cases and eight family cases were seen at the memory clinic of the University of Casablanca Neurology Department. These patients underwent standard somatic neurological examination, cognitive function assessment, brain imaging, and laboratory tests. Direct sequencing of exons 16 and 17 of the APP gene was performed on genomic DNA of AD patients. In this original Moroccan study, we identified seven novel frameshift mutations in exons 16 and 17 of the APP gene. Interestingly, only one novel splice mutation was detected in a family case. There is a strong correlation between clinical symptoms and genetic factors in Moroccan patients with a family history of AD. Therefore, mutations in APP gene exons 16 and 17 may eventually become genetic markers for AD predisposition. PMID:24627227

El Kadmiri, Nadia; Zaid, Nabil; Hachem, Ahmed; Zaid, Younes; Dubé, Marie-Pierre; Hamzi, Khalil; El Moutawakil, Bouchra; Slassi, Ilham; Nadifi, Sellama

2014-06-01

381

Spliceosomal gene mutations are frequent events in the diverse mutational spectrum of chronic myelomonocytic leukemia but largely absent in juvenile myelomonocytic leukemia  

PubMed Central

Chronic myelomonocytic leukemia is a heterogeneous disease with multifactorial molecular pathogenesis. Various recurrent somatic mutations have been detected alone or in combination in chronic myelomonocytic leukemia. Recently, recurrent mutations in spliceosomal genes have been discovered. We investigated the contribution of U2AF1, SRSF2 and SF3B1 mutations in the pathogenesis of chronic myelomonocytic leukemia and closely related diseases. We genotyped a cohort of patients with chronic myelomonocytic leukemia, secondary acute myeloid leukemia derived from chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia for somatic mutations in U2AF1, SRSF2, SF3B1 and in the other 12 most frequently affected genes in these conditions. Chromosomal abnormalities were assessed by nucleotide polymorphism array-based karyotyping. The presence of molecular lesions was correlated with clinical endpoints. Mutations in SRSF2, U2AF1 and SF3B1 were found in 32%, 13% and 6% of cases of chronic myelomonocytic leukemia, secondary acute myeloid leukemia derived from chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia, respectively. Spliceosomal genes were affected in various combinations with other mutations, including TET2, ASXL1, CBL, EZH2, RAS, IDH1/2, DNMT3A, TP53, UTX and RUNX1. Worse overall survival was associated with mutations in U2AF1 (P=0.047) and DNMT3A (P=0.015). RAS mutations had an impact on overall survival in secondary acute myeloid leukemia (P=0.0456). By comparison, our screening of juvenile myelomonocytic leukemia cases showed mutations in ASXL1 (4%), CBL (10%), and RAS (6%) but not in IDH1/2, TET2, EZH2, DNMT3A or the three spliceosomal genes. SRSF2 and U2AF1 along with TET2 (48%) and ASXL1 (38%) are frequently affected by somatic mutations in chronic myelomonocytic leukemia, quite distinctly from the profile seen in juvenile myelomonocytic leukemia. Our data also suggest that spliceosomal mutations are of ancestral origin. PMID:22773603

Kar, Sarah Abu; Jankowska, Anna; Makishima, Hideki; Visconte, Valeria; Jerez, Andres; Sugimoto, Yuka; Muramatsu, Hideki; Traina, Fabiola; Afable, Manuel; Guinta, Kathryn; Tiu, Ramon V.; Przychodzen, Bartlomiej; Sakaguchi, Hirotoshi; Kojima, Seiji; Sekeres, Mikkael A.; List, Alan F.; McDevitt, Michael A.; Maciejewski, Jaroslaw P.

2013-01-01

382

Locus heterogeneity of Dent's disease: OCRL1 and TMEM27 genes in patients with no CLCN5 mutations.  

PubMed

Dent's disease is an X-linked renal tubulopathy caused by mutations mainly affecting the CLCN5 gene. Defects in the OCRL1 gene, which is usually mutated in patients with Lowe syndrome, have recently been shown to lead to a Dent-like phenotype, called Dent's disease 2. About 25% of Dent's disease patients do not carry CLCN5/OCRL1 mutations. The CLCN4 and SLC9A6 genes have been investigated, but no mutations have been identified. The recent discovery of a novel mediator of renal amino acid transport, collectrin (the TMEM27 gene), may provide new insight on the pathogenesis of Dent's disease. We studied 31 patients showing a phenotype resembling Dent's disease but lacking any CLCN5 mutations by direct sequencing of the OCRL1 and TMEM27 genes. Five novel mutations, L88X, P161HfsX167, F270S, D506N and E720D, in the OCRL1 gene, which have not previously been reported in patients with Dent's or Lowe disease, were identified among 11 patients with the classical Dent's disease phenotype. No TMEM27 gene mutations were discovered among 26 patients, 20 of whom had an incomplete Dent's disease phenotype. Our findings confirm that OCRL1 is involved in the functional defects characteristic of Dent's disease and suggest that patients carrying missense mutations in exons where many Lowe mutations are mapped may represent a phenotypic variant of Lowe syndrome. PMID:19582483

Tosetto, Enrica; Addis, Maria; Caridi, Gianluca; Meloni, Cristiana; Emma, Francesco; Vergine, Gianluca; Stringini, Gilda; Papalia, Teresa; Barbano, Giancarlo; Ghiggeri, Gian Marco; Ruggeri, Laura; Miglietti, Nunzia; D Angelo, Angela; Melis, Maria Antonietta; Anglani, Franca

2009-10-01

383

Quantum dots immunofluorescence histochemical detection of EGFR gene mutations in the non-small cell lung cancers using mutation-specific antibodies  

PubMed Central

Background Epidermal growth factor receptor (EGFR) mutation status plays an important role in therapeutic decision making for non-small cell lung cancer (NSCLC) patients. Since EGFR mutation-specific antibodies (E746-A750del and L858R) have been developed, EGFR mutation detection by immunohistochemistry (IHC) is a suitable screening test. On this basis, we want to establish a new screening test, quantum dots immunofluorescence histochemistry (QDs-IHC), to assess EGFR gene mutation in NSCLC tissues, and we compared it to traditional IHC and amplification refractory mutation system (ARMS). Materials and methods EGFR gene mutations were detected by QDs-IHC, IHC, and ADx-ARMS in 65 cases of NSCLC composed of 55 formalin-fixed, paraffin-embedded specimens and ten pleural effusion cell blocks, including 13 squamous cell carcinomas, two adenosquamous carcinomas, and 50 adenocarcinomas. Results Positive rates of EGFR gene mutations detected by QDs-IHC, IHC, and ADx-ARMS were 40.0%, 36.9%, and 46.2%, respectively, in 65 cases of NSCLC patients. The sensitivity of QDs-IHC when detecting EGFR mutations, as compared to ADx-ARMS, was 86.7% (26/30); the specificity for both antibodies was 100.0% (26/26). IHC sensitivity was 80.0% (24/30) and the specificity was 92.31% (24/26). When detecting EGFR mutations, QDs-IHC and ADx-ARMS had perfect consistency (???=0.882; P<0.01). Excellent agreement was observed between IHC and ADx-ARMS when detecting EGFR mutations (???=0.826; P<0.01). Conclusion QDs-IHC is a simple and standardized method to detect EGFR mutations with its high sensitivity and specificity, as compared with real-time polymerase chain reaction. In addition, the development of specific antibodies against EGFR mutation proteins might be useful for the diagnosis and treatment of lung cancer. PMID:25525358

Qu, Yan-Gang; Zhang, Qian; Pan, Qi; Zhao, Xian-Da; Huang, Yan-Hua; Chen, Fu-Chun; Chen, Hong-Lei

2014-01-01

384

Influence of iron regulating genes mutations on iron status in Egyptian patients with sickle cell disease.  

PubMed

Mutations of the HAMP gene and HFE gene have a role in iron overload. We assessed the frequency of the G71D mutation of the HAMP gene and the H63D mutation of the HFE gene and the correlation between these mutations as well as the correlation between them and the iron overload in sickle cell disease (SCD) patients. Genotyping of G71D of HAMP and of H63D of HFE variants was performed by polymerase chain reaction-restriction fragment length polymorphism on 47 SCD patients and 45 controls. The iron status was assessed by serum ferritin and transferrin saturation. We found 61.7% of the patients had a wild genotype in both genes, 14.9% had a variation in HAMP-G71D, 27.7% had a variation in HFE-H63D, and 4.3% had variations in both. Patients with either HAMP-G71D or HFE-H63D variants did not show significant difference in iron status in comparison to patients with wild type genotypes. Multivariate regression analysis revealed that the number of mutations harbored by the patients tends to affect the serum ferritin level; p=0.07. Thus, The HAMP-G71D and HFE-H63D variants are not uncommon among the Egyptian SCD patients; neither of them alone was found to be a major determinant of iron overload in the studied patients. Nevertheless, the number of harboured mutations may increase the probability of iron overload in these patients. PMID:25117103

Abdel Rahman, Hala A; Abou-Elew, Heba H; El-Shorbagy, Reem M; Fawzy, Rania; Youssry, Ilham

2014-01-01

385

Origin and Ascendancy of a Chimeric Fusion Gene: The ?/?-Globin Gene of Paenungulate Mammals  

PubMed Central

The ?-globin gene (HBD) of eutherian mammals exhibits a propensity for recombinational exchange with the closely linked ?-globin gene (HBB) and has been independently converted by the HBB gene in multiple lineages. Here we report the presence of a chimeric ?/? fusion gene in the African elephant (Loxodonta africana) that was created by unequal crossing-over between misaligned HBD and HBB paralogs. The recombinant chromosome that harbors the ?/? fusion gene in elephants is structurally similar to the “anti-Lepore” duplication mutant of humans (the reciprocal exchange product of the hemoglobin Lepore deletion mutant). However, the situation in the African elephant is unique in that the chimeric ?/? fusion gene supplanted the parental HBB gene and is therefore solely responsible for synthesizing the ?-chain subunits of adult hemoglobin. A phylogenetic survey of ?-like globin genes in afrotherian and xenarthran mammals revealed that the origin of the chimeric ?/? fusion gene and the concomitant inactivation of the HBB gene predated the radiation of “Paenungulata,” a clade of afrotherian mammals that includes three orders: Proboscidea (elephants), Sirenia (dugongs and manatees), and Hyracoidea (hyraxes). The reduced fitness of the human Hb Lepore deletion mutant helps to explain why independently derived ?/? fusion genes (which occur on an anti-Lepore chromosome) have been fixed in a number of mammalian lineages, whereas the reciprocal ?/? fusion gene (which occurs on a Lepore chromosome) has yet to be documented in any nonhuman mammal. This illustrates how the evolutionary fates of chimeric fusion genes can be strongly influenced by their recombinational mode of origin. PMID:19332641

Opazo, Juan C.; Sloan, Angela M.; Campbell, Kevin L.

2009-01-01

386

A new mutation (1062 del 16) of iduronate-2-sulfatase gene from a Chinese patient with Hunter syndrome*  

PubMed Central

Objective: To identify the mutations of iduronate-2-sulfatase (IDS) gene, to reveal its mutation features, and to establish a basis for genetic counseling and prenatal gene diagnosis of Hunter syndrome. Methods: Urine glycosaminoglycans (GAGs) assay, PCR and DNA sequencing were performed to detect mutation of IDS gene of the patient and his parents. Results: The result showed that the patient was: DS(++), HS(++), KS(?), CS(?), and that both of his parents were negative. A frame-shift deletion mutation (1062 del 16) was identified in exon 7 of the patient’s IDS gene. His parents’ genotypes were normal. Conclusion: The patient’s mutation was not inherited by his parents but a novel one. The mutation probably altered the primary structure and tertiary structure of IDS enzyme protein remarkably and lowered the activity of IDS enzyme greatly. Therefore it is supposed to be the direct cause of the disorder. PMID:17657858

Guo, Yi-bin; Pan, Jing-xin; Meng, Ya-xian

2007-01-01

387

Novel mutations of the HOXD13 gene in hand and foot malformations.  

PubMed

Homeobox genes encode a set of transcription factors of fundamental importance for body patterning during embryogenesis. Hoxa9-a13 and Hoxd9-d13 play an especially important part in vertebrate limb development. Synpolydactyly (SPD) is characterized by various malformations of the limbs. The expansion of the polyalanine tract in 1OXD13 is one of its major causes. Recently, there have been many analysis studies of HOXD13 in patients with SPD and limb malformations. We analyzed HOXD13 in 100 patients with limb malformations, which affects the limbs in the distal parts of the metacarpal and/or metatarsal bones. Seven mutations in the coding region and two mutations in the 5'-untranslated region were identified. All were novel mutations. In this study, the mutations were located upstream in the homeobox. Thus, translation of the homeobox was affected by upstream mutations. Consequently, this suggested the possibility that abnormalities in the hands and feet could be caused by novel HOXD13 gene mutations. PMID:18399101

Nakano, Kayoko; Sakai, Naohiko; Yamazaki, Yasuharu; Watanabe, Hiroi; Yamada, Naoto; Sezaki, Koichiro; Susami, Takafumi; Tokunaga, Katsushi; Takato, Tsuyoshi; Uchinuma, Eiju

2007-01-01

388

Mutations of Cx26 gene (GJB2) for prelingual deafness in Taiwan.  

PubMed

Mutations in the Cx26 (GJB2) gene have been shown to be responsible for a major part of autosomal recessive non-syndromic inherited prelingual deafness. We have sequenced the coding region of GJB2 gene from 169 Taiwanese patients with prelingual deafness and 100 unrelated normal individuals. In the deaf patients, three mutations were found: two novel mutations, 551G-->A, and 299-300delAT, and one previously described mutation, 235delC. Four previously reported polymorphisms, 79G-->A, 109G-->A, 341A-->G, and 608T-->C, were also found in both deaf patients and normal individuals and one new possible polymorphism, 558G-->A, which was only found in a patient. Interestingly, we did not find the 35delG allele, which is commonly found in the Caucasian population, either in the patients or in normal individuals we examined. Our data also showed 235delC to be the most common type of mutation found in Cx26 mutants (approximately 57%). Therefore, based on our findings, we have developed a simple molecular test for the 235delC mutation and it should be of considerable help to those families to understand the cause of their children having the prelingual deafness. PMID:12111646

Wang, Yi-Chun; Kung, Chiu-Yun; Su, Mao-Chang; Su, Ching-Chyuan; Hsu, Hsiu-Mei; Tsai, Chin-Chu; Lin, Chyi-Chyang; Li, Shuan-Yow

2002-08-01

389

Mutations in tubulin genes are frequent causes of various foetal malformations of cortical development including microlissencephaly  

PubMed Central

Complex cortical malformations associated with mutations in tubulin genes are commonly referred to as “Tubulinopathies”. To further characterize the mutation frequency and phenotypes associated with tubulin mutations, we studied a cohort of 60 foetal cases. Twenty-six tubulin mutations were identified, of which TUBA1A mutations were the most prevalent (19 cases), followed by TUBB2B (6 cases) and TUBB3 (one case). Three subtypes clearly emerged. The most frequent (n?=?13) was microlissencephaly with corpus callosum agenesis, severely hypoplastic brainstem and cerebellum. The cortical plate was either absent (6/13), with a 2–3 layered pattern (5/13) or less frequently thickened (2/13), often associated with neuroglial overmigration (4/13). All cases had voluminous germinal zones and ganglionic eminences. The second subtype was lissencephaly (n?=?7), either classical (4/7) or associated with cerebellar hypoplasia (3/7) with corpus callosum agenesis (6/7). All foetuses with lissencephaly and cerebellar hypoplasia carried distinct TUBA1A mutations, while those with classical lissencephaly harbored recurrent mutations in TUBA1A (3 cases) or TUBB2B (1 case). The third group was polymicrogyria-like cortical dysplasia (n?=?6), consisting of asymmetric multifocal or generalized polymicrogyria with inconstant corpus callosum agenesis (4/6) and hypoplastic brainstem and cerebellum (3/6). Polymicrogyria was either unlayered or 4-layered with neuronal heterotopias (5/6) and occasional focal neuroglial overmigration (2/6). Three had TUBA1A mutations and 3 TUBB2B mutations. Foetal TUBA1A tubulinopathies most often consist in microlissencephaly or classical lissencephaly with corpus callosum agenesis, but polymicrogyria may also occur. Conversely, TUBB2B mutations are responsible for either polymicrogyria (4/6) or microlissencephaly (2/6). PMID:25059107

2014-01-01

390

Mutational analysis of Btk, the defective gene in X-linked agammaglobulinemia  

SciTech Connect

Recent studies have shown that X-linked agammaglobulinemia (XLA), a disorder of B cell development, is due to mutations in an scr-like cytoplasmic tyrosine kinase, Btk. Thus far, mutations in this gene have been identified by sequencing of cDNA. To permit the detection of mutations in genomic DNA, we determined the structure of Btk and identified 19 exons in 37 kb of DNA. PCR primers were designed to amplify each exon with its splice sites. Two overlapping PCR products were employed for exons longer than 230 base pairs. Single strand conformation polymorphism (SSCP) analysis was used to screen genomic DNA from 30 unrelated families presumed to carry a mutation in Btk. It was possible to amplify DNA in every reaction from every patient. None of the DNA samples demonstrated more than one aberrant SSCP pattern. Twenty three mutations were detected in 25 families. Seven point mutations resulting in amino acid substitutions were seen. An additional 7 base pair substitutions gave rise to premature stop codons. Two splice defects were noted. Small insertions or deletions, all resulting in frameshifts and premature stop codons were seen in eight patients. One patient had an A to G transition in the ATG start codon. Two mutations, both at CpG dinucleotides, were seen in more than one family. Haplotype analysis, using CA repeats closely linked to Btk, demonstrated that the mutations in these families arose independently. We conclude from these studies that the mutations in Btk in patients with XLA are highly variable. Large deletions are uncommon, although small 1 to 4 bp insertions or deletions constitute as many as one third of the mutations. Further analysis of patients with amino acid substitutions will permit structure/function correlations.

Conley, M.E.; Fitch-Hilgenberg, M.E.; Rohrer, J. [St. Jude Children`s Research Hospital, Memphis, TN (United States)

1994-09-01

391

Mutations in tubulin genes are frequent causes of various foetal malformations of cortical development including microlissencephaly.  

PubMed

Complex cortical malformations associated with mutations in tubulin genes are commonly referred to as "Tubulinopathies". To further characterize the mutation frequency and phenotypes associated with tubulin mutations, we studied a cohort of 60 foetal cases. Twenty-six tubulin mutations were identified, of which TUBA1A mutations were the most prevalent (19 cases), followed by TUBB2B (6 cases) and TUBB3 (one case). Three subtypes clearly emerged. The most frequent (n?=?13) was microlissencephaly with corpus callosum agenesis, severely hypoplastic brainstem and cerebellum. The cortical plate was either absent (6/13), with a 2-3 layered pattern (5/13) or less frequently thickened (2/13), often associated with neuroglial overmigration (4/13). All cases had voluminous germinal zones and ganglionic eminences. The second subtype was lissencephaly (n?=?7), either classical (4/7) or associated with cerebellar hypoplasia (3/7) with corpus callosum agenesis (6/7). All foetuses with lissencephaly and cerebellar hypoplasia carried distinct TUBA1A mutations, while those with classical lissencephaly harbored recurrent mutations in TUBA1A (3 cases) or TUBB2B (1 case). The third group was polymicrogyria-like cortical dysplasia (n?=?6), consisting of asymmetric multifocal or generalized polymicrogyria with inconstant corpus callosum agenesis (4/6) and hypoplastic brainstem and cerebellum (3/6). Polymicrogyria was either unlayered or 4-layered with neuronal heterotopias (5/6) and occasional focal neuroglial overmigration (2/6). Three had TUBA1A mutations and 3 TUBB2B mutations. Foetal TUBA1A tubulinopathies most often consist in microlissencephaly or classical lissencephaly with corpus callosum agenesis, but polymicrogyria may also occur. Conversely, TUBB2B mutations are responsible for either polymicrogyria (4/6) or microlissencephaly (2/6). PMID:25059107

Fallet-Bianco, Catherine; Laquerrière, Annie; Poirier, Karine; Razavi, Ferechte; Guimiot, Fabien; Dias, Patricia; Loeuillet, Laurence; Lascelles, Karine; Beldjord, Cherif; Carion, Nathalie; Toussaint, Aurélie; Revencu, Nicole; Addor, Marie-Claude; Lhermitte, Benoit; Gonzales, Marie; Martinovich, Jelena; Bessieres, Bettina; Marcy-Bonnière, Maryse; Jossic, Frédérique; Marcorelles, Pascale; Loget, Philippe; Chelly, Jamel; Bahi-Buisson, Nadia

2014-01-01

392

Journal of Data Science 11(2013), 673-714 Sequence Mutations of Genes Pertaining to Malignancy in  

E-print Network

-scale investigations of cancer genomes and robust methods for interring the function of genes. In this review, we will describe sequence mutations of several cancer-related genes and discuss their functional implications words: Cancer, cancer databases, mutations. 1. Introduction Cancer cells harbor a large number

Yeang, Chen-Hsiang

393

Targeted next-generation sequencing in steroid-resistant nephrotic syndrome: mutations in multiple glomerular genes may influence disease severity.  

PubMed

Genetic diagnosis of steroid-resistant nephrotic syndrome (SRNS) using Sanger sequencing is complicated by the high genetic heterogeneity and phenotypic variability of this disease. We aimed to improve the genetic diagnosis of SRNS by simultaneously sequencing 26 glomerular genes using massive parallel sequencing and to study whether mutations in multiple genes increase disease severity. High-throughput mutation analysis was performed in 50 SRNS and/or focal segmental glomerulosclerosis (FSGS) patients, a validation cohort of 25 patients with known pathogenic mutations, and a discovery cohort of 25 uncharacterized patients with probable genetic etiology. In the validation cohort, we identified the 42 previously known pathogenic mutations across NPHS1, NPHS2, WT1, TRPC6, and INF2 genes. In the discovery cohort, disease-causing mutations in SRNS/FSGS genes were found in nine patients. We detected three patients with mutations in an SRNS/FSGS gene and COL4A3. Two of them were familial cases and presented a more severe phenotype than family members with mutation in only one gene. In conclusion, our results show that massive parallel sequencing is feasible and robust for genetic diagnosis of SRNS/FSGS. Our results indicate that patients carrying mutations in an SRNS/FSGS gene and also in COL4A3 gene have increased disease severity.European Journal of Human Genetics advance online publication, 19 November 2014; doi:10.1038/ejhg.2014.252. PMID:25407002

Bullich, Gemma; Trujillano, Daniel; Santín, Sheila; Ossowski, Stephan; Mendizábal, Santiago; Fraga, Gloria; Madrid, Alvaro; Ariceta, Gema; Ballarín, José; Torra, Roser; Estivill, Xavier; Ars, Elisabet

2014-11-19

394

Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females  

Microsoft Academic Search

Periventricular heterotopia (PH) is a human neuronal migration disorder in which many neurons destined for the cerebral cortex fail to migrate. Previous analysis showed heterozygous mutations in the X-linked gene filamin 1 (FLN1), but examined only the first six (of 48) coding exons of the gene and hence did not assess the incidence and functional consequences of FLN1 mutations. Here

Volney L. Sheen; Peter H. Dixon; Jeremy W. Fox; Susan E. Hong; Lucy Kinton; Sanjay M. Sisodiya; John S. Duncan; Francois Dubeau; Ingrid E. Scheffer; Steven C. Schachter; Andrew Wilner; Ruth Henchy; Peter Crino; Kazuhiro Kamuro; Frances DiMario; Michel Berg; Ruben Kuzniecky; Andrew J. Cole; Edward Bromfield; Michael Biber; Donald Schomer; James Wheless; Kenneth Silver; Ganeshwaran H. Mochida; Samuel F. Berkovic; Fred Andermann; Eva Andermann; William B. Dobyns; Nicholas W. Wood; Christopher A. Walsh

2001-01-01

395

A novel MLL2 gene mutation in a Korean patient with Kabuki syndrome.  

PubMed

Kabuki syndrome (KS) is a rare genetic disease with a distinctive dysmorphic face, intellectual disability, and multiple congenital abnormalities. KS is inherited in an autosomal dominant manner. As the primary cause of KS, MLL2 mutations have been identified in 56-76% of affected individuals who have been tested, suggesting that there may be additional genes associated with KS. Recently, a few KS individuals have been found to have de novo partial or complete deletions of an X chromosome gene, KDM6A, which encodes a histone demethylase that interacts with MLL2. Nevertheless, mutations in MLL2 are the major cause of KS. Although there are a few reports of KS patients in Korea, none of these had been confirmed by genetic analysis. Here, we report a case of a Korean patient with clinical features of KS. Using direct sequencing, we identified a frameshift heterozygous mutation for MLL2: (c.5256_5257delGA;p.Lys1753Alafs*34). Clinically, the patient presented with typical facial features, and diagnosis of KS was based on the diagnostic criteria. While KS is a rare disease, other malformations that overlap with those found in individuals with KS are common. Hence, the diagnosis of KS by mutational analysis can be a valuable method for patients with KS-like syndromes. Furthermore, in the near future, other genes could be identified in patients with KS without a detectable MLL2 mutation. PMID:24019847

Kim, Soo Jin; Cho, Sung Yoon; Maeng, Se Hyun; Sohn, Young Bae; Kim, Su-Jin; Ki, Chang-Seok; Jin, Dong-Kyu

2013-08-01

396

Mutations in the TTDN1 Gene Are Associated with a Distinct Trichothiodystrophy Phenotype.  

PubMed

Trichothiodystrophy (TTD) is a rare multisystem disorder, characterized by sulfur-deficient hair with alternating dark and light "tiger tail" banding on polarized light microscopy. TTD is caused by mutations in DNA repair/transcription genes XPD, XPB or TTDA, and in TTDN1, a gene of unknown function. Although most of the TTD patients are photosensitive, patients with TTDN1 mutations were reported to be nonphotosensitive. We followed a cohort of 36 TTD patients from 2001 to 2013. We describe five patients from four families with defects in the TTDN1 gene: four had no photosensitivity, and one patient exhibited cutaneous burning. Deep phenotyping of our cohort revealed differences between the patients with and without TTDN1 mutations. Delayed bone age and seizure disorders were overrepresented in the TTDN1 group (P=0.009 and P=0.024, respectively), whereas some characteristic TTD clinical, laboratory, and imaging findings were absent. The three oldest TTDN1 patients displayed autistic behaviors in contrast to the characteristic friendly, socially interactive personality in the other patients. DNA sequencing revealed deletion mutations in TTDN1 ranging in size from a single base pair to over 120?kb. These data identify a distinct phenotype relationship in TTD caused by TTDN1 mutations and suggest a different mechanism of disease. PMID:25290684

Heller, Elizabeth R; Khan, Sikandar G; Kuschal, Christiane; Tamura, Deborah; DiGiovanna, John J; Kraemer, Kenneth H

2015-03-01

397

Development of molecular approaches to the estimation of the germinal gene mutation rate in human populations  

SciTech Connect

In view of this potential for germinal mutations to result in genetic disease, it is important to establish a basis upon which to estimate the rate of occurrence of de novo gene mutations and the impact of mutagenic agents in increasing the frequency of these events. Estimates based upon a variety of approaches place the ''spontaneous/background'' germinal gene mutation rate in humans in the neighborhood of 0.4 /times/ 10/sup -5/ events per locus per generation, or a nucleotide substitution rate of approximately 10/sup -8/ (Neel et al. 1988a) (70 substitutions/genome/generation). This rarity of events makes it difficult to establish a data base upon which to estimate the rate at which mutations occur. This is a reflection of the inability of current techniques to derive a significant amount of information from each subject and the unavailability of large cohorts for study (see Neel et al. 1988b). Thus, new approaches are required to derive the statistically-significant data bases necessary to detect an increase (or the absence of) in germinal gene mutation rate due to exposure to known or suspected mutagenic agents. 16 refs.

Perry, B.A.; Mohrenweiser, H.W.

1988-10-01

398

Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder.  

PubMed

Transitional cell carcinoma (TCC) is the most common type of bladder cancer. Here we sequenced the exomes of nine individuals with TCC and screened all the somatically mutated genes in a prevalence set of 88 additional individuals with TCC with different tumor stages and grades. In our study, we discovered a variety of genes previously unknown to be mutated in TCC. Notably, we identified genetic aberrations of the chromatin remodeling genes (UTX, MLL-MLL3, CREBBP-EP300, NCOR1, ARID1A and CHD6) in 59% of our 97 subjects with TCC. Of these genes, we showed UTX to be altered substantially more frequently in tumors of low stages and grades, highlighting its potential role in the classification and diagnosis of bladder cancer. Our results provide an overview of the genetic basis of TCC and suggest that aberration of chromatin regulation might be a hallmark of bladder cancer. PMID:21822268

Gui, Yaoting; Guo, Guangwu; Huang, Yi; Hu, Xueda; Tang, Aifa; Gao, Shengjie; Wu, Renhua; Chen, Chao; Li, Xianxin; Zhou, Liang; He, Minghui; Li, Zesong; Sun, Xiaojuan; Jia, Wenlong; Chen, Jinnong; Yang, Shangming; Zhou, Fangjian; Zhao, Xiaokun; Wan, Shengqing; Ye, Rui; Liang, Chaozhao; Liu, Zhisheng; Huang, Peide; Liu, Chunxiao; Jiang, Hui; Wang, Yong; Zheng, Hancheng; Sun, Liang; Liu, Xingwang; Jiang, Zhimao; Feng, Dafei; Chen, Jing; Wu, Song; Zou, Jing; Zhang, Zhongfu; Yang, Ruilin; Zhao, Jun; Xu, Congjie; Yin, Weihua; Guan, Zhichen; Ye, Jiongxian; Zhang, Hong; Li, Jingxiang; Kristiansen, Karsten; Nickerson, Michael L; Theodorescu, Dan; Li, Yingrui; Zhang, Xiuqing; Li, Songgang; Wang, Jian; Yang, Huanming; Wang, Jun; Cai, Zhiming

2011-09-01

399

A novel missense mutation in exon 4 of the human coproporphyrinogen oxidase gene in two patients with hereditary coproporphyria  

Microsoft Academic Search

Hereditary coproporphyria (HCP) is an autosomal dominant disease characterized by a deficiency of coproporphyrinogen oxidase.\\u000a To date, four mutations of the gene have been reported. We report here another mutation in two Japanese families with HCP,\\u000a which was revealed by analysis of polymerase chain reaction (PCR)-amplified DNA fragments of the gene by a direct-sequencing\\u000a method. A point mutation, G to

Makoto Daimon; Eishirou Gojyou; Makoto Sugawara; Keiichi Yamatani; Makoto Tominaga; Hideo Sasaki

1997-01-01

400

Prevalence of thromogenic gene mutations in women with recurrent miscarriage: A retrospective study of 1,507 patients  

PubMed Central

Objective Thromogenic gene mutations has been thought to be associated with recurrent pregnancy loss in women in Turkey. The aim of this study was to investigate the prevalence of thromogenic gene mutations such as factor V Leiden (FVL, G1691T), prothrombin (G20210A), and the methylene tetrahydrofolate reductase (MTHFR, C677T) mutation in women with recurrent pregnancy loss. Methods This descriptive study was carried out in the Department of Obstetrics and Gynaecology, Harran University School of Medicine, and included a total of 1,507 women with histories of recurrent pregnancy loss between January 2010 and June 2013. The mutations were assessed by using the polymerase chain reaction. Results The homozygous mutation frequencies of FVL, prothrombin, and MTHFR were found to be 3 (0.20%), 0 and 125 (8.29%), and the heterozygous mutation frequencies were 83 (5.51%), 61 (4.05%), and 612 (40.61%), respectively. Among the 86 FVL mutation patients, 38 also had accompanying prothrombin and MTHFR mutations. Conclusion Since the homozygous forms of the FVL-prothrombin gene mutations have low incidences and MTHFR mutation is similar to a healthy population, preconceptional thromogenic gene mutations screening seems to be controversial. PMID:25469341

Hilali, Nese Gul; Camuzcuoglu, Aysun; Camuzcuoglu, Hakan; Akbas, Halit; Kilic, Avni; Vural, Mehmet

2014-01-01