Mutation in Rice Abscisic Acid2 Results in Cell Death, Enhanced Disease-Resistance, Altered Seed Dormancy and Development.

PubMed

Liao, Yongxiang; Bai, Que; Xu, Peizhou; Wu, Tingkai; Guo, Daiming; Peng, Yongbin; Zhang, Hongyu; Deng, Xiaoshu; Chen, Xiaoqiong; Luo, Ming; Ali, Asif; Wang, Wenming; Wu, Xianjun

2018-01-01

Lesion mimic mutants display spontaneous cell death, and thus are valuable for understanding the molecular mechanism of cell death and disease resistance. Although a lot of such mutants have been characterized in rice, the relationship between lesion formation and abscisic acid (ABA) synthesis pathway is not reported. In the present study, we identified a rice mutant, lesion mimic mutant 9150 ( lmm9150 ), exhibiting spontaneous cell death, pre-harvest sprouting, enhanced growth, and resistance to rice bacterial and blast diseases. Cell death in the mutant was accompanied with excessive accumulation of H 2 O 2 . Enhanced disease resistance was associated with cell death and upregulation of defense-related genes. Map-based cloning identified a G-to-A point mutation resulting in a D-to-N substitution at the amino acid position 110 of OsABA2 (LOC_Os03g59610) in lmm9150 . Knock-out of OsABA2 through CRISPR/Cas9 led to phenotypes similar to those of lmm9150 . Consistent with the function of OsABA2 in ABA biosynthesis, ABA level in the lmm9150 mutant was significantly reduced. Moreover, exogenous application of ABA could rescue all the mutant phenotypes of lmm9150 . Taken together, our data linked ABA deficiency to cell death and provided insight into the role of ABA in rice disease resistance.

Mutations of genes in synthesis of the carotenoid precursors of ABA lead to pre-harvest sprouting and photo-oxidation in rice

PubMed Central

Fang, Jun; Chai, Chenglin; Qian, Qian; Li, Chunlai; Tang, Jiuyou; Sun, Lei; Huang, Zejun; Guo, Xiaoli; Sun, Changhui; Liu, Min; Zhang, Yan; Lu, Qingtao; Wang, Yiqin; Lu, Congming; Han, Bin; Chen, Fan; Cheng, Zhukuan; Chu, Chengcai

2008-01-01

Pre-harvest sprouting (PHS) or vivipary in cereals is an important agronomic trait that results in significant economic loss. A considerable number of mutations that cause PHS have been identified in several species. However, relatively few viviparous mutants in rice (Oryza sativa L.) have been reported. To explore the mechanism of PHS in rice, we carried out an extensive genetic screening and identified 12 PHS mutants (phs). Based on their phenotypes, these phs mutants were classified into three groups. Here we characterize in detail one of these groups, which contains mutations in genes encoding major enzymes of the carotenoid biosynthesis pathway, including phytoene desaturase (OsPDS), ζ-carotene desaturase (OsZDS), carotenoid isomerase (OsCRTISO) and lycopene β-cyclase (β-OsLCY), which are essential for the biosynthesis of carotenoid precursors of ABA. As expected, the amount of ABA was reduced in all four phs mutants compared with that in the wild type. Chlorophyll fluorescence analysis revealed the occurrence of photoinhibition in the photosystem and decreased capacity for eliminating excess energy by thermal dissipation. The greatly increased activities of reactive oxygen species (ROS) scavenging enzymes, and reduced photosystem (PS) II core proteins CP43, CP47 and D1 in leaves of the Oscrtiso/phs3-1 mutant and OsLCY RNAi transgenic rice indicated that photo-oxidative damage occurred in PS II, consistent with the accumulation of ROS in these plants. These results suggest that the impairment of carotenoid biosynthesis causes photo-oxidation and ABA-deficiency phenotypes, of which the latter is a major factor controlling the PHS trait in rice. PMID:18208525

Space environment induced mutations prefer to occur at polymorphic sites of rice genomes

NASA Astrophysics Data System (ADS)

Li, Y.; Liu, M.; Cheng, Z.; Sun, Y.

To explore the genomic characteristics of rice mutants induced by space environment, space-induced mutants 971-5, 972-4, and R955, which acquired new traits after space flight such as increased yield, reduced resistance to rice blast, and semi-dwarfism compared with their on-ground controls, 971ck, 972ck, and Bing95-503, respectively, together with other 8 japonica and 3 indica rice varieties, 17 in total, were analyzed by amplified fragment length polymorphism (AFLP) method. We chose 16 AFLP primer-pairs which generated a total of 1251 sites, of which 745 (59.6%) were polymorphic over all the genotypes. With the 16 pairs of primer combinations, 54 space-induced mutation sites were observed in 971-5, 86 in 972-4, and 5 in R955 compared to their controls, and the mutation rates were 4.3%, 6.9% and 0.4%, respectively. Interestingly, 75.9%, 84.9% and 100% of the mutation sites identified in 971-5, 972-4, and R955 occurred in polymorphic sites. This result suggests that the space environment preferentially induced mutations at polymorphic sites in rice genomes and might share a common mechanism with other types of mutagens. It also implies that polymorphic sites in genomes are potential "hotspots" for mutations induced by the space environment.

Mutations Altering Chloroplast Ribosome Phenotype in Chlamydomonas, I. Non-Mendelian Mutations*

PubMed Central

Gillham, Nicholas W.; Boynton, John E.; Burkholder, Barbara

1970-01-01

Uniparentally inherited mutations to antibiotic resistance and dependence in Chlamydomonas reinhardi exhibit an altered chloroplast ribosome phenotype. Genetic studies demonstrate an absolute correlation between the drug resistance or dependence and the ribosome phenotype in two such mutants. Images PMID:5289000

Disruptive mitochondrial DNA mutations in complex I subunits are markers of oncocytic phenotype in thyroid tumors.

PubMed

Gasparre, Giuseppe; Porcelli, Anna Maria; Bonora, Elena; Pennisi, Lucia Fiammetta; Toller, Matteo; Iommarini, Luisa; Ghelli, Anna; Moretti, Massimo; Betts, Christine M; Martinelli, Giuseppe Nicola; Ceroni, Alberto Rinaldi; Curcio, Francesco; Carelli, Valerio; Rugolo, Michela; Tallini, Giovanni; Romeo, Giovanni

2007-05-22

Oncocytic tumors are a distinctive class of proliferative lesions composed of cells with a striking degree of mitochondrial hyperplasia that are particularly frequent in the thyroid gland. To understand whether specific mitochondrial DNA (mtDNA) mutations are associated with the accumulation of mitochondria, we sequenced the entire mtDNA in 50 oncocytic lesions (45 thyroid tumors of epithelial cell derivation and 5 mitochondrion-rich breast tumors) and 52 control cases (21 nononcocytic thyroid tumors, 15 breast carcinomas, and 16 gliomas) by using recently developed technology that allows specific and reliable amplification of the whole mtDNA with quick mutation scanning. Thirteen oncocytic lesions (26%) presented disruptive mutations (nonsense or frameshift), whereas only two samples (3.8%) presented such mutations in the nononcocytic control group. In one case with multiple thyroid nodules analyzed separately, a disruptive mutation was found in the only nodule with oncocytic features. In one of the five mitochondrion-rich breast tumors, a disruptive mutation was identified. All disruptive mutations were found in complex I subunit genes, and the association between these mutations and the oncocytic phenotype was statistically significant (P=0.001). To study the pathogenicity of these mitochondrial mutations, primary cultures from oncocytic tumors and corresponding normal tissues were established. Electron microscopy and biochemical and molecular analyses showed that primary cultures derived from tumors bearing disruptive mutations failed to maintain the mutations and the oncocytic phenotype. We conclude that disruptive mutations in complex I subunits are markers of thyroid oncocytic tumors.

Testing computational prediction of missense mutation phenotypes: Functional characterization of 204 mutations of human cystathionine beta synthase

PubMed Central

Wei, Qiong; Wang, Liqun; Wang, Qiang; Kruger, Warren D.; Dunbrack, Roland L.

2010-01-01

Predicting the phenotypes of missense mutations uncovered by large-scale sequencing projects is an important goal in computational biology. High-confidence predictions can be an aid in focusing experimental and association studies on those mutations most likely to be associated with causative relationships between mutation and disease. As an aid in developing these methods further, we have derived a set of random mutations of the enzymatic domains of human cystathionine beta synthase. This enzyme is a dimeric protein that catalyzes the condensation of serine and homocysteine to produce cystathionine. Yeast missing this enzyme cannot grow on medium lacking a source of cysteine, while transfection of functional human CBS into yeast strains missing endogenous enzyme can successfully complement for the missing gene. We used PCR mutagenesis with error-prone Taq polymerase to produce 948 colonies, and compared cell growth in the presence or absence of a cysteine source as a measure of CBS function. We were able to infer the phenotypes of 204 single-site mutants, 79 of them deleterious and 125 neutral. This set was used to test the accuracy of six publicly available prediction methods for phenotype prediction of missense mutations: SIFT, PolyPhen, PMut, SNPs3D, PhD-SNP, and nsSNPAnalyzer. The top methods are PolyPhen, SIFT, and nsSNPAnalyzer, which have similar performance. Using kernel discriminant functions, we found that the difference in position-specific scoring matrix values is more predictive than the wild-type PSSM score alone, and that the relative surface area in the biologically relevant complex is more predictive than that of the monomeric proteins. PMID:20455263

Recurrent mutations in the CDKL5 gene: genotype-phenotype relationships.

PubMed

Bahi-Buisson, Nadia; Villeneuve, Nathalie; Caietta, Emilie; Jacquette, Aurélia; Maurey, Helene; Matthijs, Gert; Van Esch, Hilde; Delahaye, Andrée; Moncla, Anne; Milh, Mathieu; Zufferey, Flore; Diebold, Bertrand; Bienvenu, Thierry

2012-07-01

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been described in epileptic encephalopathies in females with infantile spasms with features that overlap with Rett syndrome. With more than 80 reported patients, the phenotype of CDKL5-related encephalopathy is well-defined. The main features consist of seizures starting before 6 months of age, severe intellectual disability with absent speech and hand stereotypies and deceleration of head growth, which resembles Rett syndrome. However, some clinical discrepancies suggested the influence of genetics and/or environmental factors. No genotype-phenotype correlation has been defined and thus there is a need to examine individual mutations. In this study, we analyzed eight recurrent CDKL5 mutations to test whether the clinical phenotype of patients with the same mutation is similar and whether patients with specific CDKL5 mutations have a milder phenotype than those with other CDKL5 mutations. Patients bearing missense mutations in the ATP binding site such as the p.Ala40Val mutation typically walked unaided, had normocephaly, better hand use ability, and less frequent refractory epilepsy when compared to girls with other CDKL5 mutations. In contrast, patients with mutations in the kinase domain (such as p.Arg59X, p.Arg134X, p.Arg178Trp/Pro/Gln, or c.145 + 2T > C) and frameshift mutations in the C-terminal region (such as c.2635_2636delCT) had a more severe phenotype with infantile spasms, refractory epileptic encephalopathy, absolute microcephaly, and inability to walk. It is important for clinicians to have this information when such patients are diagnosed. Copyright © 2012 Wiley Periodicals, Inc.

Impact of human immunodeficiency virus type 1 reverse transcriptase inhibitor drug resistance mutation interactions on phenotypic susceptibility.

PubMed

Trivedi, Vinod; Von Lindern, Jana; Montes-Walters, Miguel; Rojo, Daniel R; Shell, Elisabeth J; Parkin, Neil; O'Brien, William A; Ferguson, Monique R

2008-10-01

The role specific reverse transcriptase (RT) drug resistance mutations play in influencing phenotypic susceptibility to RT inhibitors in virus strains with complex resistance interaction patterns was assessed using recombinant viruses that consisted of RT-PCR-amplified pol fragments derived from plasma HIV-1 RNA from two treatment-experienced patients. Specific modifications of key RT amino acids were performed by site-directed mutagenesis. A panel of viruses with defined genotypic resistance mutations was assessed for phenotypic drug resistance. Introduction of M184V into several different clones expressing various RT resistance mutations uniformly decreased susceptibility to abacavir, lamivudine, and didanosine, and increased susceptibility to zidovudine, stavudine, and tenofovir; replication capacity was decreased. The L74V mutation had similar but slightly different effects, contributing to decreased susceptibility to abacavir, lamivudine, and didanosine and increased susceptibility to zidovudine and tenofovir, but in contrast to M184V, L74V contributed to decreased susceptibility to stavudine. In virus strains with the nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations K101E and G190S, the L74V mutation increased replication capacity, consistent with published observations, but replication capacity was decreased in strains without NNRTI resistance mutations. K101E and G190S together tend to decrease susceptibility to all nucleoside RT inhibitors, but the K103N mutation had little effect on nucleoside RT inhibitor susceptibility. Mutational interactions can have a substantial impact on drug resistance phenotype and replication capacity, and this has been exploited in clinical practice with the development of fixed-dose combination pills. However, we are the first to report these mutational interactions using molecularly cloned recombinant strains derived from viruses that occur naturally in HIV-infected individuals.

Impact of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Inhibitor Drug Resistance Mutation Interactions on Phenotypic Susceptibility

PubMed Central

Trivedi, Vinod; Von Lindern, Jana; Montes-Walters, Miguel; Rojo, Daniel R.; Shell, Elisabeth J.; Parkin, Neil; O'Brien, William A.

2008-01-01

Abstract The role specific reverse transcriptase (RT) drug resistance mutations play in influencing phenotypic susceptibility to RT inhibitors in virus strains with complex resistance interaction patterns was assessed using recombinant viruses that consisted of RT-PCR-amplified pol fragments derived from plasma HIV-1 RNA from two treatment-experienced patients. Specific modifications of key RT amino acids were performed by site-directed mutagenesis. A panel of viruses with defined genotypic resistance mutations was assessed for phenotypic drug resistance. Introduction of M184V into several different clones expressing various RT resistance mutations uniformly decreased susceptibility to abacavir, lamivudine, and didanosine, and increased susceptibility to zidovudine, stavudine, and tenofovir; replication capacity was decreased. The L74V mutation had similar but slightly different effects, contributing to decreased susceptibility to abacavir, lamivudine, and didanosine and increased susceptibility to zidovudine and tenofovir, but in contrast to M184V, L74V contributed to decreased susceptibility to stavudine. In virus strains with the nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations K101E and G190S, the L74V mutation increased replication capacity, consistent with published observations, but replication capacity was decreased in strains without NNRTI resistance mutations. K101E and G190S together tend to decrease susceptibility to all nucleoside RT inhibitors, but the K103N mutation had little effect on nucleoside RT inhibitor susceptibility. Mutational interactions can have a substantial impact on drug resistance phenotype and replication capacity, and this has been exploited in clinical practice with the development of fixed-dose combination pills. However, we are the first to report these mutational interactions using molecularly cloned recombinant strains derived from viruses that occur naturally in HIV-infected individuals. PMID:18844463

New insights into genotype–phenotype correlation for GLI3 mutations

PubMed Central

Démurger, Florence; Ichkou, Amale; Mougou-Zerelli, Soumaya; Le Merrer, Martine; Goudefroye, Géraldine; Delezoide, Anne-Lise; Quélin, Chloé; Manouvrier, Sylvie; Baujat, Geneviève; Fradin, Mélanie; Pasquier, Laurent; Megarbané, André; Faivre, Laurence; Baumann, Clarisse; Nampoothiri, Sheela; Roume, Joëlle; Isidor, Bertrand; Lacombe, Didier; Delrue, Marie-Ange; Mercier, Sandra; Philip, Nicole; Schaefer, Elise; Holder, Muriel; Krause, Amanda; Laffargue, Fanny; Sinico, Martine; Amram, Daniel; André, Gwenaelle; Liquier, Alain; Rossi, Massimiliano; Amiel, Jeanne; Giuliano, Fabienne; Boute, Odile; Dieux-Coeslier, Anne; Jacquemont, Marie-Line; Afenjar, Alexandra; Van Maldergem, Lionel; Lackmy-Port-Lis, Marylin; Vincent- Delorme, Catherine; Chauvet, Marie-Liesse; Cormier-Daire, Valérie; Devisme, Louise; Geneviève, David; Munnich, Arnold; Viot, Géraldine; Raoul, Odile; Romana, Serge; Gonzales, Marie; Encha-Razavi, Ferechte; Odent, Sylvie; Vekemans, Michel; Attie-Bitach, Tania

2015-01-01

The phenotypic spectrum of GLI3 mutations includes autosomal dominant Greig cephalopolysyndactyly syndrome (GCPS) and Pallister–Hall syndrome (PHS). PHS was first described as a lethal condition associating hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis. Typical GCPS combines polysyndactyly of hands and feet and craniofacial features. Genotype–phenotype correlations have been found both for the location and the nature of GLI3 mutations, highlighting the bifunctional nature of GLI3 during development. Here we report on the molecular and clinical study of 76 cases from 55 families with either a GLI3 mutation (49 GCPS and 21 PHS), or a large deletion encompassing the GLI3 gene (6 GCPS cases). Most of mutations are novel and consistent with the previously reported genotype–phenotype correlation. Our results also show a correlation between the location of the mutation and abnormal corpus callosum observed in some patients with GCPS. Fetal PHS observations emphasize on the possible lethality of GLI3 mutations and extend the phenotypic spectrum of malformations such as agnathia and reductional limbs defects. GLI3 expression studied by in situ hybridization during human development confirms its early expression in target tissues. PMID:24736735

New insights into genotype-phenotype correlation for GLI3 mutations.

PubMed

Démurger, Florence; Ichkou, Amale; Mougou-Zerelli, Soumaya; Le Merrer, Martine; Goudefroye, Géraldine; Delezoide, Anne-Lise; Quélin, Chloé; Manouvrier, Sylvie; Baujat, Geneviève; Fradin, Mélanie; Pasquier, Laurent; Megarbané, André; Faivre, Laurence; Baumann, Clarisse; Nampoothiri, Sheela; Roume, Joëlle; Isidor, Bertrand; Lacombe, Didier; Delrue, Marie-Ange; Mercier, Sandra; Philip, Nicole; Schaefer, Elise; Holder, Muriel; Krause, Amanda; Laffargue, Fanny; Sinico, Martine; Amram, Daniel; André, Gwenaelle; Liquier, Alain; Rossi, Massimiliano; Amiel, Jeanne; Giuliano, Fabienne; Boute, Odile; Dieux-Coeslier, Anne; Jacquemont, Marie-Line; Afenjar, Alexandra; Van Maldergem, Lionel; Lackmy-Port-Lis, Marylin; Vincent-Delorme, Catherine; Chauvet, Marie-Liesse; Cormier-Daire, Valérie; Devisme, Louise; Geneviève, David; Munnich, Arnold; Viot, Géraldine; Raoul, Odile; Romana, Serge; Gonzales, Marie; Encha-Razavi, Ferechte; Odent, Sylvie; Vekemans, Michel; Attie-Bitach, Tania

2015-01-01

The phenotypic spectrum of GLI3 mutations includes autosomal dominant Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS). PHS was first described as a lethal condition associating hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis. Typical GCPS combines polysyndactyly of hands and feet and craniofacial features. Genotype-phenotype correlations have been found both for the location and the nature of GLI3 mutations, highlighting the bifunctional nature of GLI3 during development. Here we report on the molecular and clinical study of 76 cases from 55 families with either a GLI3 mutation (49 GCPS and 21 PHS), or a large deletion encompassing the GLI3 gene (6 GCPS cases). Most of mutations are novel and consistent with the previously reported genotype-phenotype correlation. Our results also show a correlation between the location of the mutation and abnormal corpus callosum observed in some patients with GCPS. Fetal PHS observations emphasize on the possible lethality of GLI3 mutations and extend the phenotypic spectrum of malformations such as agnathia and reductional limbs defects. GLI3 expression studied by in situ hybridization during human development confirms its early expression in target tissues.

Wolfram Syndrome: New Mutations, Different Phenotype

PubMed Central

Pasquali, Lorenzo; Lugani, Francesca; Perri, Katia; Russo, Chiara; Tallone, Ramona; Ghiggeri, Gian Marco; Lorini, Renata; d'Annunzio, Giuseppe

2012-01-01

Background Wolfram Syndrome (WS) is an autosomal recessive neurodegenerative disorder characterized by Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness identified by the acronym “DIDMOAD”. The WS gene, WFS1, encodes a transmembrane protein called Wolframin, which recent evidence suggests may serve as a novel endoplasmic reticulum calcium channel in pancreatic β-cells and neurons. WS is a rare disease, with an estimated prevalence of 1/550.000 children, with a carrier frequency of 1/354. The aim of our study was to determine the genotype of WS patients in order to establish a genotype/phenotype correlation. Methodology/Principal Findings We clinically evaluated 9 young patients from 9 unrelated families (6 males, 3 females). Basic criteria for WS clinical diagnosis were coexistence of insulin-treated diabetes mellitus and optic atrophy occurring before 15 years of age. Genetic analysis for WFS1 was performed by direct sequencing. Molecular sequencing revealed 5 heterozygous compound and 3 homozygous mutations. All of them were located in exon 8, except one in exon 4. In one proband only an heterozygous mutation (A684V) was found. Two new variants c.2663 C>A and c.1381 A>C were detected. Conclusions/Significance Our study increases the spectrum of WFS1 mutations with two novel variants. The male patient carrying the compound mutation [c.1060_1062delTTC]+[c.2663 C>A] showed the most severe phenotype: diabetes mellitus, optic atrophy (visual acuity 5/10), deafness with deep auditory bilaterally 8000 Hz, diabetes insipidus associated to reduced volume of posterior pituitary and pons. He died in bed at the age of 13 years. The other patient carrying the compound mutation [c.409_424dup16]+[c.1381 A>C] showed a less severe phenotype (DM, OA). PMID:22238590

Lethal mutagenesis: targeting the mutator phenotype in cancer.

PubMed

Fox, Edward J; Loeb, Lawrence A

2010-10-01

The evolution of cancer and RNA viruses share many similarities. Both exploit high levels of genotypic diversity to enable extensive phenotypic plasticity and thereby facilitate rapid adaptation. In order to accumulate large numbers of mutations, we have proposed that cancers express a mutator phenotype. Similar to cancer cells, many viral populations, by replicating their genomes with low fidelity, carry a substantial mutational load. As high levels of mutation are potentially deleterious, the viral mutation frequency is thresholded at a level below which viral populations equilibrate in a traditional mutation-selection balance, and above which the population is no longer viable, i.e., the population undergoes an error catastrophe. Because their mutation frequencies are fine-tuned just below this error threshold, viral populations are susceptible to further increases in mutational load and, recently this phenomenon has been exploited therapeutically by a concept that has been termed lethal mutagenesis. Here we review the application of lethal mutagenesis to the treatment of HIV and discuss how lethal mutagenesis may represent a novel therapeutic approach for the treatment of solid cancers. Copyright © 2010 Elsevier Ltd. All rights reserved.

Noonan syndrome: Severe phenotype and PTPN11 mutations.

PubMed

Carrasco Salas, Pilar; Gómez-Molina, Gertrudis; Carreto-Alba, Páxedes; Granell-Escobar, Reyes; Vázquez-Rico, Ignacio; León-Justel, Antonio

2018-04-24

Noonan syndrome (NS) is a genetic disorder characterized by a wide range of distinctive features and health problems. It caused in 50% of cases by missense mutations in PTPN11 gene. It has been postulated that it is possible to predict the disease course based into the impact of mutations on the protein. We report two cases of severe NS phenotype including hydrops fetalis. PTPN11 gene was studied in germinal cells of both patients by sequencing. Two different mutations (p.Gly503Arg and p.Met504Val) was detected in PTPN11 gene. These mutations have been reported previously, and when they were germinal variants, patients presented classic NS, NS with other malignancies and recently, p.Gly503Arg has been also observed in a patient with severe NS and hydrops fetalis, as our cases. Therefore, these observations shade light on that it is not always possibly to determine the genotype-phenotype relation based into the impact of mutations on the protein in NS patients with PTPN11 mutations. Copyright © 2018 Elsevier España, S.L.U. All rights reserved.

Genotypic and phenotypic characterization of genetic differentiation and diversity in the USDA rice mini-core collection.

PubMed

Li, Xiaobai; Yan, Wengui; Agrama, Hesham; Hu, Biaolin; Jia, Limeng; Jia, Melissa; Jackson, Aaron; Moldenhauer, Karen; McClung, Anna; Wu, Dianxing

2010-12-01

A rice mini-core collection consisting of 217 accessions has been developed to represent the USDA core and whole collections that include 1,794 and 18,709 accessions, respectively. To improve the efficiency of mining valuable genes and broadening the genetic diversity in breeding, genetic structure and diversity were analyzed using both genotypic (128 molecular markers) and phenotypic (14 numerical traits) data. This mini-core had 13.5 alleles per locus, which is the most among the reported germplasm collections of rice. Similarly, polymorphic information content (PIC) value was 0.71 in the mini-core which is the highest with one exception. The high genetic diversity in the mini-core suggests there is a good possibility of mining genes of interest and selecting parents which will improve food production and quality. A model-based clustering analysis resulted in lowland rice including three groups, aus (39 accessions), indica (71) and their admixtures (5), upland rice including temperate japonica (32), tropical japonica (40), aromatic (6) and their admixtures (12) and wild rice (12) including glaberrima and four other species of Oryza. Group differentiation was analyzed using both genotypic distance Fst from 128 molecular markers and phenotypic (Mahalanobis) distance D(2) from 14 traits. Both dendrograms built by Fst and D(2) reached similar-differentiative relationship among these genetic groups, and the correlation coefficient showed high value 0.85 between Fst matrix and D(2) matrix. The information of genetic and phenotypic differentiation could be helpful for the association mapping of genes of interest. Analysis of genotypic and phenotypic diversity based on genetic structure would facilitate parent selection for broadening genetic base of modern rice cultivars via breeding effort.

Gaucher disease: Pseudoreversion of a disease mutation`s effects--implications for structure/function and genotype/phenotype correlations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ponce, E.; Mear, J; Grabowski, G.A.

1994-09-01

Numerous mutations ({approximately}45) of the acid {beta}-glucosidase gene have been identified in patients with Gaucher disease. Many of these have been characterized by partial sequencing of cDNAs derived by RT-PCR or PCR of genomic DNA. In addition, genotype/phenotype correlations have been based on screening for known mutations. Thus, only a part of the gene is characterized in any population of affected patients. Several Gaucher disease alleles contain multiple, authentic point mutations that raises concern about conclusions based on only partial genetic characterization. Several wild-type cDNAs for acid {beta}-glucosidase have been sequenced. One contained a cloning artifact encoding R495H. We expressedmore » this cDNA and showed that the R495H enzyme had normal kinetic and stability properties. A disease-associated allele encoding R496H has been found by several groups. The close association and similarities of these two substitutions led us to question the disease casuality of the R496H allele. To evaluate this, we created and/or expressed cDNAs encoding R495, R496 (wild-type), (R495H, R496), (R495, R496H) and (R495H, R496H). The (wild-type) and (R495H, R496) enzymes had indistinguishable properties whereas the (R495, R496H) enzyme was essentially inactive. The introduction of both mutations (R495H, R496H) produced an enzyme whose activity was 25 to 50% of the wild-type. These results indicate that a pseudoreversion to a functional enzyme can occur by introducing a functionally neutral mutation together with a severe mutation. These results have major implications to structure/function and genotype/phenotype correlations in this disease.« less

Combining high-throughput phenotyping and genome-wide association studies to reveal natural genetic variation in rice

PubMed Central

Yang, Wanneng; Guo, Zilong; Huang, Chenglong; Duan, Lingfeng; Chen, Guoxing; Jiang, Ni; Fang, Wei; Feng, Hui; Xie, Weibo; Lian, Xingming; Wang, Gongwei; Luo, Qingming; Zhang, Qifa; Liu, Qian; Xiong, Lizhong

2014-01-01

Even as the study of plant genomics rapidly develops through the use of high-throughput sequencing techniques, traditional plant phenotyping lags far behind. Here we develop a high-throughput rice phenotyping facility (HRPF) to monitor 13 traditional agronomic traits and 2 newly defined traits during the rice growth period. Using genome-wide association studies (GWAS) of the 15 traits, we identify 141 associated loci, 25 of which contain known genes such as the Green Revolution semi-dwarf gene, SD1. Based on a performance evaluation of the HRPF and GWAS results, we demonstrate that high-throughput phenotyping has the potential to replace traditional phenotyping techniques and can provide valuable gene identification information. The combination of the multifunctional phenotyping tools HRPF and GWAS provides deep insights into the genetic architecture of important traits. PMID:25295980

Field-based high throughput phenotyping rapidly identifies genomic regions controlling yield components in rice

PubMed Central

Tanger, Paul; Klassen, Stephen; Mojica, Julius P.; Lovell, John T.; Moyers, Brook T.; Baraoidan, Marietta; Naredo, Maria Elizabeth B.; McNally, Kenneth L.; Poland, Jesse; Bush, Daniel R.; Leung, Hei; Leach, Jan E.; McKay, John K.

2017-01-01

To ensure food security in the face of population growth, decreasing water and land for agriculture, and increasing climate variability, crop yields must increase faster than the current rates. Increased yields will require implementing novel approaches in genetic discovery and breeding. Here we demonstrate the potential of field-based high throughput phenotyping (HTP) on a large recombinant population of rice to identify genetic variation underlying important traits. We find that detecting quantitative trait loci (QTL) with HTP phenotyping is as accurate and effective as traditional labor-intensive measures of flowering time, height, biomass, grain yield, and harvest index. Genetic mapping in this population, derived from a cross of an modern cultivar (IR64) with a landrace (Aswina), identified four alleles with negative effect on grain yield that are fixed in IR64, demonstrating the potential for HTP of large populations as a strategy for the second green revolution. PMID:28220807

Identification and characterization of dwarf 62, a loss-of-function mutation in DLT/OsGRAS-32 affecting gibberellin metabolism in rice.

PubMed

Li, Wenqiang; Wu, Jianguo; Weng, Shili; Zhang, Yujiang; Zhang, Dapeng; Shi, Chunhai

2010-11-01

A dwarf mutant, dwarf 62 (d62), was isolated from rice cultivar 93-11 by mutagenesis with γ-rays. Under normal growth conditions, the mutant had multiple abnormal phenotypes, such as dwarfism, wide and dark-green leaf blades, reduced tiller numbers, late and asynchronous heading, short roots, partial male sterility, etc. Genetic analysis indicated that the abnormal phenotypes were controlled by the recessive mutation of a single nuclear gene. Using molecular markers, the D62 gene was fine mapped in 131-kb region at the short arm of chromosome 6. Positional cloning of D62 gene revealed that it was the same locus as DLT/OsGRAS-32, which encodes a member of the GRAS family. In previous studies, the DLT/OsGRAS-32 is confirmed to play positive roles in brassinosteroid (BR) signaling. Sequence analysis showed that the d62 carried a 2-bp deletion in ORF region of D62 gene which led to a loss-of-function mutation. The function of D62 gene was confirmed by complementation experiment. RT-PCR analysis and promoter activity analysis showed that the D62 gene expressed in all tested tissues including roots, stems, leaves and panicles of rice plant. The d62 mutant exhibited decreased activity of α-amylase in endosperm and reduced content of endogenous GA(1). The expression levels of gibberellin (GA) biosynthetic genes including OsCPS1, OsKS1, OsKO1, OsKAO, OsGA20ox2/SD1 and OsGA2ox3 were significantly increased in d62 mutant. Briefly, these results demonstrated that the D62 (DLT/OsGRAS-32) not only participated in the regulation of BR signaling, but also influenced GA metabolism in rice.

Genetic diversity of red-grained rice landraces in Hani's terraced fields based on phenotypic characteristics

NASA Astrophysics Data System (ADS)

Zhou, Xiaomei; Zheng, Yun; Zhang, Tingting; Zhang, Xiaoqian; Ma, Mengli; Meng, Hengling; Wang, Tiantao; Lu, Bingyue

2018-06-01

In order to provide useful information for protection and utilization of red-grained rice landraces from Hani's terraced fields, the phenotypic diversity of 61 red-grained rice landraces were assessed based 20 quantitative traits. The results indicated that the phenotypic diversity was abundant in red-grained rice landraces. Coefficients of variation (CV) ranged from 4.878% to 72.878%, and the largest of CV was the panicle neck length, while grain width was smallest. Shannon-Weaver diversity index (H') of 20 traits ranged from 1.464 to 2.165, the largest and the smallest H' values were observed in filled grain number and chalkiness, respectively. Cluster analysis based on unweighted pair group method showed 61 red-grain rice landraces grouped into eight clusters at a cut-off value of 6.2631. The first cluster included 11 landraces, the main cluster II involved 42 landraces, and the cluster IV included 3 landraces. Laopinzhonghongmi, Chena2, Laojingnuo, Bianhao6 and Baimi were separated from the main clusters.

Predicted Mutation Strength of Nontruncating PKD1 Mutations Aids Genotype-Phenotype Correlations in Autosomal Dominant Polycystic Kidney Disease.

PubMed

Heyer, Christina M; Sundsbak, Jamie L; Abebe, Kaleab Z; Chapman, Arlene B; Torres, Vicente E; Grantham, Jared J; Bae, Kyongtae T; Schrier, Robert W; Perrone, Ronald D; Braun, William E; Steinman, Theodore I; Mrug, Michal; Yu, Alan S L; Brosnahan, Godela; Hopp, Katharina; Irazabal, Maria V; Bennett, William M; Flessner, Michael F; Moore, Charity G; Landsittel, Douglas; Harris, Peter C

2016-09-01

Autosomal dominant polycystic kidney disease (ADPKD) often results in ESRD but with a highly variable course. Mutations to PKD1 or PKD2 cause ADPKD; both loci have high levels of allelic heterogeneity. We evaluated genotype-phenotype correlations in 1119 patients (945 families) from the HALT Progression of PKD Study and the Consortium of Radiologic Imaging Study of PKD Study. The population was defined as: 77.7% PKD1, 14.7% PKD2, and 7.6% with no mutation detected (NMD). Phenotypic end points were sex, eGFR, height-adjusted total kidney volume (htTKV), and liver cyst volume. Analysis of the eGFR and htTKV measures showed that the PKD1 group had more severe disease than the PKD2 group, whereas the NMD group had a PKD2-like phenotype. In both the PKD1 and PKD2 populations, men had more severe renal disease, but women had larger liver cyst volumes. Compared with nontruncating PKD1 mutations, truncating PKD1 mutations associated with lower eGFR, but the mutation groups were not differentiated by htTKV. PKD1 nontruncating mutations were evaluated for conservation and chemical change and subdivided into strong (mutation strength group 2 [MSG2]) and weak (MSG3) mutation groups. Analysis of eGFR and htTKV measures showed that patients with MSG3 but not MSG2 mutations had significantly milder disease than patients with truncating cases (MSG1), an association especially evident in extreme decile populations. Overall, we have quantified the contribution of genic and PKD1 allelic effects and sex to the ADPKD phenotype. Intrafamilial correlation analysis showed that other factors shared by families influence htTKV, with these additional genetic/environmental factors significantly affecting the ADPKD phenotype. Copyright © 2016 by the American Society of Nephrology.

Fragile X mutation and FG syndrome-like phenotype

DOE Office of Scientific and Technical Information (OSTI.GOV)

Piussan, C.; Mathieu, M.; Berquin, P.

1996-08-09

We present data on 4 mentally retarded brothers, 2 of whom were dizygotic twins with congenital hypotonia, constipation, head size disproportionately large for length or height, and a combination of minor anomalies suggestive of FG syndrome. These brothers have a mentally retarded full sister with similar minor anomalies and an older half-brother with the Martin-Bell syndrome. The mother is mentally retarded; 4 of 7 individuals are positive for fragile X, but all have a CGG expansion ranging from 0.2-2 to 4 kb. Although the phenotype is not completely typical of the FG syndrome and the coincidence of the FMR1 mutationmore » and segregation of the MCA/MR phenotype are highly unlikely, the FMR1 mutation may affect morphogenesis more extensively and differently than the Martin-Bell syndrome does to effect an FG syndrome-like phenotype in certain families. This phenotype does not appear to be a contiguous gene syndrome, but an effect of the FMR1 mutation on an adjacent gene must be considered. 18 refs., 4 figs.« less

Phenotypic heterogeneity and mutational spectrum in a cohort of 45 Italian males subjects with X-linked ectodermal dysplasia.

PubMed

Guazzarotti, L; Tadini, G; Mancini, G E; Giglio, S; Willoughby, C E; Callea, M; Sani, I; Nannini, P; Mameli, C; Tenconi, A A; Mauri, S; Bottero, A; Caimi, A; Morelli, M; Zuccotti, G V

2015-04-01

Ectodermal dysplasias (EDs) are a group of genetic disorders characterized by the abnormal development of the ectodermal-derived structures. X-linked hypohidrotic ectodermal dysplasia, resulting from mutations in ED1 gene, is the most common form. The main purpose of this study was to characterize the phenotype spectrum in 45 males harboring ED1 mutations. The study showed that in addition to the involvement of the major ectodermal tissues, the majority of patients also have alterations of several minor ectodermal-derived structures. Characterizing the clinical spectrum resulting from ED1 gene mutations improves diagnosis and can direct clinical care. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Field-based high throughput phenotyping rapidly identifies genomic regions controlling yield components in rice

DOE PAGES

Tanger, Paul; Klassen, Stephen; Mojica, Julius P.; ...

2017-02-21

In order to ensure food security in the face of population growth, decreasing water and land for agriculture, and increasing climate variability, crop yields must increase faster than the current rates. Increased yields will require implementing novel approaches in genetic discovery and breeding. We demonstrate the potential of field-based high throughput phenotyping (HTP) on a large recombinant population of rice to identify genetic variation underlying important traits. We find that detecting quantitative trait loci (QTL) with HTP phenotyping is as accurate and effective as traditional labor- intensive measures of flowering time, height, biomass, grain yield, and harvest index. Furthermore, geneticmore » mapping in this population, derived from a cross of an modern cultivar (IR64) with a landrace (Aswina), identified four alleles with negative effect on grain yield that are fixed in IR64, demonstrating the potential for HTP of large populations as a strategy for the second green revolution.« less

Field-based high throughput phenotyping rapidly identifies genomic regions controlling yield components in rice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tanger, Paul; Klassen, Stephen; Mojica, Julius P.

In order to ensure food security in the face of population growth, decreasing water and land for agriculture, and increasing climate variability, crop yields must increase faster than the current rates. Increased yields will require implementing novel approaches in genetic discovery and breeding. We demonstrate the potential of field-based high throughput phenotyping (HTP) on a large recombinant population of rice to identify genetic variation underlying important traits. We find that detecting quantitative trait loci (QTL) with HTP phenotyping is as accurate and effective as traditional labor- intensive measures of flowering time, height, biomass, grain yield, and harvest index. Furthermore, geneticmore » mapping in this population, derived from a cross of an modern cultivar (IR64) with a landrace (Aswina), identified four alleles with negative effect on grain yield that are fixed in IR64, demonstrating the potential for HTP of large populations as a strategy for the second green revolution.« less

Properties of rice bran oil-derived functional ingredients

USDA-ARS?s Scientific Manuscript database

Lipid ingredients that demonstrate high stability and positive health profiles without the use of trans-fats are needed in the food supply. Rice bran oil can be fractionated at low temperatures to create a series of spreads that show promise as functional ingredients. A rice bran oil-derived spread ...

Novel TMEM67 Mutations and Genotype-phenotype Correlates in Meckelin-related Ciliopathies

PubMed Central

Iannicelli, Miriam; Brancati, Francesco; Mougou-Zerelli, Soumaya; Mazzotta, Annalisa; Thomas, Sophie; Elkhartoufi, Nadia; Travaglini, Lorena; Gomes, Céline; Ardissino, Gian Luigi; Bertini, Enrico; Boltshauser, Eugen; Castorina, Pierangela; D'Arrigo, Stefano; Fischetto, Rita; Leroy, Brigitte; Loget, Philippe; Bonnière, Maryse; Starck, Lena; Tantau, Julia; Gentilin, Barbara; Majore, Silvia; Swistun, Dominika; Flori, Elizabeth; Lalatta, Faustina; Pantaleoni, Chiara; Johannes.Penzien; Grammatico, Paola; Dallapiccola, Bruno; Gleeson, Joseph G.; Attie-Bitach, Tania; Valente, Enza Maria

2010-01-01

Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67 mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin. PMID:20232449

Helicase-inactivating mutations as a basis for dominant negative phenotypes

PubMed Central

Wu, Yuliang

2010-01-01

There is ample evidence from studies of both unicellular and multicellular organisms that helicase-inactivating mutations lead to cellular dysfunction and disease phenotypes. In this review, we will discuss the mechanisms underlying the basis for abnormal phenotypes linked to mutations in genes encoding DNA helicases. Recent evidence demonstrates that a clinically relevant patient missense mutation in Fanconi Anemia Complementation Group J exerts detrimental effects on the biochemical activities of the FANC J helicase, and these molecular defects are responsible for aberrant genomic stability and a poor DNA damage response. The ability of FANC J to use the energy from AT P hydrolysis to produce the force required to unwind duplex or G-quadruplex DNA structures or destabilize protein bound to DNA is required for its DNA repair functions in vivo. Strikingly, helicase-inactivating mutations can exert a spectrum of dominant negative phenotypes, indicating that expression of the mutant helicase protein potentially interferes with normal DNA metabolism and has an effect on basic cellular processes such as DNA replication, the DNA damage response and protein trafficking. This review emphasizes that future studies of clinically relevant mutations in helicase genes will be important to understand the molecular pathologies of the associated diseases and their impact on heterozygote carriers. PMID:20980836

Microarray-based mutation detection and phenotypic characterization in Korean patients with retinitis pigmentosa

PubMed Central

Kim, Cinoo; Kim, Kwang Joong; Bok, Jeong; Lee, Eun-Ju; Kim, Dong-Joon; Oh, Ji Hee; Park, Sung Pyo; Shin, Joo Young; Lee, Jong-Young

2012-01-01

Purpose To evaluate microarray-based genotyping technology for the detection of mutations responsible for retinitis pigmentosa (RP) and to perform phenotypic characterization of patients with pathogenic mutations. Methods DNA from 336 patients with RP and 360 controls was analyzed using the GoldenGate assay with microbeads containing 95 previously reported disease-associated mutations from 28 RP genes. Mutations identified by microarray-based genotyping were confirmed by direct sequencing. Segregation analysis and phenotypic characterization were performed in patients with mutations. The disease severity was assessed by visual acuity, electroretinography, optical coherence tomography, and kinetic perimetry. Results Ten RP-related mutations of five RP genes (PRP3 pre-mRNA processing factor 3 homolog [PRPF3], rhodopsin [RHO], phosphodiesterase 6B [PDE6B], peripherin 2 [PRPH2], and retinitis pigmentosa 1 [RP1]) were identified in 26 of the 336 patients (7.7%) and in six of the 360 controls (1.7%). The p.H557Y mutation in PDE6B, which was homozygous in four patients and heterozygous in nine patients, was the most frequent mutation (2.5%). Mutation segregation was assessed in four families. Among the patients with missense mutations, the most severe phenotype occurred in patients with p.D984G in RP1; less severe phenotypes occurred in patients with p.R135W in RHO; a relatively moderate phenotype occurred in patients with p.T494M in PRPF3, p.H557Y in PDE6B, or p.W316G in PRPH2; and a mild phenotype was seen in a patient with p.D190N in RHO. Conclusions The results reveal that the GoldenGate assay may not be an efficient method for molecular diagnosis in RP patients with rare mutations, although it has proven to be reliable and efficient for high-throughput genotyping of single-nucleotide polymorphisms. The clinical features varied according to the mutations. Continuous effort to identify novel RP genes and mutations in a population is needed to improve the efficiency and

Frequency and type of inheritable mutations induced by γ rays in rice as revealed by whole genome sequencing.

PubMed

Li, Shan; Zheng, Yun-Chao; Cui, Hai-Rui; Fu, Hao-Wei; Shu, Qing-Yao; Huang, Jian-Zhong

Mutation breeding is based on the induction of genetic variations; hence knowledge of the frequency and type of induced mutations is of paramount importance for the design and implementation of a mutation breeding program. Although γ ray irradiation has been widely used since the 1960s in the breeding of about 200 economically important plant species, molecular elucidation of its genetic effects has so far been achieved largely by analysis of target genes or genomic regions. In the present study, the whole genomes of six γ-irradiated M 2 rice plants were sequenced; a total of 144-188 million high-quality (Q>20) reads were generated for each M 2 plant, resulting in genome coverage of >45 times for each plant. Single base substitution (SBS) and short insertion/deletion (Indel) mutations were detected at the average frequency of 7.5×10 -6 -9.8×10 -6 in the six M 2 rice plants (SBS being about 4 times more frequent than Indels). Structural and copy number variations, though less frequent than SBS and Indel, were also identified and validated. The mutations were scattered in all genomic regions across 12 rice chromosomes without apparent hotspots. The present study is the first genome-wide single-nucleotide resolution study on the feature and frequency of γ irradiation-induced mutations in a seed propagated crop; the findings are of practical importance for mutation breeding of rice and other crop species.

Identification of heat-sensitive QTL derived from common wild rice (Oryza rufipogon Griff.).

PubMed

Lei, Dongyang; Tan, Lubin; Liu, Fengxia; Chen, Liyun; Sun, Chuanqing

2013-03-01

Understanding the responses of rice plants to heat-stress is a challenging, yet crucial, endeavor. A set of introgression lines was previously developed using an advanced backcrossing strategy that involved the elite indica cultivar Teqing as the recipient and an accession of common wild rice (Oryza rufipongon Griff.) as the donor. In this study, we evaluated the responses of 90 of these previously developed introgression lines to heat stress. Five quantitative trait loci (QTLs) related to heat response were detected. The phenotypic variances explained by these QTLs ranged from 6.83% to 14.63%, and O. rufipogon-derived alleles at one locus reduced sensitivity to heat. A heat-sensitive introgression line, YIL106, was identified and characterized. Genotypic analysis demonstrated that YIL106 contained four introgressed segments derived from O. rufipongon and two QTLs (qHTS1-1 and qHTS3) related to heat response. Physiological tests, including measurements of chlorophyll content, electrolyte leakage, malondialdehyde content, and soluble sugar content, were consistent with the heat sensitivity observed in YIL106. Ultrastructural analysis of YIL106 mesophyll cells showed that they were severely damaged following heat stress. This suggests that modification of the cell membrane system is a primary response to heat stress in plants. Identification and characterization of the heat-sensitive line YIL106 may facilitate the isolation of genes associated with the response of rice plants to heat stress. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Phenotypic diversity in patients with lipodystrophy associated with LMNA mutations.

PubMed

Mory, Patricia B; Crispim, Felipe; Freire, Maria Beatriz S; Salles, João Eduardo N; Valério, Cynthia M; Godoy-Matos, Amelio F; Dib, Sérgio A; Moisés, Regina S

2012-09-01

Mutations in LMNA have been linked to diverse disorders called laminopathies, which display heterogeneous phenotypes and include diseases affecting muscles, axonal neurons, progeroid syndromes, and lipodystrophies. Among the lipodystrophies, LMNA mutations have been reported most frequently in patients with familial partial lipodystrophy (FPLD) of the Dunnigan variety; however, phenotypic heterogeneity in the pattern of body fat loss has been observed. In this study, we searched for LMNA mutations in patients with various forms of lipodystrophy. We studied 21 unrelated individuals with lipodystrophy. Subjects underwent a complete clinical evaluation and were classified as typical FPLD (n=12), atypical partial lipodystrophy (n=7), or generalized lipodystrophy (n=2). Molecular analysis of LMNA gene, analysis of body fat by dual-energy X-ray absorptiometry, and biochemical measurements were performed. ALL PATIENTS WITH TYPICAL FPLD WERE FOUND TO CARRY LMNA MUTATIONS: seven patients harbored the heterozygous p.R482W (c.1444C>T), two patients harbored the p.R482Q (c.1445G>A), and two individuals harbored the novel heterozygous variant p.N466D (c.1396A>G), all in exon 8. Also, a homozygous p.R584H (c.1751 G>A) mutation in exon 11 was found. Among patients with atypical partial lipodystrophy, two of them were found to have LMNA mutations: a novel heterozygous p.R582C variation (c.1744 C>T) in exon 11 and a heterozygous substitution p.R349W (c.1045C>T) in exon 6. Among patients with generalized lipodystrophy, only one harbored LMNA mutation, a heterozygous p.T10I (c.29C>T) in exon 1. We have identified LMNA mutations in phenotypically diverse lipodystrophies. Also, our study broadens the spectrum of LMNA mutations in lipodystrophy.

Allelic heterogeneity of FGF5 mutations causes the long-hair phenotype in dogs.

PubMed

Dierks, C; Mömke, S; Philipp, U; Distl, O

2013-08-01

Hitherto, the only known mutant gene leading to the long-hair phenotype in mammals is the fibroblast growth factor 5 (FGF5). In many dog breeds, the previously discovered FGF5:p.Cys95Phe mutation appeared completely concordant with the long-hair phenotype, but for some breeds, the long-hair phenotype could not be resolved. First, we studied the role of the FGF5:p.Cys95Phe and FGF5:g.145_150dupACCAGC mutations in 268 dogs descending from 27 breeds and seven wolves. As these mutations did not explain all the long-hair phenotypes, all exons and their neighbouring regions of FGF5 were re-sequenced. We detected three novel mutations in the coding sequence and one novel non-coding splice-site mutation in FGF5 associated with the long-hair phenotype. The FGF5:p.Ala193Val polymorphism was perfectly consistent with long hair in Akitas and probably in Siberian huskies, too. Dogs of the long-hair breed Samoyed were either homozygous or compound heterozygous for the FGF5:p.Ala193Val or the FGF5:p.Cys95Phe polymorphisms respectively. The two newly detected polymorphisms FGF5:c.559_560dupGG and FGF5:g.8193T>A and the known mutation FGF5:p.Cys95Phe explained the long-hair phenotype of all Afghan hounds analysed. An FGF5:c.556_571del16 mutation was found in one longhaired Eurasier. All long-hair-associated mutations follow a recessive mode of inheritance, and allelic heterogeneity was a common finding in breeds other than Akita. © 2013 The Authors, Animal Genetics © 2013 Stichting International Foundation for Animal Genetics.

Comparison of space flight and heavy ion radiation induced genomic/epigenomic mutations in rice (Oryza sativa)

NASA Astrophysics Data System (ADS)

Shi, Jinming; Lu, Weihong; Sun, Yeqing

2014-04-01

Rice seeds, after space flight and low dose heavy ion radiation treatment were cultured on ground. Leaves of the mature plants were obtained for examination of genomic/epigenomic mutations by using amplified fragment length polymorphism (AFLP) and methylation sensitive amplification polymorphism (MSAP) method, respectively. The mutation sites were identified by fragment recovery and sequencing. The heritability of the mutations was detected in the next generation. Results showed that both space flight and low dose heavy ion radiation can induce significant alterations on rice genome and epigenome (P < 0.05). For both genetic and epigenetic assays, while there was no significant difference in mutation rates and their ability to be inherited to the next generation, the site of mutations differed between the space flight and radiation treated groups. More than 50% of the mutation sites were shared by two radiation treated groups, radiated with different LET value and dose, while only about 20% of the mutation sites were shared by space flight group and radiation treated group. Moreover, in space flight group, we found that DNA methylation changes were more prone to occur on CNG sequence than CG sequence. Sequencing results proved that both space flight and heavy ion radiation induced mutations were widely spread on rice genome including coding region and repeated region. Our study described and compared the characters of space flight and low dose heavy ion radiation induced genomic/epigenomic mutations. Our data revealed the mechanisms of application of space environment for mutagenesis and crop breeding. Furthermore, this work implicated that the nature of mutations induced under space flight conditions may involve factors beyond ion radiation.

A protein domain-centric approach for the comparative analysis of human and yeast phenotypically relevant mutations

PubMed Central

2013-01-01

Background The body of disease mutations with known phenotypic relevance continues to increase and is expected to do so even faster with the advent of new experimental techniques such as whole-genome sequencing coupled with disease association studies. However, genomic association studies are limited by the molecular complexity of the phenotype being studied and the population size needed to have adequate statistical power. One way to circumvent this problem, which is critical for the study of rare diseases, is to study the molecular patterns emerging from functional studies of existing disease mutations. Current gene-centric analyses to study mutations in coding regions are limited by their inability to account for the functional modularity of the protein. Previous studies of the functional patterns of known human disease mutations have shown a significant tendency to cluster at protein domain positions, namely position-based domain hotspots of disease mutations. However, the limited number of known disease mutations remains the main factor hindering the advancement of mutation studies at a functional level. In this paper, we address this problem by incorporating mutations known to be disruptive of phenotypes in other species. Focusing on two evolutionarily distant organisms, human and yeast, we describe the first inter-species analysis of mutations of phenotypic relevance at the protein domain level. Results The results of this analysis reveal that phenotypic mutations from yeast cluster at specific positions on protein domains, a characteristic previously revealed to be displayed by human disease mutations. We found over one hundred domain hotspots in yeast with approximately 50% in the exact same domain position as known human disease mutations. Conclusions We describe an analysis using protein domains as a framework for transferring functional information by studying domain hotspots in human and yeast and relating phenotypic changes in yeast to diseases in

Phenotypic variability in patients with Fanconi anemia and biallelic FANCF mutations.

PubMed

Tryon, Rebecca; Zierhut, Heather; MacMillan, Margaret L; Wagner, John E

2017-01-01

Fanconi anemia is a heterogeneous genetic disorder that is characterized by progressive bone marrow failure, congenital anomalies, and markedly increased risk for malignancies. Mutations in the FANCF (FA-F) gene represent approximately 2% of affected patients. Currently, information on the phenotypic findings of patients with Fanconi anemia from biallelic mutations in FANCF is limited. Here, we report three patients who illustrate the clinical variability within the FA-F group. This analysis suggests a more severe phenotype for those with the common c.484_485delCT mutation. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies

PubMed Central

Ilkovski, Biljana; Pagnamenta, Alistair T.; O'Grady, Gina L.; Kinoshita, Taroh; Howard, Malcolm F.; Lek, Monkol; Thomas, Brett; Turner, Anne; Christodoulou, John; Sillence, David; Knight, Samantha J.L.; Popitsch, Niko; Keays, David A.; Anzilotti, Consuelo; Goriely, Anne; Waddell, Leigh B.; Brilot, Fabienne; North, Kathryn N.; Kanzawa, Noriyuki; Macarthur, Daniel G.; Taylor, Jenny C.; Kini, Usha; Murakami, Yoshiko; Clarke, Nigel F.

2015-01-01

Glycosylphosphatidylinositol (GPI)-anchored proteins are ubiquitously expressed in the human body and are important for various functions at the cell surface. Mutations in many GPI biosynthesis genes have been described to date in patients with multi-system disease and together these constitute a subtype of congenital disorders of glycosylation. We used whole exome sequencing in two families to investigate the genetic basis of disease and used RNA and cellular studies to investigate the functional consequences of sequence variants in the PIGY gene. Two families with different phenotypes had homozygous recessive sequence variants in the GPI biosynthesis gene PIGY. Two sisters with c.137T>C (p.Leu46Pro) PIGY variants had multi-system disease including dysmorphism, seizures, severe developmental delay, cataracts and early death. There were significantly reduced levels of GPI-anchored proteins (CD55 and CD59) on the surface of patient-derived skin fibroblasts (∼20–50% compared with controls). In a second, consanguineous family, two siblings had moderate development delay and microcephaly. A homozygous PIGY promoter variant (c.-540G>A) was detected within a 7.7 Mb region of autozygosity. This variant was predicted to disrupt a SP1 consensus binding site and was shown to be associated with reduced gene expression. Mutations in PIGY can occur in coding and non-coding regions of the gene and cause variable phenotypes. This article contributes to understanding of the range of disease phenotypes and disease genes associated with deficiencies of the GPI-anchor biosynthesis pathway and also serves to highlight the potential importance of analysing variants detected in 5′-UTR regions despite their typically low coverage in exome data. PMID:26293662

Patterns of nucleotide diversity and phenotypes of two domestication related genes (OsC1 and Wx) in indigenous rice varieties in Northeast India

PubMed Central

2014-01-01

Background During the domestication of crops, individual plants with traits desirable for human needs have been selected from their wild progenitors. Consequently, genetic and nucleotide diversity of genes associated with these selected traits in crop plants are expected to be lower than their wild progenitors. In the present study, we surveyed the pattern of nucleotide diversity of two selected trait specific genes, Wx and OsC1, which regulate amylose content and apiculus coloration respectively in cultivated rice varieties. The analyzed samples were collected from a wide geographic area in Northeast (NE) India, and included contrasting phenotypes considered to be associated with selected genes, namely glutinous and nonglutinous grains and colored and colorless apiculus. Results No statistically significant selection signatures were detected in both Wx and OsC1gene sequences. However, low level of selection that varied across the length of each gene was evident. The glutinous type varieties showed higher levels of nucleotide diversity at the Wx locus (πtot = 0.0053) than nonglutinous type varieties (πtot = 0.0043). The OsC1 gene revealed low levels of selection among the colorless apiculus varieties with lower nucleotide diversity (πtot = 0.0010) than in the colored apiculus varieties (πtot = 0.0023). Conclusions The results revealed that functional mutations at Wx and OsC1genes considered to be associated with specific phenotypes do not necessarily correspond to the phenotypes in indigenous rice varieties in NE India. This suggests that other than previously reported genomic regions may also be involved in determination of these phenotypes. PMID:24935343

Targeted next-generation sequencing extends the phenotypic and mutational spectrums for EYS mutations

PubMed Central

Gu, Shun; Tian, Yuanyuan; Chen, Xue

2016-01-01

Purpose We aim to determine genetic lesions with a phenotypic correlation in four Chinese families with autosomal recessive retinitis pigmentosa (RP). Methods Medical histories were carefully reviewed. All patients received comprehensive ophthalmic evaluations. The next-generation sequencing (NGS) approach targeting a panel of 205 retinal disease–relevant genes and 15 candidate genes was selectively performed on probands from the four recruited families for mutation detection. Online predictive software and crystal structure modeling were also applied to test the potential pathogenic effects of identified mutations. Results Of the four families, two were diagnosed with RP sino pigmento (RPSP). Patients with RPSP claimed to have earlier RP age of onset but slower disease progression. Five mutations in the eyes shut homolog (EYS) gene, involving two novel (c.7228+1G>A and c.9248G>A) and three recurrent mutations (c.4957dupA, c.6416G>A and c.6557G>A), were found as RP causative in the four families. The missense variant c.5093T>C was determined to be a variant of unknown significance (VUS) due to the variant’s colocalization in the same allele with the reported pathogenic mutation c.6416G>A. The two novel variants were further confirmed absent in 100 unrelated healthy controls. Online predictive software indicated potential pathogenicity of the three missense mutations. Further, crystal structural modeling suggested generation of two abnormal hydrogen bonds by the missense mutation p.G2186E (c.6557G>A) and elongation of its neighboring β-sheet induced by p.G3083D (c.9248G>A), which could alter the tertiary structure of the eys protein and thus interrupt its physicochemical properties. Conclusions Taken together, with the targeted NGS approach, we reveal novel EYS mutations and prove the efficiency of targeted NGS in the genetic diagnoses of RP. We also first report the correlation between EYS mutations and RPSP. The genotypic-phenotypic relationship in all

Targeted next-generation sequencing extends the phenotypic and mutational spectrums for EYS mutations.

PubMed

Gu, Shun; Tian, Yuanyuan; Chen, Xue; Zhao, Chen

2016-01-01

We aim to determine genetic lesions with a phenotypic correlation in four Chinese families with autosomal recessive retinitis pigmentosa (RP). Medical histories were carefully reviewed. All patients received comprehensive ophthalmic evaluations. The next-generation sequencing (NGS) approach targeting a panel of 205 retinal disease-relevant genes and 15 candidate genes was selectively performed on probands from the four recruited families for mutation detection. Online predictive software and crystal structure modeling were also applied to test the potential pathogenic effects of identified mutations. Of the four families, two were diagnosed with RP sino pigmento (RPSP). Patients with RPSP claimed to have earlier RP age of onset but slower disease progression. Five mutations in the eyes shut homolog (EYS) gene, involving two novel (c.7228+1G>A and c.9248G>A) and three recurrent mutations (c.4957dupA, c.6416G>A and c.6557G>A), were found as RP causative in the four families. The missense variant c.5093T>C was determined to be a variant of unknown significance (VUS) due to the variant's colocalization in the same allele with the reported pathogenic mutation c.6416G>A. The two novel variants were further confirmed absent in 100 unrelated healthy controls. Online predictive software indicated potential pathogenicity of the three missense mutations. Further, crystal structural modeling suggested generation of two abnormal hydrogen bonds by the missense mutation p.G2186E (c.6557G>A) and elongation of its neighboring β-sheet induced by p.G3083D (c.9248G>A), which could alter the tertiary structure of the eys protein and thus interrupt its physicochemical properties. Taken together, with the targeted NGS approach, we reveal novel EYS mutations and prove the efficiency of targeted NGS in the genetic diagnoses of RP. We also first report the correlation between EYS mutations and RPSP. The genotypic-phenotypic relationship in all Chinese patients carrying mutations in the EYS

Phenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations.

PubMed

Fergelot, Patricia; Van Belzen, Martine; Van Gils, Julien; Afenjar, Alexandra; Armour, Christine M; Arveiler, Benoit; Beets, Lex; Burglen, Lydie; Busa, Tiffany; Collet, Marie; Deforges, Julie; de Vries, Bert B A; Dominguez Garrido, Elena; Dorison, Nathalie; Dupont, Juliette; Francannet, Christine; Garciá-Minaúr, Sixto; Gabau Vila, Elisabeth; Gebre-Medhin, Samuel; Gener Querol, Blanca; Geneviève, David; Gérard, Marion; Gervasini, Cristina Giovanna; Goldenberg, Alice; Josifova, Dragana; Lachlan, Katherine; Maas, Saskia; Maranda, Bruno; Moilanen, Jukka S; Nordgren, Ann; Parent, Philippe; Rankin, Julia; Reardon, Willie; Rio, Marlène; Roume, Joëlle; Shaw, Adam; Smigiel, Robert; Sojo, Amaia; Solomon, Benjamin; Stembalska, Agnieszka; Stumpel, Constance; Suarez, Francisco; Terhal, Paulien; Thomas, Simon; Touraine, Renaud; Verloes, Alain; Vincent-Delorme, Catherine; Wincent, Josephine; Peters, Dorien J M; Bartsch, Oliver; Larizza, Lidia; Lacombe, Didier; Hennekam, Raoul C

2016-12-01

Rubinstein-Taybi syndrome (RSTS) is a developmental disorder characterized by a typical face and distal limbs abnormalities, intellectual disability, and a vast number of other features. Two genes are known to cause RSTS, CREBBP in 60% and EP300 in 8-10% of clinically diagnosed cases. Both paralogs act in chromatin remodeling and encode for transcriptional co-activators interacting with >400 proteins. Up to now 26 individuals with an EP300 mutation have been published. Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients. We compare the data to 308 individuals with CREBBP mutations. We demonstrate that EP300 mutations cause a phenotype that typically resembles the classical RSTS phenotype due to CREBBP mutations to a great extent, although most facial signs are less marked with the exception of a low-hanging columella. The limb anomalies are more similar to those in CREBBP mutated individuals except for angulation of thumbs and halluces which is very uncommon in EP300 mutated individuals. The intellectual disability is variable but typically less marked whereas the microcephaly is more common. All types of mutations occur but truncating mutations and small rearrangements are most common (86%). Missense mutations in the HAT domain are associated with a classical RSTS phenotype but otherwise no genotype-phenotype correlation is detected. Pre-eclampsia occurs in 12/52 mothers of EP300 mutated individuals versus in 2/59 mothers of CREBBP mutated individuals, making pregnancy with an EP300 mutated fetus the strongest known predictor for pre-eclampsia. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Robust phenotyping strategies for evaluation of stem non-structural carbohydrates (NSC) in rice

PubMed Central

Wang, Diane R.; Wolfrum, Edward J.; Virk, Parminder; Ismail, Abdelbagi; Greenberg, Anthony J.; McCouch, Susan R.

2016-01-01

Rice plants (Oryza sativa) accumulate excess photoassimilates in the form of non-structural carbohydrates (NSCs) in their stems prior to heading that can later be mobilized to supplement photosynthate production during grain-filling. Despite longstanding interest in stem NSC for rice improvement, the dynamics of NSC accumulation, remobilization, and re-accumulation that have genetic potential for optimization have not been systematically investigated. Here we conducted three pilot experiments to lay the groundwork for large-scale diversity studies on rice stem NSC. We assessed the relationship of stem NSC components with 21 agronomic traits in large-scale, tropical yield trials using 33 breeder-nominated lines, established an appropriate experimental design for future genetic studies using a Bayesian framework to sample sub-datasets from highly replicated greenhouse data using 36 genetically diverse genotypes, and used 434 phenotypically divergent rice stem samples to develop two partial least-squares (PLS) models using near-infrared (NIR) spectra for accurate, rapid prediction of rice stem starch, sucrose, and total non-structural carbohydrates. We find evidence that stem reserves are most critical for short-duration varieties and suggest that pre-heading stem NSC is worthy of further experimentation for breeding early maturing rice. PMID:27707775

Genetic correction of tauopathy phenotypes in neurons derived from human induced pluripotent stem cells.

PubMed

Fong, Helen; Wang, Chengzhong; Knoferle, Johanna; Walker, David; Balestra, Maureen E; Tong, Leslie M; Leung, Laura; Ring, Karen L; Seeley, William W; Karydas, Anna; Kshirsagar, Mihir A; Boxer, Adam L; Kosik, Kenneth S; Miller, Bruce L; Huang, Yadong

2013-01-01

Tauopathies represent a group of neurodegenerative disorders characterized by the accumulation of pathological TAU protein in brains. We report a human neuronal model of tauopathy derived from induced pluripotent stem cells (iPSCs) carrying a TAU-A152T mutation. Using zinc-finger nuclease-mediated gene editing, we generated two isogenic iPSC lines: one with the mutation corrected, and another with the homozygous mutation engineered. The A152T mutation increased TAU fragmentation and phosphorylation, leading to neurodegeneration and especially axonal degeneration. These cellular phenotypes were consistent with those observed in a patient with TAU-A152T. Upon mutation correction, normal neuronal and axonal morphologies were restored, accompanied by decreases in TAU fragmentation and phosphorylation, whereas the severity of tauopathy was intensified in neurons with the homozygous mutation. These isogenic TAU-iPSC lines represent a critical advancement toward the accurate modeling and mechanistic study of tauopathies with human neurons and will be invaluable for drug-screening efforts and future cell-based therapies.

Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene.

PubMed

Horvath, Rita; Hudson, Gavin; Ferrari, Gianfrancesco; Fütterer, Nancy; Ahola, Sofia; Lamantea, Eleonora; Prokisch, Holger; Lochmüller, Hanns; McFarland, Robert; Ramesh, V; Klopstock, Thomas; Freisinger, Peter; Salvi, Fabrizio; Mayr, Johannes A; Santer, Rene; Tesarova, Marketa; Zeman, Jiri; Udd, Bjarne; Taylor, Robert W; Turnbull, Douglass; Hanna, Michael; Fialho, Doreen; Suomalainen, Anu; Zeviani, Massimo; Chinnery, Patrick F

2006-07-01

Mutations in the gene coding for the catalytic subunit of the mitochondrial DNA (mtDNA) polymerase gamma (POLG1) have recently been described in patients with diverse clinical presentations, revealing a complex relationship between genotype and phenotype in patients and their families. POLG1 was sequenced in patients from different European diagnostic and research centres to define the phenotypic spectrum and advance understanding of the recurrence risks. Mutations were identified in 38 cases, with the majority being sporadic compound heterozygotes. Eighty-nine DNA sequence changes were identified, including 2 predicted to alter a splice site, 1 predicted to cause a premature stop codon and 13 predicted to cause novel amino acid substitutions. The majority of children had a mutation in the linker region, often 1399G-->A (A467T), and a mutation affecting the polymerase domain. Others had mutations throughout the gene, and 11 had 3 or more substitutions. The clinical presentation ranged from the neonatal period to late adult life, with an overlapping phenotypic spectrum from severe encephalopathy and liver failure to late-onset external ophthalmoplegia, ataxia, myopathy and isolated muscle pain or epilepsy. There was a strong gender bias in children, with evidence of an environmental interaction with sodium valproate. POLG1 mutations cause an overlapping clinical spectrum of disease with both dominant and recessive modes of inheritance. 1399G-->A (A467T) is common in children, but complete POLG1 sequencing is required to identify multiple mutations that can have complex implications for genetic counselling.

Alzheimer's Disease Phenotypes and Genotypes Associated with Mutations in Presenilin 2

ERIC Educational Resources Information Center

Jayadev, Suman; Leverenz, James B.; Steinbart, Ellen; Stahl, Justin; Klunk, William; Yu, Cheng-En; Bird, Thomas D.

2010-01-01

Mutations in presenilin 2 are rare causes of early onset familial Alzheimer's disease. Eighteen presenilin 2 mutations have been reported, although not all have been confirmed pathogenic. Much remains to be learned about the range of phenotypes associated with these mutations. We have analysed our unique collection of 146 affected cases in 11…

The Sequences of 1504 Mutants in the Model Rice Variety Kitaake Facilitate Rapid Functional Genomic Studies

PubMed Central

Pham, Nikki T.; Wei, Tong; Schackwitz, Wendy S.; Lipzen, Anna M.; Duong, Phat Q.; Jones, Kyle C.; Ruan, Deling; Bauer, Diane; Peng, Yi; Schmutz, Jeremy

2017-01-01

The availability of a whole-genome sequenced mutant population and the cataloging of mutations of each line at a single-nucleotide resolution facilitate functional genomic analysis. To this end, we generated and sequenced a fast-neutron-induced mutant population in the model rice cultivar Kitaake (Oryza sativa ssp japonica), which completes its life cycle in 9 weeks. We sequenced 1504 mutant lines at 45-fold coverage and identified 91,513 mutations affecting 32,307 genes, i.e., 58% of all rice genes. We detected an average of 61 mutations per line. Mutation types include single-base substitutions, deletions, insertions, inversions, translocations, and tandem duplications. We observed a high proportion of loss-of-function mutations. We identified an inversion affecting a single gene as the causative mutation for the short-grain phenotype in one mutant line. This result reveals the usefulness of the resource for efficient, cost-effective identification of genes conferring specific phenotypes. To facilitate public access to this genetic resource, we established an open access database called KitBase that provides access to sequence data and seed stocks. This population complements other available mutant collections and gene-editing technologies. This work demonstrates how inexpensive next-generation sequencing can be applied to generate a high-density catalog of mutations. PMID:28576844

Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies.

PubMed

Ilkovski, Biljana; Pagnamenta, Alistair T; O'Grady, Gina L; Kinoshita, Taroh; Howard, Malcolm F; Lek, Monkol; Thomas, Brett; Turner, Anne; Christodoulou, John; Sillence, David; Knight, Samantha J L; Popitsch, Niko; Keays, David A; Anzilotti, Consuelo; Goriely, Anne; Waddell, Leigh B; Brilot, Fabienne; North, Kathryn N; Kanzawa, Noriyuki; Macarthur, Daniel G; Taylor, Jenny C; Kini, Usha; Murakami, Yoshiko; Clarke, Nigel F

2015-11-01

Glycosylphosphatidylinositol (GPI)-anchored proteins are ubiquitously expressed in the human body and are important for various functions at the cell surface. Mutations in many GPI biosynthesis genes have been described to date in patients with multi-system disease and together these constitute a subtype of congenital disorders of glycosylation. We used whole exome sequencing in two families to investigate the genetic basis of disease and used RNA and cellular studies to investigate the functional consequences of sequence variants in the PIGY gene. Two families with different phenotypes had homozygous recessive sequence variants in the GPI biosynthesis gene PIGY. Two sisters with c.137T>C (p.Leu46Pro) PIGY variants had multi-system disease including dysmorphism, seizures, severe developmental delay, cataracts and early death. There were significantly reduced levels of GPI-anchored proteins (CD55 and CD59) on the surface of patient-derived skin fibroblasts (∼20-50% compared with controls). In a second, consanguineous family, two siblings had moderate development delay and microcephaly. A homozygous PIGY promoter variant (c.-540G>A) was detected within a 7.7 Mb region of autozygosity. This variant was predicted to disrupt a SP1 consensus binding site and was shown to be associated with reduced gene expression. Mutations in PIGY can occur in coding and non-coding regions of the gene and cause variable phenotypes. This article contributes to understanding of the range of disease phenotypes and disease genes associated with deficiencies of the GPI-anchor biosynthesis pathway and also serves to highlight the potential importance of analysing variants detected in 5'-UTR regions despite their typically low coverage in exome data. © The Author 2015. Published by Oxford University Press.

Phenotypic Involvement in Females with the FMR1 Gene Mutation.

ERIC Educational Resources Information Center

Riddle, J. E.; Cheema, A.; Sobesky, W. E.; Gardner, S. C.; Taylor, A. K.; Pennington, B. F.; Hagerman, R. J.

1998-01-01

A study investigated phenotypic effects seen in 114 females with premutation and 41 females (ages 18-58) with full Fragile X mental retardation gene mutation. Those with the full mutation had a greater incidence of hand-flapping, eye contact problems, special education help for reading and math, and grade retention. (Author/CR)

Phenotypic variability in patients with osteogenesis imperfecta caused by BMP1 mutations.

PubMed

Pollitt, Rebecca C; Saraff, Vrinda; Dalton, Ann; Webb, Emma A; Shaw, Nick J; Sobey, Glenda J; Mughal, M Zulf; Hobson, Emma; Ali, Farhan; Bishop, Nicholas J; Arundel, Paul; Högler, Wolfgang; Balasubramanian, Meena

2016-12-01

Osteogenesis Imperfecta (OI) is an inherited bone fragility disorder most commonly associated with autosomal dominant mutations in the type I collagen genes. Autosomal recessive mutations in a number of genes have also been described, including the BMP1 gene that encodes the mammalian Tolloid (mTLD) and its shorter isoform bone morphogenic protein-1 (BMP1). To date, less than 20 individuals with OI have been identified with BMP1 mutations, with skeletal phenotypes ranging from mild to severe and progressively deforming. In the majority of patients, bone fragility was associated with increased bone mineral density (BMD); however, the full range of phenotypes associated with BMP1 remains unclear. Here, we describe three children with mutations in BMP1 associated with a highly variable phenotype: a sibship homozygous for the c.2188delC mutation that affects only the shorter BMP1 isoform and a further patient who is compound heterozygous for a c.1293C>G nonsense mutation and a c.1148G>A missense mutation in the CUB1 domain. These individuals had recurrent fractures from early childhood, are hypermobile and have no evidence of dentinogenesis imperfecta. The homozygous siblings with OI had normal areal BMD by dual energy X-ray absorptiometry whereas the third patient presented with a high bone mass phenotype. Intravenous bisphosphonate therapy was started in all patients, but discontinued in two patients and reduced in another due to concerns about increasing bone stiffness leading to chalk-stick fractures. Given the association of BMP1-related OI with very high bone material density, concerns remain whether anti-resorptive therapy is indicated in this ultra-rare form of OI.© 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Robust phenotyping strategies for evaluation of stem non-structural carbohydrates (NSC) in rice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Diane R.; Wolfrum, Edward J.; Virk, Parminder

Rice plants ( Oryza sativa) accumulate excess photoassimilates in the form of non-structural carbohydrates (NSCs) in their stems prior to heading that can later be mobilized to supplement photosynthate production during grain-filling. Despite longstanding interest in stem NSC for rice improvement, the dynamics of NSC accumulation, remobilization, and re-accumulation that have genetic potential for optimization have not been systematically investigated. Here we conducted three pilot experiments to lay the groundwork for large-scale diversity studies on rice stem NSC. We assessed the relationship of stem NSC components with 21 agronomic traits in large-scale, tropical yield trials using 33 breeder-nominated lines, establishedmore » an appropriate experimental design for future genetic studies using a Bayesian framework to sample sub-datasets from highly replicated greenhouse data using 36 genetically diverse genotypes, and used 434 phenotypically divergent rice stem samples to develop two partial least-squares (PLS) models using near-infrared (NIR) spectra for accurate, rapid prediction of rice stem starch, sucrose, and total non-structural carbohydrates. Lastly, we find evidence that stem reserves are most critical for short-duration varieties and suggest that pre-heading stem NSC is worthy of further experimentation for breeding early maturing rice.« less

Robust phenotyping strategies for evaluation of stem non-structural carbohydrates (NSC) in rice.

PubMed

Wang, Diane R; Wolfrum, Edward J; Virk, Parminder; Ismail, Abdelbagi; Greenberg, Anthony J; McCouch, Susan R

2016-11-01

Rice plants (Oryza sativa) accumulate excess photoassimilates in the form of non-structural carbohydrates (NSCs) in their stems prior to heading that can later be mobilized to supplement photosynthate production during grain-filling. Despite longstanding interest in stem NSC for rice improvement, the dynamics of NSC accumulation, remobilization, and re-accumulation that have genetic potential for optimization have not been systematically investigated. Here we conducted three pilot experiments to lay the groundwork for large-scale diversity studies on rice stem NSC. We assessed the relationship of stem NSC components with 21 agronomic traits in large-scale, tropical yield trials using 33 breeder-nominated lines, established an appropriate experimental design for future genetic studies using a Bayesian framework to sample sub-datasets from highly replicated greenhouse data using 36 genetically diverse genotypes, and used 434 phenotypically divergent rice stem samples to develop two partial least-squares (PLS) models using near-infrared (NIR) spectra for accurate, rapid prediction of rice stem starch, sucrose, and total non-structural carbohydrates. We find evidence that stem reserves are most critical for short-duration varieties and suggest that pre-heading stem NSC is worthy of further experimentation for breeding early maturing rice. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology.

Robust phenotyping strategies for evaluation of stem non-structural carbohydrates (NSC) in rice

DOE PAGES

Wang, Diane R.; Wolfrum, Edward J.; Virk, Parminder; ...

2016-10-05

Rice plants ( Oryza sativa) accumulate excess photoassimilates in the form of non-structural carbohydrates (NSCs) in their stems prior to heading that can later be mobilized to supplement photosynthate production during grain-filling. Despite longstanding interest in stem NSC for rice improvement, the dynamics of NSC accumulation, remobilization, and re-accumulation that have genetic potential for optimization have not been systematically investigated. Here we conducted three pilot experiments to lay the groundwork for large-scale diversity studies on rice stem NSC. We assessed the relationship of stem NSC components with 21 agronomic traits in large-scale, tropical yield trials using 33 breeder-nominated lines, establishedmore » an appropriate experimental design for future genetic studies using a Bayesian framework to sample sub-datasets from highly replicated greenhouse data using 36 genetically diverse genotypes, and used 434 phenotypically divergent rice stem samples to develop two partial least-squares (PLS) models using near-infrared (NIR) spectra for accurate, rapid prediction of rice stem starch, sucrose, and total non-structural carbohydrates. Lastly, we find evidence that stem reserves are most critical for short-duration varieties and suggest that pre-heading stem NSC is worthy of further experimentation for breeding early maturing rice.« less

Mutations Altering Chloroplast Ribosome Phenotype in Chlamydomonas, II. A New Mendelian Mutation*

PubMed Central

Boynton, John E.; Gillham, Nicholas W.; Burkholder, Barbara

1970-01-01

A new mutation of Chlamydomonas reinhardi, cr-1, is characterized. The mutation exhibits Mendelian inheritance and affects the sedimentation velocity and formation of intact chloroplast ribosomes. The mutant grows reasonably well when supplied with sodium acetate as a carbon source, but poorly when forced to grow photosynthetically using carbon dioxide. Since the mutant cr-1 accumulates large subunits of the chloroplast ribosome, we postulate that it is blocked in the formation of the small subunit. A tentative model explaining the behavior of the several mutants in Chlamydomonas now known to have altered chloroplast ribosomal phenotypes is presented. Images PMID:16591885

Novel SOX2 mutations and genotype-phenotype correlation in anophthalmia and microphthalmia.

PubMed

Schneider, Adele; Bardakjian, Tanya; Reis, Linda M; Tyler, Rebecca C; Semina, Elena V

2009-12-01

SOX2 represents a High Mobility Group domain containing transcription factor that is essential for normal development in vertebrates. Mutations in SOX2 are known to result in a spectrum of severe ocular phenotypes in humans, also typically associated with other systemic defects. Ocular phenotypes include anophthalmia/microphthalmia (A/M), optic nerve hypoplasia, ocular coloboma and other eye anomalies. We screened 51 unrelated individuals with A/M and identified SOX2 mutations in the coding region of the gene in 10 individuals. Seven of the identified mutations are novel alterations, while the remaining three individuals carry the previously reported recurrent 20-nucleotide deletion in SOX2, c.70del20. Among the SOX2-positive cases, seven patients had bilateral A/M and mutations resulting in premature termination of the normal protein sequence (7/38; 18% of all bilateral cases), one patient had bilateral A/M associated with a single amino acid insertion (1/38; 3% of bilateral cases), and the final two patients demonstrated unilateral A/M associated with missense mutations (2/13; 15% of all unilateral cases). These findings and review of previously reported cases suggest a potential genotype/phenotype correlation for SOX2 mutations with missense changes generally leading to less severe ocular defects. In addition, we report a new familial case of affected siblings with maternal mosaicism for the identified SOX2 mutation, which further underscores the importance of parental testing to provide accurate genetic counseling to families.

Novel SOX2 Mutations and Genotype-Phenotype Correlation in Anophthalmia and Microphthalmia

PubMed Central

Schneider, Adele; Bardakjian, Tanya; Reis, Linda M.; Tyler, Rebecca C.; Semina, Elena V.

2009-01-01

SOX2 represents a High Mobility Group domain containing transcription factor that is essential for normal development in vertebrates. Mutations in SOX2 are known to result in a spectrum of severe ocular phenotypes in humans, also typically associated with other systemic defects. Ocular phenotypes include anophthalmia/microphthalmia (A/M), optic nerve hypoplasia, ocular coloboma and other eye anomalies. We screened 51 unrelated individuals with A/M and indentified SOX2 mutations in the coding region of the gene in 10 individuals. Seven of the identified mutations are novel alterations, while the remaining three individuals carry the previously reported recurrent 20-nucleotide deletion in SOX2, c.70del20. Among the SOX2-positive cases, seven patients had bilateral A/M and mutations resulting in premature termination of the normal protein sequence (7/38; 18% of all bilateral cases), one patient had bilateral A/M associated with a single amino acid insertion (1/38; 3% of bilateral cases), and the final two patients demonstrated unilateral A/M associated with missense mutations (2/13; 15% of all unilateral cases). These findings and review of previously reported cases suggest a potential genotype/phenotype correlation for SOX2 mutations with missense changes generally leading to less severe ocular defects. In addition, we report a new familial case of affected siblings with maternal mosaicism for the identified SOX2 mutation, which further underscores the importance of parental testing to provide accurate genetic counseling to families. PMID:19921648

Novel EDA mutation in X-linked hypohidrotic ectodermal dysplasia and genotype-phenotype correlation.

PubMed

Zeng, B; Lu, H; Xiao, X; Zhou, L; Lu, J; Zhu, L; Yu, D; Zhao, W

2015-11-01

X-linked hypohidrotic ectodermal dysplasia (XLHED) is characterized by abnormalities of hair, teeth, and sweat glands, while non-syndromic hypodontia (NSH) affects only teeth. Mutations in Ectodysplasin A (EDA) underlie both XLHED and NSH. This study investigated the genetic causes of six hypohidrotic ectodermal dysplasia (HED) patients and genotype-phenotype correlation. The EDA gene of six patients with HED was sequenced. Bioinformatics analysis and structural modeling for the mutations were performed. The records of 134 patients with XLHED and EDA-related NSH regarding numbers of missing permanent teeth from this study and 20 articles were reviewed. Nonparametric tests were used to analyze genotype-phenotype correlations. In four of the six patients, we identified a novel mutation c.852T>G (p.Phe284Leu) and three reported mutations: c.467G>A (p.Arg156His), c.776C>A (p.Ala259Glu), and c.871G>A (p.Gly291Arg). They were predicted to be pathogenic by bioinformatics analysis and structural modeling. Genotype-phenotype correlation analysis revealed that truncating mutations were associated with more missing teeth. Missense mutations and the mutations affecting the TNF homology domain were correlated with fewer missing teeth. This study extended the mutation spectrum of XLHED and revealed the relationship between genotype and the number of missing permanent teeth. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

dNTP pool levels modulate mutator phenotypes of error-prone DNA polymerase ε variants.

PubMed

Williams, Lindsey N; Marjavaara, Lisette; Knowels, Gary M; Schultz, Eric M; Fox, Edward J; Chabes, Andrei; Herr, Alan J

2015-05-12

Mutator phenotypes create genetic diversity that fuels tumor evolution. DNA polymerase (Pol) ε mediates leading strand DNA replication. Proofreading defects in this enzyme drive a number of human malignancies. Here, using budding yeast, we show that mutator variants of Pol ε depend on damage uninducible (Dun)1, an S-phase checkpoint kinase that maintains dNTP levels during a normal cell cycle and up-regulates dNTP synthesis upon checkpoint activation. Deletion of DUN1 (dun1Δ) suppresses the mutator phenotype of pol2-4 (encoding Pol ε proofreading deficiency) and is synthetically lethal with pol2-M644G (encoding altered Pol ε base selectivity). Although pol2-4 cells cycle normally, pol2-M644G cells progress slowly through S-phase. The pol2-M644G cells tolerate deletions of mediator of the replication checkpoint (MRC) 1 (mrc1Δ) and radiation sensitive (Rad) 9 (rad9Δ), which encode mediators of checkpoint responses to replication stress and DNA damage, respectively. The pol2-M644G mutator phenotype is partially suppressed by mrc1Δ but not rad9Δ; neither deletion suppresses the pol2-4 mutator phenotype. Thus, checkpoint activation augments the Dun1 effect on replication fidelity but is not required for it. Deletions of genes encoding key Dun1 targets that negatively regulate dNTP synthesis, suppress the dun1Δ pol2-M644G synthetic lethality and restore the mutator phenotype of pol2-4 in dun1Δ cells. DUN1 pol2-M644G cells have constitutively high dNTP levels, consistent with checkpoint activation. In contrast, pol2-4 and POL2 cells have similar dNTP levels, which decline in the absence of Dun1 and rise in the absence of the negative regulators of dNTP synthesis. Thus, dNTP pool levels correlate with Pol ε mutator severity, suggesting that treatments targeting dNTP pools could modulate mutator phenotypes for therapy.

Proteomic analysis of high yield rice variety mutated from spaceflight

NASA Astrophysics Data System (ADS)

Ma, Y.; Cheng, Z.; Wang, W.; Sun, Y.

Seeds of pure rice varieties were flown on Chinese recoverable satellite, JB-1, for a 15-day flight in 1996. Many mutant rice varieties with various phenotypes were generated after continuous selection and breeding. Among the mutants, a variety 971-5 showed a significant increase in grain yield compared to its control (971ck). In this study, proteomic analysis of both mutant variety 971-5 and control variety 971ck were carried out to investigate the changes of protein expression level in their leaves at three different growth stages (early and middle stage of tillering, and booting stage). Results showed that (1) almost all differentially expressed proteins were down-regulated in 971-5 with only one exception, (2) the percentages of differentially expressed proteins were 3.1%, 2.1% and 3.1% at the three stages, respectively, and (3) one protein showed a significant alteration in its molecular weight (MW). These data demonstrated that the space environment can alter the expression level of rice proteins both quantitatively and qualitatively.

Correlation between connexin 32 gene mutations and clinical phenotype in X-linked dominant Charcot-Marie-Tooth neuropathy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ionasescu, V.; Ionasescu, R.; Searby, C.

1996-06-14

We studied the relationship between the genotype and clinical phenotype in 27 families with dominant X-linked Charcot-Marie-Tooth (CMTX1) neuropathy. Twenty-two families showed mutations in the coding region of the connexin32 (cx32) gene. The mutations include four nonsense mutations, eight missense mutations, two medium size deletions, and one insertion. Most missense mutations showed a mild clinical phenotype (five out of eight), whereas all nonsense mutations, the larger of the two deletions, and the insertion that produced frameshifts showed severe phenotypes. Five CMTX1 families with mild clinical phenotype showed no point mutations of the cx32 gene coding region. Three of these familiesmore » showed positive genetic linkage with the markers of the Xq13.1 region. The genetic linkage of the remaining two families could not be evaluated because of their small size. 25 refs., 1 fig., 1 tab.« less

A rare CYP21A2 mutation in a congenital adrenal hyperplasia kindred displaying genotype-phenotype nonconcordance.

PubMed

Khattab, Ahmed; Yuen, Tony; Al-Malki, Sultan; Yau, Mabel; Kazmi, Diya; Sun, Li; Harbison, Madeleine; Haider, Shozeb; Zaidi, Mone; New, Maria I

2016-01-01

Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency is caused by the autosomal recessive inheritance of mutations in the gene CYP21A2. CYP21A2 mutations lead to variable impairment of the 21-hydroxylase enzyme, which, in turn, is associated with three clinical phenotypes, namely, salt wasting, simple virilizing, and nonclassical CAH. However, it is known that a given mutation can associate with different clinical phenotypes, resulting in a high rate of genotype-phenotype nonconcordance. We aimed to study the genotype-phenotype nonconcordance in a family with three siblings affected with nonclassical CAH. All had hormonal evidence of nonclassical CAH, but this phenotype could not be explained by the genotype obtained from commercial CYP21A2 genetic testing, which revealed heterozygosity for the maternal 30 kb deletion mutation. We performed Sanger sequencing of the entire CYP21A2 gene in this family to search for a rare mutation that was not covered by commercial testing and found in the three siblings a second, rare c.1097G>A (p.R366H) mutation in exon 8. Computational modeling confirmed that this was a mild mutation consistent with nonclassical CAH. We recommend that sequencing of entire genes for rare mutations should be carried out when genotype-phenotype nonconcordance is observed in patients with autosomal recessive monogenic disorders, including CAH. © 2015 New York Academy of Sciences.

Disruption of a Rice Pentatricopeptide Repeat Protein Causes a Seedling-Specific Albino Phenotype and Its Utilization to Enhance Seed Purity in Hybrid Rice Production1[W][OA

PubMed Central

Su, Ning; Hu, Mao-Long; Wu, Dian-Xing; Wu, Fu-Qing; Fei, Gui-Lin; Lan, Ying; Chen, Xiu-Ling; Shu, Xiao-Li; Zhang, Xin; Guo, Xiu-Ping; Cheng, Zhi-Jun; Lei, Cai-Lin; Qi, Cun-Kou; Jiang, Ling; Wang, Haiyang; Wan, Jian-Min

2012-01-01

The pentatricopeptide repeat (PPR) gene family represents one of the largest gene families in higher plants. Accumulating data suggest that PPR proteins play a central and broad role in modulating the expression of organellar genes in plants. Here we report a rice (Oryza sativa) mutant named young seedling albino (ysa) derived from the rice thermo/photoperiod-sensitive genic male-sterile line Pei'ai64S, which is a leading male-sterile line for commercial two-line hybrid rice production. The ysa mutant develops albino leaves before the three-leaf stage, but the mutant gradually turns green and recovers to normal green at the six-leaf stage. Further investigation showed that the change in leaf color in ysa mutant is associated with changes in chlorophyll content and chloroplast development. Map-based cloning revealed that YSA encodes a PPR protein with 16 tandem PPR motifs. YSA is highly expressed in young leaves and stems, and its expression level is regulated by light. We showed that the ysa mutation has no apparent negative effects on several important agronomic traits, such as fertility, stigma extrusion rate, selfed seed-setting rate, hybrid seed-setting rate, and yield heterosis under normal growth conditions. We further demonstrated that ysa can be used as an early marker for efficient identification and elimination of false hybrids in commercial hybrid rice production, resulting in yield increases by up to approximately 537 kg ha−1. PMID:22430843

Multigene knockout utilizing off-target mutations of the CRISPR/Cas9 system in rice.

PubMed

Endo, Masaki; Mikami, Masafumi; Toki, Seiichi

2015-01-01

The clustered regularly interspaced short palindromic repeat (CRISPR)-associated endonuclease 9 (CRISPR/Cas9) system has been demonstrated to be a robust genome engineering tool in a variety of organisms including plants. However, it has been shown that the CRISPR/Cas9 system cleaves genomic DNA sequences containing mismatches to the guide RNA strand. We expected that this low specificity could be exploited to induce multihomeologous and multiparalogous gene knockouts. In the case of polyploid plants, simultaneous modification of multiple homeologous genes, i.e. genes with similar but not identical DNA sequences, is often needed to obtain a desired phenotype. Even in diploid plants, disruption of multiparalogous genes, which have functional redundancy, is often needed. To validate the applicability of the CRISPR/Cas9 system to target mutagenesis of paralogous genes in rice, we designed a single-guide RNA (sgRNA) that recognized 20 bp sequences of cyclin-dependent kinase B2 (CDKB2) as an on-target locus. These 20 bp possess similarity to other rice CDK genes (CDKA1, CDKA2 and CDKB1) with different numbers of mismatches. We analyzed mutations in these four CDK genes in plants regenerated from Cas9/sgRNA-transformed calli and revealed that single, double and triple mutants of CDKA2, CDKB1 and CDKB2 can be created by a single sgRNA. © The Author 2014. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists.

Pharmacological reversal of a pain phenotype in iPSC-derived sensory neurons and patients with inherited erythromelalgia.

PubMed

Cao, Lishuang; McDonnell, Aoibhinn; Nitzsche, Anja; Alexandrou, Aristos; Saintot, Pierre-Philippe; Loucif, Alexandre J C; Brown, Adam R; Young, Gareth; Mis, Malgorzata; Randall, Andrew; Waxman, Stephen G; Stanley, Philip; Kirby, Simon; Tarabar, Sanela; Gutteridge, Alex; Butt, Richard; McKernan, Ruth M; Whiting, Paul; Ali, Zahid; Bilsland, James; Stevens, Edward B

2016-04-20

In common with other chronic pain conditions, there is an unmet clinical need in the treatment of inherited erythromelalgia (IEM). TheSCN9Agene encoding the sodium channel Nav1.7 expressed in the peripheral nervous system plays a critical role in IEM. A gain-of-function mutation in this sodium channel leads to aberrant sensory neuronal activity and extreme pain, particularly in response to heat. Five patients with IEM were treated with a new potent and selective compound that blocked the Nav1.7 sodium channel resulting in a decrease in heat-induced pain in most of the patients. We derived induced pluripotent stem cell (iPSC) lines from four of five subjects and produced sensory neurons that emulated the clinical phenotype of hyperexcitability and aberrant responses to heat stimuli. When we compared the severity of the clinical phenotype with the hyperexcitability of the iPSC-derived sensory neurons, we saw a trend toward a correlation for individual mutations. The in vitro IEM phenotype was sensitive to Nav1.7 blockers, including the clinical test agent. Given the importance of peripherally expressed sodium channels in many pain conditions, our approach may have broader utility for a wide range of pain and sensory conditions. Copyright © 2016, American Association for the Advancement of Science.

The Sequences of 1504 Mutants in the Model Rice Variety Kitaake Facilitate Rapid Functional Genomic Studies.

PubMed

Li, Guotian; Jain, Rashmi; Chern, Mawsheng; Pham, Nikki T; Martin, Joel A; Wei, Tong; Schackwitz, Wendy S; Lipzen, Anna M; Duong, Phat Q; Jones, Kyle C; Jiang, Liangrong; Ruan, Deling; Bauer, Diane; Peng, Yi; Barry, Kerrie W; Schmutz, Jeremy; Ronald, Pamela C

2017-06-01

The availability of a whole-genome sequenced mutant population and the cataloging of mutations of each line at a single-nucleotide resolution facilitate functional genomic analysis. To this end, we generated and sequenced a fast-neutron-induced mutant population in the model rice cultivar Kitaake ( Oryza sativa ssp japonica ), which completes its life cycle in 9 weeks. We sequenced 1504 mutant lines at 45-fold coverage and identified 91,513 mutations affecting 32,307 genes, i.e., 58% of all rice genes. We detected an average of 61 mutations per line. Mutation types include single-base substitutions, deletions, insertions, inversions, translocations, and tandem duplications. We observed a high proportion of loss-of-function mutations. We identified an inversion affecting a single gene as the causative mutation for the short-grain phenotype in one mutant line. This result reveals the usefulness of the resource for efficient, cost-effective identification of genes conferring specific phenotypes. To facilitate public access to this genetic resource, we established an open access database called KitBase that provides access to sequence data and seed stocks. This population complements other available mutant collections and gene-editing technologies. This work demonstrates how inexpensive next-generation sequencing can be applied to generate a high-density catalog of mutations. © 2017 American Society of Plant Biologists. All rights reserved.

SHOX mutations in idiopathic short stature and Leri-Weill dyschondrosteosis: frequency and phenotypic variability.

PubMed

Jorge, Alexander A L; Souza, Silvia C; Nishi, Miriam Y; Billerbeck, Ana E; Libório, Débora C C; Kim, Chong A; Arnhold, Ivo J P; Mendonca, Berenice B

2007-01-01

The frequency of SHOX mutations in children with idiopathic short stature (ISS) has been found to be variable. We analysed the SHOX gene in children with ISS and Leri-Weill dyschondrosteosis (LWD) and evaluated the phenotypic variability in patients harbouring SHOX mutations. Sixty-three ISS, nine LWD children and 21 affected relatives. SHOX gene deletion was evaluated by fluorescence in situ hybridization (FISH), Southern blotting and segregation study of polymorphic marker. Point mutations were assessed by direct DNA sequencing. None of the ISS patients presented SHOX deletions, but two (3.2%) presented heterozygous point mutations, including the novel R147H mutation. However, when ISS patients were selected by sitting height : height ratio (SH/H) for age > 2 SD, mutation frequency detection increased to 22%. Eight (89%) LWD patients had SHOX deletions, but none had point mutations. Analysis of the other relatives in the families carrying SHOX mutations identified 14 children and 17 adult patients. A broad phenotypic variability was observed in all families regarding short stature severity and Madelung deformities. However, the presence of disproportional height, assessed by SH/H, was observed in all children and 82% of adult patients, being the most common feature in our patients with SHOX mutations. Patients with SHOX mutations present a broad phenotypic variability. SHOX mutations are very frequent in LWD (89%), in opposition to ISS (3.2%) in our cohort. The use of SH/H SDS as a selection criterion increases the frequency of SHOX mutation detection to 22% and should be used for selecting ISS children to undergo SHOX mutation molecular studies.

Mutations in MITF and PAX3 cause "splashed white" and other white spotting phenotypes in horses.

PubMed

Hauswirth, Regula; Haase, Bianca; Blatter, Marlis; Brooks, Samantha A; Burger, Dominik; Drögemüller, Cord; Gerber, Vincent; Henke, Diana; Janda, Jozef; Jude, Rony; Magdesian, K Gary; Matthews, Jacqueline M; Poncet, Pierre-André; Svansson, Vilhjálmur; Tozaki, Teruaki; Wilkinson-White, Lorna; Penedo, M Cecilia T; Rieder, Stefan; Leeb, Tosso

2012-01-01

During fetal development neural-crest-derived melanoblasts migrate across the entire body surface and differentiate into melanocytes, the pigment-producing cells. Alterations in this precisely regulated process can lead to white spotting patterns. White spotting patterns in horses are a complex trait with a large phenotypic variance ranging from minimal white markings up to completely white horses. The "splashed white" pattern is primarily characterized by an extremely large blaze, often accompanied by extended white markings at the distal limbs and blue eyes. Some, but not all, splashed white horses are deaf. We analyzed a Quarter Horse family segregating for the splashed white coat color. Genome-wide linkage analysis in 31 horses gave a positive LOD score of 1.6 in a region on chromosome 6 containing the PAX3 gene. However, the linkage data were not in agreement with a monogenic inheritance of a single fully penetrant mutation. We sequenced the PAX3 gene and identified a missense mutation in some, but not all, splashed white Quarter Horses. Genome-wide association analysis indicated a potential second signal near MITF. We therefore sequenced the MITF gene and found a 10 bp insertion in the melanocyte-specific promoter. The MITF promoter variant was present in some splashed white Quarter Horses from the studied family, but also in splashed white horses from other horse breeds. Finally, we identified two additional non-synonymous mutations in the MITF gene in unrelated horses with white spotting phenotypes. Thus, several independent mutations in MITF and PAX3 together with known variants in the EDNRB and KIT genes explain a large proportion of horses with the more extreme white spotting phenotypes.

[Index screening and comprehensive evaluation of phenotypic traits of low nitrogen tolerance using BILs population derived from Dongxiang wild rice (Oryza rufipogon Griff)].

PubMed

Hu, Biao-lin; Li, Xia; Wan, Yong; Qiu, Zai-hui; Nie, Yuan-yuan; Xie, Jian-kun

2015-08-01

To identify the low nitrogen tolerance of Dongxiang wild rice (DXWR) and its progenies, ten phenotypic traits including plant height (PH), heading day (HD), panicle length (PL), number of effective tillers per plant (NETP), number of filled grains per panicle (NFGP), number of grains per panicle (NGP), grain density (GD), spikelet fertility (SF), 1000-grain mass (TGM) and grain yield per plant (GYP) were studied under normal and low nitrogen treatments, using backcross inbred lines (BILs) of Xieqingzao B//DXWR/Xieqingzao B in BC1 F12. Comprehensive evaluation on the low nitrogen tolerance of the BILs population was conducted using principal component analysis and the subordinate function. The evaluation results indicated that the low nitrogen tolerance of the line 116, 143 and 157 was the strongest, which could be served as the intermediate materials for genetic studies on the low nitrogen tolerance of DXWR and breeding for the low nitrogen tolerance in rice. The optimal regression equation of the low nitrogen tolerance in rice was established using stepwise regression analysis. The relative values of five traits including PH, NGP, SF, TGM and GYP were screened out and could be used as comprehensive evaluation indices for the low nitrogen tolerance in the whole growth stage. Therefore, more attention should be paid to the relative values of these five traits, especially for NGP and GYP, in the genetic improvement of the low nitrogen tolerance in rice.

Mutation Update and Genotype–Phenotype Correlations of Novel and Previously Described Mutations in TPM2 and TPM3 Causing Congenital Myopathies

PubMed Central

Marttila, Minttu; Lehtokari, Vilma-Lotta; Marston, Steven; Nyman, Tuula A.; Barnerias, Christine; Beggs, Alan H.; Bertini, Enrico; Ceyhan-Birsoy, OÖzge; Cintas, Pascal; Gerard, Marion; Gilbert-Dussardier, Brigitte; Hogue, Jacob S.; Longman, Cheryl; Eymard, Bruno; Frydman, Moshe; Kang, Peter B.; Klinge, Lars; Kolski, Hanna; Lochmüller, Hans; Magy, Laurent; Manel, Véronique; Mayer, Michèle; Mercuri, Eugenio; North, Kathryn N.; Peudenier-Robert, Sylviane; Pihko, Helena; Probst, Frank J.; Reisin, Ricardo; Stewart, Willie; Taratuto, Ana Lia; de Visser, Marianne; Wilichowski, Ekkehard; Winer, John; Nowak, Kristen; Laing, Nigel G.; Winder, Tom L.; Monnier, Nicole; Clarke, Nigel F.; Pelin, Katarina; Grönholm, Mikaela; Wallgren-Pettersson, Carina

2014-01-01

Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core-rod myopathy, congenital fiber-type disproportion, distal arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2 and 20 of TPM3 have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal-dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca2+ sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with nonhypercontractile ones (2/22 and 1/22), whereas patients with the non-hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin–actin association or tropomyosin head-to-tail binding. PMID:24692096

Influence of rice straw-derived dissolved organic matter on lactic acid fermentation by Rhizopus oryzae.

PubMed

Chen, Xingxuan; Wang, Xiahui; Xue, Yiyun; Zhang, Tian-Ao; Li, Yuhao; Hu, Jiajun; Tsang, Yiu Fai; Zhang, Hongsheng; Gao, Min-Tian

2018-06-01

Rice straw can be used as carbon sources for lactic acid fermentation. However, only a small amount of lactic acid is produced even though Rhizopus oryzae can consume glucose in rice straw-derived hydrolysates. This study correlated the inhibitory effect of rice straw with rice straw-derived dissolved organic matter (DOM). Lactic acid fermentations with and without DOM were conducted to investigate the effect of DOM on lactic acid fermentation by R. oryzae. Fermentation using control medium with DOM showed a similar trend to fermentation with rice straw-derived hydrolysates, showing that DOM contained the major inhibitor of rice straw. DOM assay indicated that it mainly consisted of polyphenols and polysaccharides. The addition of polyphenols and polysaccharides derived from rice straw confirmed that lactic acid fermentation was promoted by polysaccharides and significantly inhibited by polyphenols. The removal of polyphenols also improved lactic acid production. However, the loss of polysaccharides during the removal of polyphenols resulted in low glucose consumption. This study is the first to investigate the effects of rice straw-derived DOM on lactic acid fermentation by R. oryzae. The results may provide a theoretical basis for identifying inhibitors and promoters associated with lactic acid fermentation and for establishing suitable pretreatment methods. Copyright © 2018 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Transposon-mediated epigenetic regulation contributes to phenotypic diversity and environmental adaptation in rice.

PubMed

Song, Xianwei; Cao, Xiaofeng

2017-04-01

Transposable elements (TEs) have long been regarded as 'selfish DNA', and are generally silenced by epigenetic mechanisms. However, work in the past decade has identified positive roles for TEs in generating genomic novelty and diversity in plants. In particular, recent studies suggested that TE-induced epigenetic alterations and modification of gene expression contribute to phenotypic variation and adaptation to geography or stress. These findings have led many to regard TEs, not as junk DNA, but as sources of control elements and genomic diversity. As a staple food crop and model system for genomic research on monocot plants, rice (Oryza sativa) has a modest-sized genome that harbors massive numbers of DNA transposons (class II transposable elements) scattered across the genome, which may make TE regulation of genes more prevalent. In this review, we summarize recent progress in research on the functions of rice TEs in modulating gene expression and creating new genes. We also examine the contributions of TEs to phenotypic diversity and adaptation to environmental conditions. Copyright © 2017 Elsevier Ltd. All rights reserved.

Novel types of COMP mutations and genotype-phenotype association in pseudoachondroplasia and multiple epiphyseal dysplasia.

PubMed

Mabuchi, Akihiko; Manabe, Noriyo; Haga, Nobuhiko; Kitoh, Hiroshi; Ikeda, Toshiyuki; Kawaji, Hiroyuki; Tamai, Kazuya; Hamada, Junichiro; Nakamura, Shigeru; Brunetti-Pierri, Nicola; Kimizuka, Mamori; Takatori, Yoshio; Nakamura, Kozo; Nishimura, Gen; Ohashi, Hirofumi; Ikegawa, Shiro

2003-01-01

Mutations in the gene encoding cartilage oligomeric matrix protein ( COMP) cause two skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). More than 40 mutations have been identified; however, genotype-phenotype relationships are not well delineated. Further, mutations other than in-frame insertion/deletions and substitutions have not been found, and currently known mutations are clustered within relatively small regions. Here we report the identification of nine novel and three recurrent COMP mutations in PSACH and MED patients. These include two novel types of mutations; the first, a gross deletion spanning an exon-intron junction, causes an exon deletion. The second, a frameshift mutation that results in a truncation of the C-terminal domain, is the first known truncating mutation in the COMP gene. The remaining mutations, other than a novel exon 18 mutation, affected highly conserved aspartate or cysteine residues in the calmodulin-like repeat (CLR) region. Genotype-phenotype analysis revealed a correlation between the position and type of mutations and the severity of short stature. Mutations in the seventh CLR produced more severe short stature compared with mutations elsewhere in the CLRs ( P=0.0003) and elsewhere in the COMP gene ( P=0.0007). Patients carrying mutations within the five-aspartates repeat (aa 469-473) in the seventh CLR were extremely short (below -6 SD). Patients with deletion mutations were significantly shorter than those with substitution mutations ( P=0.0024). These findings expand the mutation spectrum of the COMP gene and highlight genotype-phenotype relationships, facilitating improved genetic diagnosis and analysis of COMP function in humans.

Duchenne/Becker muscular dystrophy: correlation of phenotype by electroretinography with sites of dystrophin mutations.

PubMed

Pillers, D A; Fitzgerald, K M; Duncan, N M; Rash, S M; White, R A; Dwinnell, S J; Powell, B R; Schnur, R E; Ray, P N; Cibis, G W; Weleber, R G

1999-01-01

The dark-adapted electroretinogram (ERG) of patients with Duchenne and Becker muscular dystrophy (DMD/BMD) shows a marked reduction in b-wave amplitude. Genotype-phenotype studies of mouse models for DMD show position-specific effects of the mutations upon the phenotype: mice with 5' defects of dystrophin have normal ERGs, those with defects in the central region have a normal b-wave amplitude associated with prolonged implicit times for both the b-wave and oscillatory potentials, and mice with 3' defects have a phenotype similar to that seen in DMD/BMD patients. The mouse studies suggest a key role for the carboxyl terminal dystrophin isoform, Dp260, in retinal electrophysiology. We have undertaken a systematic evaluation of DMD/BMD patients through clinical examination and review of the literature in order to determine whether the position-specific effects of mutations noted in the mouse are present in man. We have found that, in man, a wider variation of DMD defects correlate with reductions in the b-wave amplitude. Individuals with normal ERGs have mutations predominantly located 5' of the transcript initiation site of Dp260. Our results suggest that the most important determinant in the ERG b-wave phenotype is the mutation position, rather than muscle disease severity. Forty-six per cent of patients with mutations 5' of the Dp260 transcript start site have abnormal ERGs, as opposed to 94% with more distal mutations. The human genotype-phenotype correlations are consistent with a role for Dp260 in normal retinal electrophysiology and may also reflect the expression of other C-terminal dystrophin isoforms and their contributions to retinal signal transmission.

A Novel Founder Mutation in MYBPC3: Phenotypic Comparison With the Most Prevalent MYBPC3 Mutation in Spain.

PubMed

Sabater-Molina, María; Saura, Daniel; García-Molina Sáez, Esperanza; González-Carrillo, Josefa; Polo, Luis; Pérez-Sánchez, Inmaculada; Olmo, María Del Carmen; Oliva-Sandoval, María José; Barriales-Villa, Roberto; Carbonell, Pablo; Pascual-Figal, Domigo; Gimeno, Juan R

2017-02-01

Mutations in MYBPC3 are the cause of hypertrophic cardiomyopathy (HCM). Although most lead to a truncating protein, the severity of the phenotype differs. We describe the clinical phenotype of a novel MYBPC3 mutation, p.Pro108Alafs*9, present in 13 families from southern Spain and compare it with the most prevalent MYBPC3 mutation in this region (c.2308+1 G>A). We studied 107 relatives of 13 index cases diagnosed as HCM carriers of the p.Pro108Alafs*9 mutation. Pedigree analysis, clinical evaluation, and genotyping were performed. A total of 54 carriers of p.Pro108Alafs*9 were identified, of whom 39 had HCM. There were 5 cases of sudden death in the 13 families. Disease penetrance was greater as age increased and HCM patients were more frequently male and developed disease earlier than female patients. The phenotype was similar in p.Pro108Alafs*9 and in c.2308+1 G>A, but differences were found in several risk factors and in survival. There was a trend toward a higher left ventricular mass in p.Pro108Alafs*9 vs c.2308+1G>A. Cardiac magnetic resonance revealed a similar extent and pattern of fibrosis. The p.Pro108Alafs*9 mutation is associated with HCM, high penetrance, and disease onset in middle age. Copyright © 2016 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

The Sequences of 1,504 Mutants in the Model Rice Variety Kitaake Facilitate Rapid Functional Genomic Studies

DOE PAGES

Li, Guotian; Jain, Rashmi; Chern, Mawsheng; ...

2017-06-02

The availability of a whole-genome sequenced mutant population and the cataloging of mutations of each line at a single-nucleotide resolution facilitate functional genomic analysis. To this end, we generated and sequenced a fast-neutron-induced mutant population in the model rice cultivar Kitaake (Oryza sativa ssp japonica), which completes its life cycle in 9 weeks. We sequenced 1504 mutant lines at 45-fold coverage and identified 91,513 mutations affecting 32,307 genes, i.e., 58% of all rice genes. We detected an average of 61 mutations per line. Mutation types include single-base substitutions, deletions, insertions, inversions, translocations, and tandem duplications. We observed a high proportionmore » of loss-of-function mutations. We identified an inversion affecting a single gene as the causative mutation for the short-grain phenotype in one mutant line. This result reveals the usefulness of the resource for efficient, cost-effective identification of genes conferring specific phenotypes. To facilitate public access to this genetic resource, we established an open access database called KitBase that provides access to sequence data and seed stocks. This population complements other available mutant collections and gene-editing technologies. In conclusion, this work demonstrates how inexpensive next-generation sequencing can be applied to generate a high-density catalog of mutations.« less

AB071. Mutations of AR gene in Vietnamese patients: genotype and phenotype

PubMed Central

Dung, Vu Chi; Fukami, Maki; Ngoc, Can Thi Bich; Thao, Bui Phuong; Khanh, Nguyen Ngoc; Nga, Pham Thu; Dat, Nguyen Phu; Ogata, Tsutomu

2015-01-01

Androgen insensitivity syndrome (AIS) is the most common specific cause of 46,XY disorder in sex development. The androgen signaling pathway is complex but so far, the only gene linked with AIS is the androgen receptor (AR). Mutations in the AR are found in most subjects with complete AIS but in partial AIS, the rate has varied 28-73%, depending on the case selection. More than over 800 entries of mutations causing AIS, representing over 500 different AR mutations from more than 850 patients with AIS have been reported. We aim to describe clinical manifestations and to identify mutation of AR in Vietnamese patients with AIS. This case series study included 12 patients from 9 unrelated families with AIS. The gonadal position and external genitalia were evaluated clinically and using ultrasound. The mutation analysis of AR was performed using PCR and direct sequencing. The age of diagnosis was 1 to 83 years old. 8/12 cases were complete androgen insensitivity syndrome (CAIS) (female external genitalia) and 4 cases were predominantly female partial AIS phenotype. Four cases had two labial testes, six cases had inguinal testes and two cases had abdominal testes. Five different mutations of AR were identified from seven cases of three unrelated families including three novel ones. The novel missense mutation p.L701F (c.2103G > T) was identified in a patient of 83 years of age. The novel missense mutation p.L705F (c.2113C > T) was identified in two sibs. The novel mutation p. W752S (c.2256G > T) was identified in a child with CAIS phenotype and had family history. The reported missense mutation p.V747M was identified in two sibs. The reported mutation p.V867M (c.2599G > A) was identified in a child with female phenotype. Our study identified three novel and two reported mutation in the AR gene that may provide us new insights into the molecular mechanisms of AIS. The expanded database of these mutations should benefit patients in the diagnosis and treatment of this

A Mutator Phenotype Promoting the Emergence of Spontaneous Oxidative Stress-Resistant Mutants in Campylobacter jejuni.

PubMed

Dai, Lei; Sahin, Orhan; Tang, Yizhi; Zhang, Qijing

2017-12-15

Campylobacter jejuni is a leading cause of foodborne illnesses worldwide. As a microaerophilic organism, C. jejuni must be able to defend against oxidative stress encountered both in the host and in the environment. How Campylobacter utilizes a mutation-based mechanism for adaptation to oxidative stress is still unknown. Here we present a previously undescribed phenotypic and genetic mechanism that promotes the emergence of oxidative stress-resistant mutants. Specifically, we showed that a naturally occurring mutator phenotype, resulting from a loss of function mutation in the DNA repair enzyme MutY, increased oxidative stress resistance (OX R ) in C. jejuni We further demonstrated that MutY malfunction did not directly contribute to the OX R phenotype but increased the spontaneous mutation rate in the peroxide regulator gene perR , which functions as a repressor for multiple genes involved in oxidative stress resistance. Mutations in PerR resulted in loss of its DNA binding function and derepression of PerR-controlled oxidative stress defense genes, thereby conferring an OX R phenotype and facilitating Campylobacter survival under oxidative stress. These findings reveal a new mechanism that promotes the emergence of spontaneous OX R mutants in bacterial organisms. IMPORTANCE Although a mutator phenotype has been shown to promote antibiotic resistance in many bacterial species, little is known about its contribution to the emergence of OX R mutants. This work describes the link between a mutator phenotype and the enhanced emergence of OX R mutants as well as its underlying mechanism involving DNA repair and mutations in PerR. Since DNA repair systems and PerR are well conserved in many bacterial species, especially in Gram positives, the same mechanism may operate in multiple bacterial species. Additionally, we developed a novel method that allows for rapid quantification of spontaneous OX R mutants in a bacterial population. This method represents a technical

Parkin Mutations Reduce the Complexity of Neuronal Processes in iPSC-derived Human Neurons

PubMed Central

Ren, Yong; Jiang, Houbo; Hu, Zhixing; Fan, Kevin; Wang, Jun; Janoschka, Stephen; Wang, Xiaomin; Ge, Shaoyu; Feng, Jian

2015-01-01

Parkinson’s disease (PD) is characterized by the degeneration of nigral dopaminergic (DA) neurons and non-DA neurons in many parts of the brain. Mutations of parkin, an E3 ubiquitin ligase that strongly binds to microtubules, are the most frequent cause of recessively inherited Parkinson’s disease. The lack of robust PD phenotype in parkin knockout mice suggests a unique vulnerability of human neurons to parkin mutations. Here, we show that the complexity of neuronal processes as measured by total neurite length, number of terminals, number of branch points and Sholl analysis, was greatly reduced in induced pluripotent stem cell (iPSC)-derived TH+ or TH− neurons from PD patients with parkin mutations. Consistent with these, microtubule stability was significantly decreased by parkin mutations in iPSC-derived neurons. Overexpression of parkin, but not its PD-linked mutant nor GFP, restored the complexity of neuronal processes and the stability of microtubules. Consistent with these, the microtubule-depolymerizing agent colchicine mimicked the effect of parkin mutations by decreasing neurite length and complexity in control neurons while the microtubule-stabilizing drug taxol mimicked the effect of parkin overexpression by enhancing the morphology of parkin-deficient neurons. The results suggest that parkin maintains the morphological complexity of human neurons by stabilizing microtubules. PMID:25332110

Phenotypic similarities and differences in patients with a p.Met112Ile mutation in SOX10.

PubMed

Pingault, Veronique; Pierre-Louis, Laurence; Chaoui, Asma; Verloes, Alain; Sarrazin, Elisabeth; Brandberg, Goran; Bondurand, Nadege; Uldall, Peter; Manouvrier-Hanu, Sylvie

2014-09-01

Waardenburg syndrome (WS) is characterized by an association of pigmentation abnormalities and sensorineural hearing loss. Four types, defined on clinical grounds, have been delineated, but this phenotypic classification correlates imperfectly with known molecular anomalies. SOX10 mutations have been found in patients with type II and type IV WS (i.e., with Hirschsprung disease), more complex syndromes, and partial forms of the disease. The phenotype induced by SOX10 mutations is highly variable and, except for the neurological forms of the disease, no genotype-phenotype correlation has been characterized to date. There is no mutation hotspot in SOX10 and most cases are sporadic, making it particularly difficult to correlate the phenotypic and genetic variability. This study reports on three independent families with SOX10 mutations predicted to result in the same missense mutation at the protein level (p.Met112Ile), offering a rare opportunity to improve our understanding of the mechanisms underlying phenotypic variability. The pigmentation defects of these patients are very similar, and the neurological symptoms showed a somewhat similar evolution over time, indicating a potential partial genotype-phenotype correlation. However, variability in gastrointestinal symptoms suggests that other genetic factors contribute to the expression of these phenotypes. No correlation between the rs2435357 polymorphism of RET and the expression of Hirschsprung disease was found. In addition, one of the patients has esophageal achalasia, which has rarely been described in WS. © 2014 Wiley Periodicals, Inc.

Phenotypic similarities and differences in patients with a p.Met112Ile mutation in SOX10

PubMed Central

Pingault, Veronique; Pierre-Louis, Laurence; Chaoui, Asma; Verloes, Alain; Sarrazin, Elisabeth; Brandberg, Goran; Bondurand, Nadege; Uldall, Peter; Manouvrier-Hanu, Sylvie

2014-01-01

Waardenburg syndrome (WS) is characterized by an association of pigmentation abnormalities and sensorineural hearing loss. Four types, defined on clinical grounds, have been delineated, but this phenotypic classification correlates imperfectly with known molecular anomalies. SOX10 mutations have been found in patients with type II and type IV WS (i.e., with Hirschsprung disease), more complex syndromes, and partial forms of the disease. The phenotype induced by SOX10 mutations is highly variable and, except for the neurological forms of the disease, no genotype-phenotype correlation has been characterized to date. There is no mutation hotspot in SOX10 and most cases are sporadic, making it particularly difficult to correlate the phenotypic and genetic variability. This study reports on three independent families with SOX10 mutations predicted to result in the same missense mutation at the protein level (p.Met112Ile), offering a rare opportunity to improve our understanding of the mechanisms underlying phenotypic variability. The pigmentation defects of these patients are very similar, and the neurological symptoms showed a somewhat similar evolution over time, indicating a potential partial genotype-phenotype correlation. However, variability in gastrointestinal symptoms suggests that other genetic factors contribute to the expression of these phenotypes. No correlation between the rs2435357 polymorphism of RET and the expression of Hirschsprung disease was found. In addition, one of the patients has esophageal achalasia, which has rarely been described in WS. PMID:24845202

A FBN1 mutation association with different phenotypes of Marfan syndrome in a Chinese family.

PubMed

Li, Yapeng; Xu, Jianhua; Chen, Mingjie; Du, Binbin; Li, Qiaoli; Xing, Qinghe; Zhang, Yanzhou

2016-09-01

Previous studies demonstrated that patients with different FBN1 mutations often present more considerable phenotypic variation compared to different members of the related family carrying a same mutation. The purpose of our study was to identify pathogenic mutation and provide more information about genotype-phenotypic correlations in a large Chinese family with Marfan syndrome. 15 related family members from a Chinese 4-generation pedigree with Marfan syndrome underwent physical, ophthalmologic, radiological and cardiovascular examinations. The propositus has De Bakey III aortic dissection and didn't fulfill the revised Ghent criteria for Marfan syndrome. Nine family members have ectopia lentis and their echocardiogram was normal. Five other family members have no evidence of Marfan syndrome. Genomic DNA was isolated from blood leukocytes. The exome sequencing was employed on the propositus, then the Sanger sequencing was conducted for mutation verification in other 14 participants of this family. The causative mutation in FBN1 discovered in the propositus was a known heterozygous missense mutation, c.1633T>G (p.R545C), in exon 14 (NM 000138). This same mutation was also identified in all 9 ectopia lentis patients and one unaffected 8-year-old girl. However, the same mutation was not discovered in other 4 unaffected family members. Our data enhance the information of genotype-phenotype correlation owing to FBN1 mutations. To our current knowledge, we firstly reported that the same FBN1 mutation, c. 1633C>T (Arg545Cys), was detected simultaneously in three different cardinal phenotypes (ectopia lentis, aortic dissection and unaffected) within one family. The unaffected girl with FBN1 mutation may presumably represent a rare case of nonpenetrance. Copyright © 2016 Elsevier B.V. All rights reserved.

An ENU mutagenesis-derived mouse model with a dominant Jak1 mutation resembling phenotypes of systemic autoimmune disease.

PubMed

Sabrautzki, Sibylle; Janas, Eva; Lorenz-Depiereux, Bettina; Calzada-Wack, Julia; Aguilar-Pimentel, Juan A; Rathkolb, Birgit; Adler, Thure; Cohrs, Christian; Hans, Wolfgang; Diener, Susanne; Fuchs, Helmut; Gailus-Durner, Valerie; Busch, Dirk H; Höfler, Heinz; Ollert, Markus; Strom, Tim M; Wolf, Eckhard; Neff, Frauke; Hrabě de Angelis, Martin

2013-08-01

Within the Munich, Germany, N-ethyl-N-nitrosourea mouse mutagenesis program, we isolated a dominant Jak1 mouse model resembling phenotypic characteristics related to autoimmune disease. Chromosomal sequencing revealed a new Jak1 (p.Ser645Pro) point mutation at the conserved serine of the pseudokinase domain, corresponding to a somatic human mutation (p.Ser646Phe) inducing a constitutive activation of the Janus kinase (JAK)/STAT pathway. Morphologically, all Jak1(S645P+/-) mice showed a progressive structural deterioration of ears starting at the age of 4 months, with mononuclear cell infiltration into the dermis. Female mutant mice, in particular, developed severe skin lesions in the neck from 7 months of age. The IHC analysis of these lesions showed an activation of Stat3 downstream to Jak1(S645P) and elevated tissue levels of IL-6. Histopathological analysis of liver revealed a nodular regenerative hyperplasia. In the spleen, the number of Russell bodies was doubled, correlating with significant increased levels of all immunoglobulin isotypes and anti-DNA antibodies in serum. Older mutant mice developed thrombocytopenia and altered microcytic red blood cell counts. Jak1(S645P+/-) mice showed phenotypes related to impaired bone metabolism as increased carboxy-terminal collagen cross-link-1 levels and alkaline phosphatase activities in plasma, hypophosphatemia, and strongly decreased bone morphometric values. Taken together, Jak1(S645P+/-) mice showed an increased activation of the IL-6-JAK-STAT pathway leading to a systemic lupus erythematosus-like phenotype and offering a new valuable tool to study the role of the JAK/STAT pathway in disease development. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Phenotypic characteristics of Alzheimer patients carrying an ABCA7 mutation.

PubMed

Van den Bossche, Tobi; Sleegers, Kristel; Cuyvers, Elise; Engelborghs, Sebastiaan; Sieben, Anne; De Roeck, Arne; Van Cauwenberghe, Caroline; Vermeulen, Steven; Van den Broeck, Marleen; Laureys, Annelies; Peeters, Karin; Mattheijssens, Maria; Vandenbulcke, Mathieu; Vandenberghe, Rik; Martin, Jean-Jacques; De Deyn, Peter P; Cras, Patrick; Van Broeckhoven, Christine

2016-06-07

To generate a clinical and pathologic phenotype of patients carrying rare loss-of-function mutations in ABCA7, identified in a Belgian Alzheimer patient cohort and in an autosomal dominant family. We performed a retrospective review of available data records, medical records, results of CSF analyses and neuroimaging studies, and neuropathology data. The mean onset age of the mutation carriers (n = 22) was 73.4 ± 8.4 years with a wide age range of 36 (54-90) years, which was independent of APOE genotype and cerebrovascular disease. The mean disease duration was 5.7 ± 3.0 years (range 2-12 years). A positive family history was recorded for 10 carriers (45.5%). All patient carriers except one presented with memory complaints. The 4 autopsied brains showed typical immunohistochemical changes of late-onset Alzheimer disease. All patients carrying a loss-of-function mutation in ABCA7 exhibited a classical Alzheimer disease phenotype, though with a striking wide onset age range, suggesting the influence of unknown modifying factors. © 2016 American Academy of Neurology.

Phenotypic characteristics of Alzheimer patients carrying an ABCA7 mutation

PubMed Central

Van den Bossche, Tobi; Sleegers, Kristel; Cuyvers, Elise; Engelborghs, Sebastiaan; Sieben, Anne; De Roeck, Arne; Van Cauwenberghe, Caroline; Vermeulen, Steven; Van den Broeck, Marleen; Laureys, Annelies; Peeters, Karin; Mattheijssens, Maria; Vandenbulcke, Mathieu; Vandenberghe, Rik; Martin, Jean-Jacques; De Deyn, Peter P.; Cras, Patrick

2016-01-01

Objective: To generate a clinical and pathologic phenotype of patients carrying rare loss-of-function mutations in ABCA7, identified in a Belgian Alzheimer patient cohort and in an autosomal dominant family. Methods: We performed a retrospective review of available data records, medical records, results of CSF analyses and neuroimaging studies, and neuropathology data. Results: The mean onset age of the mutation carriers (n = 22) was 73.4 ± 8.4 years with a wide age range of 36 (54–90) years, which was independent of APOE genotype and cerebrovascular disease. The mean disease duration was 5.7 ± 3.0 years (range 2–12 years). A positive family history was recorded for 10 carriers (45.5%). All patient carriers except one presented with memory complaints. The 4 autopsied brains showed typical immunohistochemical changes of late-onset Alzheimer disease. Conclusions: All patients carrying a loss-of-function mutation in ABCA7 exhibited a classical Alzheimer disease phenotype, though with a striking wide onset age range, suggesting the influence of unknown modifying factors. PMID:27037232

Mutations in MITF and PAX3 Cause “Splashed White” and Other White Spotting Phenotypes in Horses

PubMed Central

Blatter, Marlis; Brooks, Samantha A.; Burger, Dominik; Drögemüller, Cord; Gerber, Vincent; Henke, Diana; Janda, Jozef; Jude, Rony; Magdesian, K. Gary; Matthews, Jacqueline M.; Poncet, Pierre-André; Svansson, Vilhjálmur; Tozaki, Teruaki; Wilkinson-White, Lorna; Penedo, M. Cecilia T.; Rieder, Stefan; Leeb, Tosso

2012-01-01

During fetal development neural-crest-derived melanoblasts migrate across the entire body surface and differentiate into melanocytes, the pigment-producing cells. Alterations in this precisely regulated process can lead to white spotting patterns. White spotting patterns in horses are a complex trait with a large phenotypic variance ranging from minimal white markings up to completely white horses. The “splashed white” pattern is primarily characterized by an extremely large blaze, often accompanied by extended white markings at the distal limbs and blue eyes. Some, but not all, splashed white horses are deaf. We analyzed a Quarter Horse family segregating for the splashed white coat color. Genome-wide linkage analysis in 31 horses gave a positive LOD score of 1.6 in a region on chromosome 6 containing the PAX3 gene. However, the linkage data were not in agreement with a monogenic inheritance of a single fully penetrant mutation. We sequenced the PAX3 gene and identified a missense mutation in some, but not all, splashed white Quarter Horses. Genome-wide association analysis indicated a potential second signal near MITF. We therefore sequenced the MITF gene and found a 10 bp insertion in the melanocyte-specific promoter. The MITF promoter variant was present in some splashed white Quarter Horses from the studied family, but also in splashed white horses from other horse breeds. Finally, we identified two additional non-synonymous mutations in the MITF gene in unrelated horses with white spotting phenotypes. Thus, several independent mutations in MITF and PAX3 together with known variants in the EDNRB and KIT genes explain a large proportion of horses with the more extreme white spotting phenotypes. PMID:22511888

Deriving a Mutation Index of Carcinogenicity Using Protein Structure and Protein Interfaces

PubMed Central

Hakas, Jarle; Pearl, Frances; Zvelebil, Marketa

2014-01-01

With the advent of Next Generation Sequencing the identification of mutations in the genomes of healthy and diseased tissues has become commonplace. While much progress has been made to elucidate the aetiology of disease processes in cancer, the contributions to disease that many individual mutations make remain to be characterised and their downstream consequences on cancer phenotypes remain to be understood. Missense mutations commonly occur in cancers and their consequences remain challenging to predict. However, this knowledge is becoming more vital, for both assessing disease progression and for stratifying drug treatment regimes. Coupled with structural data, comprehensive genomic databases of mutations such as the 1000 Genomes project and COSMIC give an opportunity to investigate general principles of how cancer mutations disrupt proteins and their interactions at the molecular and network level. We describe a comprehensive comparison of cancer and neutral missense mutations; by combining features derived from structural and interface properties we have developed a carcinogenicity predictor, InCa (Index of Carcinogenicity). Upon comparison with other methods, we observe that InCa can predict mutations that might not be detected by other methods. We also discuss general limitations shared by all predictors that attempt to predict driver mutations and discuss how this could impact high-throughput predictions. A web interface to a server implementation is publicly available at http://inca.icr.ac.uk/. PMID:24454733

DNA transposon activity is associated with increased mutation rates in genes of rice and other grasses

PubMed Central

Wicker, Thomas; Yu, Yeisoo; Haberer, Georg; Mayer, Klaus F. X.; Marri, Pradeep Reddy; Rounsley, Steve; Chen, Mingsheng; Zuccolo, Andrea; Panaud, Olivier; Wing, Rod A.; Roffler, Stefan

2016-01-01

DNA (class 2) transposons are mobile genetic elements which move within their ‘host' genome through excising and re-inserting elsewhere. Although the rice genome contains tens of thousands of such elements, their actual role in evolution is still unclear. Analysing over 650 transposon polymorphisms in the rice species Oryza sativa and Oryza glaberrima, we find that DNA repair following transposon excisions is associated with an increased number of mutations in the sequences neighbouring the transposon. Indeed, the 3,000 bp flanking the excised transposons can contain over 10 times more mutations than the genome-wide average. Since DNA transposons preferably insert near genes, this is correlated with increases in mutation rates in coding sequences and regulatory regions. Most importantly, we find this phenomenon also in maize, wheat and barley. Thus, these findings suggest that DNA transposon activity is a major evolutionary force in grasses which provide the basis of most food consumed by humankind. PMID:27599761

Root-Derived Short-Chain Suberin Diacids from Rice and Rape Seed in a Paddy Soil under Rice Cultivar Treatments

PubMed Central

Ji, Haishi; Ding, Yuanjun; Liu, Xiaoyu; Li, Lianqing; Zhang, Dengxiao; Li, Zichuan; Sun, Jingling; Lashari, Muhammad Siddique; Joseph, Stephen; Meng, Yuanduo; Kuzyakov, Yakov; Pan, Genxing

2015-01-01

Suberin-derived substituted fatty acids have been shown to be potential biomarkers for plant-derived carbon (C) in soils across ecosystems. Analyzing root derived suberin compounds bound in soil could help to understand the root input into a soil organic carbon pool. In this study, bound lipids were extracted and identified in root and topsoil samples. Short-chain suberin diacids were quantified under rice (Oryza sativa L.) and rape (Brassica campestris) rotations with different cultivar combinations in a Chinese rice paddy. After removal of free lipids with sequential extraction, the residual bound lipids were obtained with saponification and derivatization before analysis using gas chromatography–mass spectrometry (GC-MS). Diacids C16 and C18 in bound lipids were detected both in rice and rape root samples, while diacids C20 and C22 were detected only in rape root samples. Accordingly, diacids were quantified in both rhizosphere and bulk soil (0–15 cm). The amount of total root-derived diacids in bulk soil varied in a range of 5.6–9.6 mg/kg across growth stages and crop seasons. After one year-round rice-rape rotation, root-derived suberin diacids were maintained at a level of 7–9 mg/kg in bulk soil; this was higher under a super rice cultivar LY than under a hybrid cultivar IIY. While concentrations of the analyzed diacids were generally higher in rhizosphere than in bulk soil, the total diacid (DA) concentration was higher at the time of rape harvest than at rice harvest, suggesting that rape roots made a major contribution to the preservation of diacids in the paddy. Moreover, the net change in the concentration and the ratios of C16:0 DA to C18:1 DA, and of C16:0 DA to C18:0 DA, over a whole growing season, were greater under LY than under IIY, though there was no difference between cultivars within a single growth stage. Overall, total concentration of root-derived suberin diacids was found to be positively correlated to soil organic carbon

Root-Derived Short-Chain Suberin Diacids from Rice and Rape Seed in a Paddy Soil under Rice Cultivar Treatments.

PubMed

Ji, Haishi; Ding, Yuanjun; Liu, Xiaoyu; Li, Lianqing; Zhang, Dengxiao; Li, Zichuan; Sun, Jingling; Lashari, Muhammad Siddique; Joseph, Stephen; Meng, Yuanduo; Kuzyakov, Yakov; Pan, Genxing

2015-01-01

Suberin-derived substituted fatty acids have been shown to be potential biomarkers for plant-derived carbon (C) in soils across ecosystems. Analyzing root derived suberin compounds bound in soil could help to understand the root input into a soil organic carbon pool. In this study, bound lipids were extracted and identified in root and topsoil samples. Short-chain suberin diacids were quantified under rice (Oryza sativa L.) and rape (Brassica campestris) rotations with different cultivar combinations in a Chinese rice paddy. After removal of free lipids with sequential extraction, the residual bound lipids were obtained with saponification and derivatization before analysis using gas chromatography-mass spectrometry (GC-MS). Diacids C16 and C18 in bound lipids were detected both in rice and rape root samples, while diacids C20 and C22 were detected only in rape root samples. Accordingly, diacids were quantified in both rhizosphere and bulk soil (0-15 cm). The amount of total root-derived diacids in bulk soil varied in a range of 5.6-9.6 mg/kg across growth stages and crop seasons. After one year-round rice-rape rotation, root-derived suberin diacids were maintained at a level of 7-9 mg/kg in bulk soil; this was higher under a super rice cultivar LY than under a hybrid cultivar IIY. While concentrations of the analyzed diacids were generally higher in rhizosphere than in bulk soil, the total diacid (DA) concentration was higher at the time of rape harvest than at rice harvest, suggesting that rape roots made a major contribution to the preservation of diacids in the paddy. Moreover, the net change in the concentration and the ratios of C16:0 DA to C18:1 DA, and of C16:0 DA to C18:0 DA, over a whole growing season, were greater under LY than under IIY, though there was no difference between cultivars within a single growth stage. Overall, total concentration of root-derived suberin diacids was found to be positively correlated to soil organic carbon concentration

The Rice AAA-ATPase OsFIGNL1 Is Essential for Male Meiosis

PubMed Central

Zhang, Peipei; Zhang, Yingxin; Sun, Lianping; Sinumporn, Sittipun; Yang, Zhengfu; Sun, Bin; Xuan, Dandan; Li, Zihe; Yu, Ping; Wu, Weixun; Wang, Kejian; Cao, Liyong; Cheng, Shihua

2017-01-01

Meiosis is crucial in reproduction of plants and ensuring genetic diversity. Although several genes involved in homologous recombination and DNA repair have been reported, their functions in rice (Oryza sativa) male meiosis remain poorly understood. Here, we isolated and characterized the rice OsFIGNL1 (OsFidgetin-like 1) gene, encoding a conserved AAA-ATPase, and explored its function and importance in male meiosis and pollen formation. The rice Osfignl1 mutant exhibited normal vegetative growth, but failed to produce seeds and displayed pollen abortion phenotype. Phenotypic comparisons between the wild-type and Osfignl1 mutant demonstrated that OsFIGNL1 is required for anther development, and that the recessive mutation of this gene causes male sterility in rice. Complementation and CRISPR/Cas9 experiments demonstrated that wild-type OsFIGNL1 is responsible for the male sterility phenotype. Subcellular localization showed that OsFIGNL1-green fluorescent protein was exclusively localized in the nucleus of rice protoplasts. Male meiosis in the Osfignl1 mutant exhibited abnormal chromosome behavior, including chromosome bridges and multivalent chromosomes at diakinesis, lagging chromosomes, and chromosome fragments during meiosis. Yeast two-hybrid assays demonstrated OsFIGNL1 could interact with RAD51A1, RAD51A2, DMC1A, DMC1B, and these physical interactions were further confirmed by BiFC assay. Taken together, our results suggest that OsFIGNL1 plays an important role in regulation of male meiosis and anther development. PMID:29021797

Norrie-Warburg syndrome: two novel mutations in patients with classical clinical phenotype.

PubMed

Gal, A; Veske, A; Jojart, G; Grammatico, B; Huber, B; Gu, S; del Porto, G; Senyi, K

1996-01-01

Norrie-Warburg syndrome (NWS) is a rare X-linked disorder characterized by blindness, which is invariable, deafness and mental disturbances, which are present occasionally. We describe here two novel mutations, a missense mutation (C126S) and a 1-base pair insertion (insT466/T467), together with a recurrent mutation (M1V), found in patients presenting with the classical clinical phenotype of NWS. All three mutations are likely to result in prominent structural changes of the norrin protein.

Expanding the phenotypic and mutational spectrum in microcephalic osteodysplastic primordial dwarfism type I.

PubMed

Abdel-Salam, Ghada M H; Abdel-Hamid, Mohamed S; Issa, Mahmoud; Magdy, Ahmed; El-Kotoury, Ahmed; Amr, Khalda

2012-06-01

Mutations in the RNU4ATAC gene cause microcephalic osteodysplastic primordial dwarfism type I. It encodes U4atac, a small nuclear RNA that is a component of the minor spliceosome. Six distinct mutations in 30 patients diagnosed as microcephalic osteodysplastic primordial dwarfism type I have been described. We report on three additional patients from two unrelated families presenting with a milder phenotype of microcephalic osteodysplastic primordial dwarfism type I and metopic synostosis. Patient 1 had two novel heterozygous mutations in the 3' prime stem-loop, g.66G > C and g.124G > A while Patients 2 and 3 had a homozygous mutation g.55G > A in the 5' prime stem-loop. Although they manifested the known spectrum of clinical features of microcephalic osteodysplastic primordial dwarfism type I, they lacked evidence of severe developmental delay and neurological symptoms. These findings expand the mutational and phenotypic spectrum of this syndrome. Copyright © 2012 Wiley Periodicals, Inc.

Point Mutations in c-Myc Uncouple Neoplastic Transformation from Multiple Other Phenotypes in Rat Fibroblasts

PubMed Central

Graves, J. Anthony; Rothermund, Kristi; Wang, Tao; Qian, Wei; Van Houten, Bennett; Prochownik, Edward V.

2010-01-01

Deregulation of c-Myc (Myc) occurs in many cancers. In addition to transforming various cell types, Myc also influences additional transformation-associated cellular phenotypes including proliferation, survival, genomic instability, reactive oxygen species production, and metabolism. Although Myc is wild type in most cancers (wtMyc), it occasionally acquires point mutations in certain lymphomas. Some of these mutations confer a survival advantage despite partially attenuating proliferation and transformation. Here, we have evaluated four naturally-occurring or synthetic point mutations of Myc for their ability to affect these phenotypes, as well as to promote genomic instability, to generate reactive oxygen species and to up-regulate aerobic glycolysis and oxidative phosphorylation. Our findings indicate that many of these phenotypes are genetically and functionally independent of one another and are not necessary for transformation. Specifically, the higher rate of glucose metabolism known to be associated with wtMyc deregulation was found to be independent of transformation. One mutation (Q131R) was greatly impaired for nearly all of the studied Myc phenotypes, yet was able to retain some ability to transform. These findings indicate that, while the Myc phenotypes examined here make additive contributions to transformation, none, with the possible exception of increased reliance on extracellular glutamine for survival, are necessary for achieving this state. PMID:21060841

Genome-wide annotation of mutations in a phenotyped mutant library provides an efficient platform for discovery of casual gene mutations

USDA-ARS?s Scientific Manuscript database

Ethyl methanesulfonate (EMS) efficiently generates high-density mutations in genomes. Conventionally, these mutations are identified by techniques that can detect single-nucleotide mismatches in heteroduplexes of individual PCR amplicons. We applied whole-genome sequencing to 256-phenotyped mutant l...

Comparison of phenotyping methods for resistance to stem rot and aggregated sheath spot in rice

USDA-ARS?s Scientific Manuscript database

Stem and sheath diseases caused by Sclerotium oryzae Cattaneo (SCL) and Rhizoctonia oryzae-sativae Sawada Mordue (ROS) can severely reduce rice (Oryza sativa L.) yield and grain quality. Genetic resistance is the best strategy to control them. Phenotypic selection for resistance is hampered due to a...

Analysis of Hungarian patients with Rett syndrome phenotype for MECP2, CDKL5 and FOXG1 gene mutations.

PubMed

Hadzsiev, Kinga; Polgar, Noemi; Bene, Judit; Komlosi, Katalin; Karteszi, Judit; Hollody, Katalin; Kosztolanyi, Gyorgy; Renieri, Alessandra; Melegh, Bela

2011-03-01

Rett syndrome (RTT) is characterized by a relatively specific clinical phenotype. We screened 152 individuals with RTT phenotype. A total of 22 different known MECP2 mutations were identified in 42 subjects (27.6%). Of the 22 mutations, we identified 7 (31.8%) frameshift-causing deletions, 4 (18.2%) nonsense, 10 (45.5%) missense mutations and one insertion (4.5%). The most frequent pathologic changes were: p.Thr158Met (14.2%) and p.Arg133Cys (11.9%) missense, and p.Arg255Stop (9.5%) and p.Arg294Stop (9.5%) nonsense mutations. We also detected the c.925C >T (p.Arg309Trp) mutation in an affected patient, whose role in RTT pathogenesis is still unknown. Patients without detectable MECP2 defects were screened for mutations of cyclin-dependent kinase-like 5 (CDKL5) gene, responsible for the early-onset variant of RTT. We discovered two novel mutations: c.607G >T resulting in a termination codon at aa203, disrupting the catalytic domain, and c.1708G >T leading to a stop at aa570 of the C terminus. Both patients with CDKL5 mutation presented therapy-resistant epilepsy and a phenotype fitting with the diagnosis of early-onset variant of RTT. No FOXG1 mutation was detected in any of the remaining patients. A total of 110 (72.5%) patients remained without molecular genetic diagnosis that necessitates further search for novel gene mutations in this phenotype. Our results also suggest the need of screening for CDKL5 mutations in patients with Rett phenotype tested negative for MECP2 mutations.

Escape to Ferality: The Endoferal Origin of Weedy Rice from Crop Rice through De-Domestication

PubMed Central

Gettler, Kyle A.; Burgos, Nilda R.; Fischer, Albert J.

2016-01-01

Domestication is the hallmark of evolution and civilization and harnesses biodiversity through selection for specific traits. In regions where domesticated lines are grown near wild relatives, congeneric sources of aggressive weedy genotypes cause major economic losses. Thus, the origins of weedy genotypes where no congeneric species occur raise questions regarding management effectiveness and evolutionary mechanisms responsible for weedy population success. Since eradication in the 1970s, California growers avoided weedy rice through continuous flood culture and zero-tolerance guidelines, preventing the import, presence, and movement of weedy seeds. In 2003, after decades of no reported presence in California, a weedy rice population was confirmed in dry-seeded fields. Our objectives were to identify the origins and establishment of this population and pinpoint possible phenotypes involved. We show that California weedy rice is derived from a different genetic source among a broad range of AA genome Oryzas and is most recently diverged from O. sativa temperate japonica cultivated in California. In contrast, other weedy rice ecotypes in North America (Southern US) originate from weedy genotypes from China near wild Oryza, and are derived through existing crop-wild relative crosses. Analyses of morphological data show that California weedy rice subgroups have phenotypes like medium-grain or gourmet cultivars, but have colored pericarp, seed shattering, and awns like wild relatives, suggesting that reversion to non-domestic or wild-like traits can occur following domestication, despite apparent fixation of domestication alleles. Additionally, these results indicate that preventive methods focused on incoming weed sources through contamination may miss burgeoning weedy genotypes that rapidly adapt, establish, and proliferate. Investigating the common and unique evolutionary mechanisms underlying global weed origins and subsequent interactions with crop relatives sheds

Escape to Ferality: The Endoferal Origin of Weedy Rice from Crop Rice through De-Domestication.

PubMed

Kanapeckas, Kimberly L; Vigueira, Cynthia C; Ortiz, Aida; Gettler, Kyle A; Burgos, Nilda R; Fischer, Albert J; Lawton-Rauh, Amy L

Domestication is the hallmark of evolution and civilization and harnesses biodiversity through selection for specific traits. In regions where domesticated lines are grown near wild relatives, congeneric sources of aggressive weedy genotypes cause major economic losses. Thus, the origins of weedy genotypes where no congeneric species occur raise questions regarding management effectiveness and evolutionary mechanisms responsible for weedy population success. Since eradication in the 1970s, California growers avoided weedy rice through continuous flood culture and zero-tolerance guidelines, preventing the import, presence, and movement of weedy seeds. In 2003, after decades of no reported presence in California, a weedy rice population was confirmed in dry-seeded fields. Our objectives were to identify the origins and establishment of this population and pinpoint possible phenotypes involved. We show that California weedy rice is derived from a different genetic source among a broad range of AA genome Oryzas and is most recently diverged from O. sativa temperate japonica cultivated in California. In contrast, other weedy rice ecotypes in North America (Southern US) originate from weedy genotypes from China near wild Oryza, and are derived through existing crop-wild relative crosses. Analyses of morphological data show that California weedy rice subgroups have phenotypes like medium-grain or gourmet cultivars, but have colored pericarp, seed shattering, and awns like wild relatives, suggesting that reversion to non-domestic or wild-like traits can occur following domestication, despite apparent fixation of domestication alleles. Additionally, these results indicate that preventive methods focused on incoming weed sources through contamination may miss burgeoning weedy genotypes that rapidly adapt, establish, and proliferate. Investigating the common and unique evolutionary mechanisms underlying global weed origins and subsequent interactions with crop relatives sheds

Clinical phenotype of 5 females with a CDKL5 mutation.

PubMed

Stalpers, Xenia L; Spruijt, Liesbeth; Yntema, Helger G; Verrips, Aad

2012-01-01

Mutations in the X-linked cyclin dependent kinase like 5 (CDKL5) gene have been reported in approximately 80 patients since the first description in 2003. The clinical presentation partly corresponds with Rett syndrome, considering clinical features as intellectual disability, hypotonia, and poor visual, language, and motor development. However, these patients do not meet the consensus criteria for Rett syndrome since they lack the clear period of regression. Furthermore, in contrast to Rett syndrome, patients with CDKL5 mutations, have seizures or infantile spasms starting in the first weeks of life. We present clinical phenotype of 5 girls having a mutation in the CDKL5 gene. All mutations are novel and are pathogenic since they either lead to a frameshift in the reading frame or affect a consensus splice site. Four of the mutations are detected de novo in the affected girl.

A novel CISD2 mutation associated with a classical Wolfram syndrome phenotype alters Ca2+ homeostasis and ER-mitochondria interactions

PubMed Central

Rouzier, Cécile; Moore, David; Delorme, Cécile; Lacas-Gervais, Sandra; Ait-El-Mkadem, Samira; Fragaki, Konstantina; Burté, Florence; Serre, Valérie; Bannwarth, Sylvie; Chaussenot, Annabelle; Catala, Martin

2017-01-01

Abstract Wolfram syndrome (WS) is a progressive neurodegenerative disease characterized by early-onset optic atrophy and diabetes mellitus, which can be associated with more extensive central nervous system and endocrine complications. The majority of patients harbour pathogenic WFS1 mutations, but recessive mutations in a second gene, CISD2, have been described in a small number of families with Wolfram syndrome type 2 (WFS2). The defining diagnostic criteria for WFS2 also consist of optic atrophy and diabetes mellitus, but unlike WFS1, this phenotypic subgroup has been associated with peptic ulcer disease and an increased bleeding tendency. Here, we report on a novel homozygous CISD2 mutation (c.215A > G; p.Asn72Ser) in a Moroccan patient with an overlapping phenotype suggesting that Wolfram syndrome type 1 and type 2 form a continuous clinical spectrum with genetic heterogeneity. The present study provides strong evidence that this particular CISD2 mutation disturbs cellular Ca2+ homeostasis with enhanced Ca2+ flux from the ER to mitochondria and cytosolic Ca2+ abnormalities in patient-derived fibroblasts. This Ca2+ dysregulation was associated with increased ER-mitochondria contact, a swollen ER lumen and a hyperfused mitochondrial network in the absence of overt ER stress. Although there was no marked alteration in mitochondrial bioenergetics under basal conditions, culture of patient-derived fibroblasts in glucose-free galactose medium revealed a respiratory chain defect in complexes I and II, and a trend towards decreased ATP levels. Our results provide important novel insight into the potential disease mechanisms underlying the neurodegenerative consequences of CISD2 mutations and the subsequent development of multisystemic disease. PMID:28335035

The Phenotypic Spectrum of DYT24 Due to ANO3 Mutations

PubMed Central

Stamelou, Maria; Charlesworth, Gavin; Cordivari, Carla; Schneider, Susanne A; Kägi, Georg; Sheerin, Una-Marie; Rubio-Agusti, Ignacio; Batla, Amit; Houlden, Henry; Wood, Nicholas W; Bhatia, Kailash P

2014-01-01

Genes causing primary dystonia are rare. Recently, pathogenic mutations in the anoctamin 3 gene (ANO3) have been identified to cause autosomal dominant craniocervical dystonia and have been assigned to the dystonia locus dystonia-24 (DYT24). Here, we expand on the phenotypic spectrum of DYT24 and provide demonstrative videos. Moreover, tremor recordings were performed, and back-averaged electroencephalography, sensory evoked potentials, and C-reflex studies were carried out in two individuals who carried two different mutations in ANO3. Ten patients from three families are described. The age at onset ranged from early childhood to the forties. Cervical dystonia was the most common site of onset followed by laryngeal dystonia. The characteristic feature in all affected individuals was the presence of tremor, which contrasts DYT24 from the typical DYT6 phenotype. Tremor was the sole initial manifestation in some individuals with ANO3 mutations, leading to misdiagnosis as essential tremor. Electrophysiology in two patients with two different mutations showed co-contraction of antagonist muscles, confirming dystonia, and a 6-Hz arm tremor at rest, which increased in amplitude during action. In one of the studied patients, clinically superimposed myoclonus was observed. The duration of the myoclonus was in the range of 250 msec at about 3 Hz, which is more consistent with subcortical myoclonus. In summary, ANO3 causes a varied phenotype of young-onset or adult-onset craniocervical dystonia with tremor and/or myoclonic jerks. Patients with familial cervical dystonia who also have myoclonus-dystonia as well as patients with prominent tremor and mild dystonia should be tested for ANO3 mutations. © 2014 The Authors. Movement Disorders published by International Parkinson and Movement Disorder Society PMID:24442708

Mutations in the gene for X-linked adrenoleukodystrophy in patients with different clinical phenotypes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Braun, A.; Ambach, H.; Kammerer, S.

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-bindingmore » 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.« less

PHENOTYPIC VARIABILITY IN INDIVIDUALS WITH TYPE V OSTEOGENESIS IMPERFECTA WITH IDENTICAL IFITM5 MUTATIONS

PubMed Central

Fitzgerald, Jamie; Holden, Paul; Wright, Hollis; Wilmot, Beth; Hata, Abigail; Steiner, Robert D.; Basel, Don

2016-01-01

Background Osteogenesis imperfecta (OI) type V is a dominantly inherited skeletal dysplasia characterized by fractures and progressive deformity of long bones. In addition, patients often present with radial head dislocation, hyperplastic callus, and calcification of the forearm interosseous membrane. Recently, a specific mutation in the IFITM5 gene was found to be responsible for OI type V. This mutation, a C to T transition 14 nucleotides upstream from the endogenous start codon, creates a new start methionine that appears to be preferentially used by the translational machinery. However, the mechanism by which the lengthened protein results in a dominant type of OI is unknown. Methods and Results We report 7 ethnically diverse (African-American, Caucasian, Hispanic, and African) individuals with OI type V from 2 families and 2 sporadic cases. Exome sequencing failed to identify a causative mutation. Using Sanger sequencing, we found that all affected individuals in our cohort possess the c.−14 IFITM5 variant, further supporting the notion that OI type V is caused by a single, discrete mutation. Our patient cohort demonstrated inter-and intrafamilial phenotypic variability, including a father with classic OI type V whose daughter had a phenotype similar to OI type I. This clinical variability suggests that modifier genes influence the OI type V phenotype. We also confirm that the mutation creates an aberrant IFITM5 protein containing an additional 5 amino acids at the N-terminus. Conclusions The variable clinical signs in these cases illustrate the significant variability of the OI type V phenotype caused by the c.−14 IFITM5 mutation. The affected individuals are more ethnically diverse than previously reported. PMID:28824928

Identification and Phenotypic Characterization of ZEBRA LEAF16 Encoding a β-Hydroxyacyl-ACP Dehydratase in Rice

PubMed Central

Liu, Ziwen; Wang, Zhiyuan; Gu, Han; You, Jia; Hu, Manman; Zhang, Yujun; Zhu, Ze; Wang, Yihua; Liu, Shijia; Chen, Liangming; Liu, Xi; Tian, Yunlu; Zhou, Shirong; Jiang, Ling; Liu, Linglong; Wan, Jianmin

2018-01-01

The chloroplast is a self-independent organelle and contains its own transcription and translation systems. The establishment of genetic systems is vital for normal plant growth and development. We isolated a rice zebra leaf 16 (zl16) mutant derived from rice cultivar 9311. The zl16 mutant showed chlorotic abnormalities in the transverse sectors of the young leaves of seedlings. The use of transmission electron microscopy (TEM) demonstrated that dramatic defects occurred in variegated zl16 leaves during the early development of a chloroplast. Map-based cloning revealed that ZL16 encodes a β-hydroxyacyl-ACP dehydratase (HAD) involved in de novo fatty acid synthesis. Compared with the wild type, a missense mutation (Arg164Trp) in the zl16 mutant was identified, which significantly reduced enzymatic activity and altered the three-dimensional modeling structure of the putative protein. ZL16 was ubiquitously expressed in various plant organs, with a pronounced level in the young leaf. A subcellular localization experiment indicated that ZL16 was targeted in the chloroplast. Furthermore, we analyzed the expression of some nuclear genes involved in chloroplast development, and found they were altered in the zl16 mutant. RNA-Seq analysis indicated that some genes related to cell membrane constituents were downregulated in the mutant. An in vivo metabolic assay revealed that the total fatty acid content in the mutant was significantly decreased relative to the wild type. Our results indicate that HAD is essential for the development of chloroplasts by regulating the synthesis of fatty acids in rice. PMID:29946330

A novel mutation in the AGXT gene causing primary hyperoxaluria type I: genotype-phenotype correlation.

PubMed

M'Dimegh, Saoussen; Aquaviva-Bourdain, Cécile; Omezzine, Asma; M'Barek, Ibtihel; Souche, Geneviéve; Zellama, Dorsaf; Abidi, Kamel; Achour, Abdelattif; Gargah, Tahar; Abroug, Saoussen; Bouslama, Ali

2016-09-01

Primary hyperoxaluria type I (PH1) is an autosomal recessive metabolic disorder caused by inherited mutations in the AGXT gene encoding liver peroxisomal alanine : glyoxylate aminotransferase (AGT) which is deficient or mistargeted to mitochondria. PH1 shows considerable phenotypic and genotypic heterogeneity. The incidence and severity of PH1 varies in different geographic regions. DNA samples of the affected members from two unrelated Tunisian families were tested by amplifying and sequencing each of the AGXT exons and intron-exon junctions. We identified a novel frameshift mutation in the AGXT gene, the c.406_410dupACTGC resulting in a truncated protein (p.Gln137Hisfs*19). It is found in homozygous state in two nonconsanguineous unrelated families from Tunisia. These molecular findings provide genotype/phenotype correlations in the intrafamilial phenotypic and permit accurate carrier detection, and prenatal diagnosis. The novel p.Gln137Hisfs*19 mutation detected in our study extend the spectrum of known AGXT gene mutations in Tunisia.

Multi-layered mutation in hedgehog-related genes in Gorlin syndrome may affect the phenotype.

PubMed

Onodera, Shoko; Saito, Akiko; Hasegawa, Daigo; Morita, Nana; Watanabe, Katsuhito; Nomura, Takeshi; Shibahara, Takahiko; Ohba, Shinsuke; Yamaguchi, Akira; Azuma, Toshifumi

2017-01-01

Gorlin syndrome is a genetic disorder of autosomal dominant inheritance that predisposes the affected individual to a variety of disorders that are attributed largely to heterozygous germline patched1 (PTCH1) mutations. PTCH1 is a hedgehog (Hh) receptor as well as a repressor, mutation of which leads to constitutive activation of Hh pathway. Hh pathway encompasses a wide variety of cellular signaling cascades, which involve several molecules; however, no associated genotype-phenotype correlations have been reported. Recently, mutations in Suppressor of fused homolog (SUFU) or PTCH2 were reported in patients with Gorlin syndrome. These facts suggest that multi-layered mutations in Hh pathway may contribute to the development of Gorlin syndrome. We demonstrated multiple mutations of Hh-related genes in addition to PTCH1, which possibly act in an additive or multiplicative manner and lead to Gorlin syndrome. High-throughput sequencing was performed to analyze exome sequences in four unrelated Gorlin syndrome patient genomes. Mutations in PTCH1 gene were detected in all four patients. Specific nucleotide variations or frameshift variations of PTCH1 were identified along with the inferred amino acid changes in all patients. We further filtered 84 different genes which are closely related to Hh signaling. Fifty three of these had enough coverage of over ×30. The sequencing results were filtered and compared to reduce the number of sequence variants identified in each of the affected individuals. We discovered three genes, PTCH2, BOC, and WNT9b, with mutations with a predicted functional impact assessed by MutationTaster2 or PolyPhen-2 (Polymorphism Phenotyping v2) analysis. It is noticeable that PTCH2 and BOC are Hh receptor molecules. No significant mutations were observed in SUFU. Multi-layered mutations in Hh pathway may change the activation level of the Hh signals, which may explain the wide phenotypic variability of Gorlin syndrome.

Swedish CDKN2A mutation carriers do not present the atypical mole syndrome phenotype.

PubMed

Nielsen, Kari; Harbst, Katja; Måsbäck, Anna; Jönsson, Göran; Borg, Ake; Olsson, Håkan; Ingvar, Christian

2010-08-01

Phenotypic characteristics were examined in melanoma-prone southern Swedish CDKN2A (p16-113insArg/p14ARF-128insSer) mutation families, in relation to the CDKN2A genotype, nevi, clinically atypical nevi (CAN) and melanoma. Individuals from eight melanoma-prone families, with index patients carrying the CDKN2A mutation, were offered skin examinations and genotyping (CDKN2A and MC1R). Ninety-three individuals above 18 years of age participated; 29 invasive melanomas in 16 patients were recorded, all in the 38 verified CDKN2A mutation carriers. Median age at diagnosis was 36 years. Several MC1R variants were observed. A significant correlation to CAN (P=0.01) and red hair colour (P=0.02) could be confirmed in melanoma patients. A positive mutation status (CDKN2A) was correlated to one or more CAN (P=0.007) but neither to blue eyes, red hair colour, heavy freckling nor high number of nevi. For mutation carriers, median total naevus count was 24 and interquartile range was 12-47 (mean 31); whereas for the whole cohort, median total naevus count was 12 and interquartile range was 5-25 (mean 22). No participant fulfilled the atypical mole syndrome phenotype criteria. Melanomas were diagnosed only in mutation carriers, and melanoma diagnosis was statistically correlated to the presence of one or more CAN and red hair colour, supporting the possible synergistic effect of a MC1R mutation on increased risk of melanoma in patients with a CDKN2A mutation. Family history, with verified tumour diagnoses, remains an important clinical tool for finding mutation carriers for referral to clinical geneticists and simultaneous presence of CAN in probable mutation carriers might strengthen this indication. The atypical mole syndrome phenotype was, however, not verified in the studied families and total naevus counts were low.

The SAM domain of ANKS6 has different interacting partners and mutations can induce different cystic phenotypes.

PubMed

Bakey, Zeineb; Bihoreau, Marie-Thérèse; Piedagnel, Rémi; Delestré, Laure; Arnould, Catherine; de Villiers, Alexandre d'Hotman; Devuyst, Olivier; Hoffmann, Sigrid; Ronco, Pierre; Gauguier, Dominique; Lelongt, Brigitte

2015-08-01

The ankyrin repeat and sterile α motif (SAM) domain-containing six gene (Anks6) is a candidate for polycystic kidney disease (PKD). Originally identified in the PKD/Mhm(cy/+) rat model of PKD, the disease is caused by a mutation (R823W) in the SAM domain of the encoded protein. Recent studies support the etiological role of the ANKS6 SAM domain in human cystic diseases, but its function in kidney remains unknown. To investigate the role of ANKS6 in cyst formation, we screened an archive of N-ethyl-N-nitrosourea-treated mice and derived a strain carrying a missense mutation (I747N) within the SAM domain of ANKS6. This mutation is only six amino acids away from the PKD-causing mutation (R823W) in cy/+ rats. Evidence of renal cysts in these mice confirmed the crucial role of the SAM domain of ANKS6 in kidney function. Comparative phenotype analysis in cy/+ rats and our Anks6(I747N) mice further showed that the two models display noticeably different PKD phenotypes and that there is a defective interaction between ANKS6 with ANKS3 in the rat and between ANKS6 and BICC1 (bicaudal C homolog 1) in the mouse. Thus, our data demonstrate the importance of ANKS6 for kidney structure integrity and the essential mediating role of its SAM domain in the formation of protein complexes.

Phenotype/genotype correlation in a case series of Stargardt's patients identifies novel mutations in the ABCA4 gene.

PubMed

Gemenetzi, M; Lotery, A J

2013-11-01

To investigate phenotypic variability in terms of best-corrected visual acuity (BCVA) in patients with Stargardt disease (STGD) and confirmed ABCA4 mutations. Entire coding region analysis of the ABCA4 gene by direct sequencing of seven patients with clinical findings of STGD seen in the Retina Clinics of Southampton Eye Unit between 2002 and 2011.Phenotypic variables recorded were BCVA, fluorescein angiographic appearance, electrophysiology, and visual fields. All patients had heterozygous amino acid-changing variants (missense mutations) in the ABCA4 gene. A splice sequence change was found in a 30-year-old patient with severly affected vision. Two novel sequence changes were identified: a missense mutation in a mildly affected 44-year-old patient and a frameshift mutation in a severly affected 34-year-old patient. The identified ABCA4 mutations were compatible with the resulting phenotypes in terms of BCVA. Higher BCVAs were recorded in patients with missense mutations. Sequence changes, predicted to have more deleterious effect on protein function, resulted in a more severe phenotype. This case series of STGD patients demonstrates novel genotype/phenotype correlations, which may be useful to counselling of patients. This information may prove useful in selection of candidates for clinical trials in ABCA4 disease.

Functional analysis of mutations in SLC7A9, and genotype-phenotype correlation in non-Type I cystinuria.

PubMed

Font, M A; Feliubadaló, L; Estivill, X; Nunes, V; Golomb, E; Kreiss, Y; Pras, E; Bisceglia, L; d'Adamo, A P; Zelante, L; Gasparini, P; Bassi, M T; George , A L; Manzoni, M; Riboni, M; Ballabio, A; Borsani, G; Reig, N; Fernández, E; Zorzano, A; Bertran, J; Palacín, M

2001-02-15

Cystinuria (OMIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids that results in nephrolithiasis of cystine. Mutations in SLC3A1, which encodes rBAT, cause Type I cystinuria, and mutations in SLC7A9, which encodes a putative subunit of rBAT (b(o,+)AT), cause non-Type I cystinuria. Here we describe the genomic structure of SLC7A9 (13 exons) and 28 new mutations in this gene that, together with the seven previously reported, explain 79% of the alleles in 61 non-Type I cystinuria patients. These data demonstrate that SLC7A9 is the main non-Type I cystinuria gene. Mutations G105R, V170M, A182T and R333W are the most frequent SLC7A9 missense mutations found. Among heterozygotes carrying these mutations, A182T heterozygotes showed the lowest urinary excretion values of cystine and dibasic amino acids. Functional analysis of mutation A182T after co-expression with rBAT in HeLa cells revealed significant residual transport activity. In contrast, mutations G105R, V170M and R333W are associated to a complete or almost complete loss of transport activity, leading to a more severe urinary phenotype in heterozygotes. SLC7A9 mutations located in the putative transmembrane domains of b(o,+)AT and affecting conserved amino acid residues with a small side chain generate a severe phenotype, while mutations in non-conserved residues give rise to a mild phenotype. These data provide the first genotype-phenotype correlation in non-Type I cystinuria, and show that a mild urinary phenotype in heterozygotes may associate with mutations with significant residual transport activity.

THE FUNDUS PHENOTYPE ASSOCIATED WITH THE p.Ala243Val BEST1 MUTATION.

PubMed

Khan, Kamron N; Islam, Farrah; Moore, Anthony T; Michaelides, Michel

2018-03-01

To describe a highly recognizable and reproducible retinal phenotype associated with a specific BEST1 mutation-p.Ala243Val. Retrospective review of consecutive cases where genetic testing has identified p.Ala243Val BEST1 as the cause of disease. Electronic patient records were used to extract demographic, as well as functional and anatomical data. These data were compared with those observed with the most common BEST1 genotype, p.Arg218Cys. Eight individuals (six families) were identified with the p.Ala243Val BEST1 mutation and seven patients with the pathologic variant p.Arg218Cys. No patients with mutation of codon 243 knowingly had a family history of retinal disease, whereas all patients with the p.Arg218Cys variant did. The maculopathy was bilateral in all cases. The p.Ala243Val mutation was associated with a pattern dystrophy-type appearance, most visible with near-infrared reflectance and fundus autofluorescence imaging. This phenotype was never observed with any other genotype. This mutation was associated with an older median age of symptom onset (median = 42, interquartile range = 22) compared with those harboring the p.Arg218Cys mutation (median = 18, interquartile range = 12; Mann-Whitney U test; P < 0.05). Despite their older age, the final recorded acuity seemed to be better in the p.Ala243Val group (median = 0.55, interquartile range = 0.6475; median = 0.33, interquartile range = 0.358), although this did not reach statistical significance (Mann-Whitney U test; P > 0.05). The mutation p.Ala243Val is associated with highly recognizable and reproducible pattern dystrophy-like phenotype. Patients develop symptoms at a later age and tend to have better preservation of electrooculogram amplitudes.

Inactivating mutations in ESCO2 cause SC phocomelia and Roberts syndrome: no phenotype-genotype correlation.

PubMed

Schüle, Birgitt; Oviedo, Angelica; Johnston, Kathreen; Pai, Shashidhar; Francke, Uta

2005-12-01

The rare, autosomal recessive Roberts syndrome (RBS) is characterized by tetraphocomelia, profound growth deficiency of prenatal onset, craniofacial anomalies, microcephaly, and mental deficiency. SC phocomelia (SC) has a milder phenotype, with a lesser degree of limb reduction and with survival to adulthood. Since heterochromatin repulsion (HR) is characteristic for both disorders and is not complemented in somatic-cell hybrids, it has been hypothesized that the disorders are allelic. Recently, mutations in ESCO2 (establishment of cohesion 1 homolog 2) on 8p21.1 have been reported in RBS. To determine whether ESCO2 mutations are also responsible for SC, we studied three families with SC and two families in which variable degrees of limb and craniofacial abnormalities, detected by fetal ultrasound, led to pregnancy terminations. All cases were positive for HR. We identified seven novel mutations in exons 3-8 of ESCO2. In two families, affected individuals were homozygous--for a 5-nucleotide deletion in one family and a splice-site mutation in the other. In three nonconsanguineous families, probands were compound heterozygous for a single-nucleotide insertion or deletion, a nonsense mutation, or a splice-site mutation. Abnormal splice products were characterized at the RNA level. Since only protein-truncating mutations were identified, regardless of clinical severity, we conclude that genotype does not predict phenotype. Having established that RBS and SC are caused by mutations in the same gene, we delineated the clinical phenotype of the tetraphocomelia spectrum that is associated with HR and ESCO2 mutations and differentiated it from other types of phocomelia that are negative for HR.

The phenotypic spectrum in patients with arginine to cysteine mutations in the COL2A1 gene

PubMed Central

Hoornaert, K P; Dewinter, C; Vereecke, I; Beemer, F A; Courtens, W; Fryer, A; Fryssira, H; Lees, M; Müllner‐Eidenböck, A; Rimoin, D L; Siderius, L; Superti‐Furga, A; Temple, K; Willems, P J; Zankl, A; Zweier, C; De Paepe, A; Coucke, P; Mortier, G R

2006-01-01

Background The majority of COL2A1 missense mutations are substitutions of obligatory glycine residues in the triple helical domain. Only a few non‐glycine missense mutations have been reported and among these, the arginine to cysteine substitutions predominate. Objective To investigate in more detail the phenotype resulting from arginine to cysteine mutations in the COL2A1 gene. Methods The clinical and radiographic phenotype of all patients in whom an arginine to cysteine mutation in the COL2A1 gene was identified in our laboratory, was studied and correlated with the abnormal genotype. The COL2A1 genotyping involved DHPLC analysis with subsequent sequencing of the abnormal fragments. Results Six different mutations (R75C, R365C, R519C, R704C, R789C, R1076C) were found in 11 unrelated probands. Each mutation resulted in a rather constant and site‐specific phenotype, but a perinatally lethal disorder was never observed. Spondyloarthropathy with normal stature and no ocular involvement were features of patients with the R75C, R519C, or R1076C mutation. Short third and/or fourth toes was a distinguishing feature of the R75C mutation and brachydactyly with enlarged finger joints a key feature of the R1076C substitution. Stickler dysplasia with brachydactyly was observed in patients with the R704C mutation. The R365C and R789C mutations resulted in classic Stickler dysplasia and spondyloepiphyseal dysplasia congenita (SEDC), respectively. Conclusions Arginine to cysteine mutations are rather infrequent COL2A1 mutations which cause a spectrum of phenotypes including classic SEDC and Stickler dysplasia, but also some unusual entities that have not yet been recognised and described as type II collagenopathies. PMID:16155195

Same MSH2 Gene Mutation But Variable Phenotypes in 2 Families With Lynch Syndrome: Two Case Reports and Review of Genotype-Phenotype Correlation.

PubMed

Liccardo, Raffaella; De Rosa, Marina; Duraturo, Francesca

2018-01-01

Lynch syndrome is an autosomal dominant syndrome that can be subdivided into Lynch syndrome I, or site-specific colonic cancer, and Lynch syndrome II, or extracolonic cancers, particularly carcinomas of the stomach, endometrium, biliary and pancreatic systems, and urinary tract. Lynch syndrome is associated with point mutations and large rearrangements in DNA MisMatch Repair ( MMR ) genes. This syndrome shows a variable phenotypic expression in people who carry pathogenetic mutations. So far, a correlation in genotype-phenotype has not been definitely established. In this study, we describe 2 Lynch syndrome cases presenting with the same genotype but different phenotypes and discuss possible reasons for this.

Loss‐of‐function mutation of rice SLAC7 decreases chloroplast stability and induces a photoprotection mechanism in rice

PubMed Central

Fan, Xiaolei; Wu, Jiemin; Chen, Taiyu; Tie, Weiwei; Chen, Hao; Zhou, Fei

2015-01-01

Abstract Plants absorb sunlight to power the photochemical reactions of photosynthesis, which can potentially damage the photosynthetic machinery. However, the mechanism that protects chloroplasts from the damage remains unclear. In this work, we demonstrated that rice (Oryza sativa L.) SLAC7 is a generally expressed membrane protein. Loss‐of‐function of SLAC7 caused continuous damage to the chloroplasts of mutant leaves under normal light conditions. Ion leakage indicators related to leaf damage such as H2O2 and abscisic acid levels were significantly higher in slac7‐1 than in the wild type. Consistently, the photosynthesis efficiency and Fv/Fm ratio of slac7‐1 were significantly decreased (similar to photoinhibition). In response to chloroplast damage, slac7‐1 altered its leaf morphology (curled or fused leaf) by the synergy between plant hormones and transcriptional factors to decrease the absorption of light, suggesting that a photoprotection mechanism for chloroplast damage was activated in slac7‐1. When grown in dark conditions, slac7‐1 displayed a normal phenotype. SLAC7 under the control of the AtSLAC1 promoter could partially complement the phenotypes of Arabidopsis slac1 mutants, indicating a partial conservation of SLAC protein functions. These results suggest that SLAC7 is essential for maintaining the chloroplast stability in rice. PMID:25739330

Exploring the Phenotypic Space and the Evolutionary History of a Natural Mutation in Drosophila melanogaster.

PubMed

Ullastres, Anna; Petit, Natalia; González, Josefa

2015-07-01

A major challenge of modern Biology is elucidating the functional consequences of natural mutations. Although we have a good understanding of the effects of laboratory-induced mutations on the molecular- and organismal-level phenotypes, the study of natural mutations has lagged behind. In this work, we explore the phenotypic space and the evolutionary history of a previously identified adaptive transposable element insertion. We first combined several tests that capture different signatures of selection to show that there is evidence of positive selection in the regions flanking FBti0019386 insertion. We then explored several phenotypes related to known phenotypic effects of nearby genes, and having plausible connections to fitness variation in nature. We found that flies with FBti0019386 insertion had a shorter developmental time and were more sensitive to stress, which are likely to be the adaptive effect and the cost of selection of this mutation, respectively. Interestingly, these phenotypic effects are not consistent with a role of FBti0019386 in temperate adaptation as has been previously suggested. Indeed, a global analysis of the population frequency of FBti0019386 showed that climatic variables explain well the FBti0019386 frequency patterns only in Australia. Finally, although FBti0019386 insertion could be inducing the formation of heterochromatin by recruiting HP1a (Heterochromatin Protein 1a) protein, the insertion is associated with upregulation of sra in adult females. Overall, our integrative approach allowed us to shed light on the evolutionary history, the relevant fitness effects, and the likely molecular mechanisms of an adaptive mutation and highlights the complexity of natural genetic variants. © The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Phenotypic heterogeneity associated with a novel mutation (Gly112Glu) in the Norrie disease protein.

PubMed

Allen, R C; Russell, S R; Streb, L M; Alsheikheh, A; Stone, E M

2006-02-01

To determine the molecular pathology and clinical severity of two pedigrees with a history of early retinal detachment and peripheral retinal vascular abnormalities. Longitudinal cohort study. A longitudinal clinical study and DNA analysis was performed on 49 family members of two pedigrees. Nine individuals were found to be hemizygous for a mutation at codon 112 (Gly112Glu) of the Norrie disease protein (NDP) in one pedigree. Significant phenotypic heterogeneity was found. The proband presented with a unilateral subtotal retinal detachment at the age of 3 years, and subsequently developed a slowly progressive tractional retinal detachment involving the macula in the contralateral eye at the age of 4 years. One individual had only mild peripheral retinal pigmentary changes with normal vision at the age of 79 years. The remaining seven individuals had varying degrees of peripheral retinal vascular abnormalities and anterior segment findings. Seven affected members of a second pedigree affected by a previously reported mutation, Arg74Cys, also demonstrated wide ocular phenotypic variation. A novel mutation (Gly112Glu), which represents the most carboxy located, NDP mutation reported, results in significant phenotypic heterogeneity. These data support the contention that the spectrum of ocular disease severity associated with these NDP mutations is broad. Use of terms that characterize this entity by phenotypic appearance, such as familial exudative vitreoretinopathy, do not adequately communicate the potential spectrum of severity of this disorder to affected or carrier family members.

Amelogenesis Imperfecta: 1 Family, 2 Phenotypes, and 2 Mutated Genes.

PubMed

Prasad, M K; Laouina, S; El Alloussi, M; Dollfus, H; Bloch-Zupan, A

2016-12-01

Amelogenesis imperfecta (AI) is a clinically and genetically heterogeneous group of diseases characterized by enamel defects. The authors have identified a large consanguineous Moroccan family segregating different clinical subtypes of hypoplastic and hypomineralized AI in different individuals within the family. Using targeted next-generation sequencing, the authors identified a novel heterozygous nonsense mutation in COL17A1 (c.1873C>T, p.R625*) segregating with hypoplastic AI and a novel homozygous 8-bp deletion in C4orf26 (c.39_46del, p.Cys14Glyfs*18) segregating with hypomineralized-hypoplastic AI in this family. This study highlights the phenotypic and genotypic heterogeneity of AI that can exist even within a single consanguineous family. Furthermore, the identification of novel mutations in COL17A1 and C4orf26 and their correlation with distinct AI phenotypes can contribute to a better understanding of the pathophysiology of AI and the contribution of these genes to amelogenesis. © International & American Associations for Dental Research 2016.

The association of multiple interacting genes with specific phenotypes in rice using gene coexpression networks.

PubMed

Ficklin, Stephen P; Luo, Feng; Feltus, F Alex

2010-09-01

Discovering gene sets underlying the expression of a given phenotype is of great importance, as many phenotypes are the result of complex gene-gene interactions. Gene coexpression networks, built using a set of microarray samples as input, can help elucidate tightly coexpressed gene sets (modules) that are mixed with genes of known and unknown function. Functional enrichment analysis of modules further subdivides the coexpressed gene set into cofunctional gene clusters that may coexist in the module with other functionally related gene clusters. In this study, 45 coexpressed gene modules and 76 cofunctional gene clusters were discovered for rice (Oryza sativa) using a global, knowledge-independent paradigm and the combination of two network construction methodologies. Some clusters were enriched for previously characterized mutant phenotypes, providing evidence for specific gene sets (and their annotated molecular functions) that underlie specific phenotypes.

Variability in dentofacial phenotypes in four families with WNT10A mutations

PubMed Central

Vink, Christian P; Ockeloen, Charlotte W; ten Kate, Sietske; Koolen, David A; Ploos van Amstel, Johannes Kristian; Kuijpers-Jagtman, Anne-Marie; van Heumen, Celeste C; Kleefstra, Tjitske; Carels, Carine E L

2014-01-01

This article describes the inter- and intra-familial phenotypic variability in four families with WNT10A mutations. Clinical characteristics of the patients range from mild to severe isolated tooth agenesis, over mild symptoms of ectodermal dysplasia, to more severe syndromic forms like odonto-onycho-dermal dysplasia (OODD) and Schöpf–Schulz–Passarge syndrome (SSPS). Recurrent WNT10A mutations were identified in all affected family members and the associated symptoms are presented with emphasis on the dentofacial phenotypes obtained with inter alia three-dimensional facial stereophotogrammetry. A comprehensive overview of the literature regarding WNT10A mutations, associated conditions and developmental defects is presented. We conclude that OODD and SSPS should be considered as variable expressions of the same WNT10A genotype. In all affected individuals, a dished-in facial appearance was observed which might be helpful in the clinical setting as a clue to the underlying genetic etiology. PMID:24398796

Effect of rice variety on the physicochemical properties of the modified rice powders and their derived mucoadhesive gels.

PubMed

Okonogi, Siriporn; Kaewpinta, Adchareeya; Khongkhunthian, Sakornrat; Yotsawimonwat, Songwut

2015-06-01

In the present study; the glutinous Niaw Sanpatong (NSP) and Niaw Koko-6 (NKK), and the non-glutinous Jasmine (JM) and Saohai (SH) were chemically modified. The difference of these rice varieties on the physicochemical characteristics of the modified rice powders and the properties of the derived gels were evaluated. X-ray diffractometer was used for crystalline structure investigation of the rice powders and gels. A parallel plate rheometer was used to measure the rheological property of the gels. It was found that the non-glutinous varieties produced gels with higher mucoadhesive properties than the glutinous rice. Rheological behavior of JM and SH gels was pseudoplastic without yield value whereas that of NSP and NKK gels was plastic with the yield values of 1077.4 ± 185.9 and 536.1 ± 45.8 millipascals-second (mPas), respectively. These different properties are considered to be due to the amylose content in different rice variety. The results suggest that the non-glutinous rice varieties with high amylose content are the most suitable for preparing gels as local delivery systems via the mucosal membrane.

Genotype–phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in the MPZ gene

PubMed Central

Feely, Shawna; Scherer, Steven S.; Herrmann, David N.; Burns, Joshua; Muntoni, Francesco; Li, Jun; Siskind, Carly E.; Day, John W.; Laura, Matilde; Sumner, Charlotte J.; Lloyd, Thomas E.; Ramchandren, Sindhu; Shy, Rosemary R.; Grider, Tiffany; Bacon, Chelsea; Finkel, Richard S.; Yum, Sabrina W.; Moroni, Isabella; Piscosquito, Giuseppe; Pareyson, Davide; Reilly, Mary M.; Shy, Michael E.

2015-01-01

We aimed to characterize genotype–phenotype correlations and establish baseline clinical data for peripheral neuropathies caused by mutations in the myelin protein zero (MPZ) gene. MPZ mutations are the second leading cause of Charcot–Marie–Tooth disease type 1. Recent research makes clinical trials for patients with MPZ mutations a realistic possibility. However, the clinical severity varies with different mutations and natural history data on progression is sparse. We present cross-sectional data to begin to define the phenotypic spectrum and clinical baseline of patients with these mutations. A cohort of patients with MPZ gene mutations was identified in 13 centres of the Inherited Neuropathies Consortium - Rare Disease Clinical Research Consortium (INC-RDCRC) between 2009 and 2012 and at Wayne State University between 1996 and 2009. Patient phenotypes were quantified by the Charcot–Marie–Tooth disease neuropathy score version 1 or 2 and the Charcot–Marie–Tooth disease paediatric scale outcome instruments. Genetic testing was performed in all patients and/or in first- or second-degree relatives to document mutation in MPZ gene indicating diagnosis of Charcot–Marie–Tooth disease type 1B. There were 103 patients from 71 families with 47 different MPZ mutations with a mean age of 40 years (range 3–84 years). Patients and mutations were separated into infantile, childhood and adult-onset groups. The infantile onset group had higher Charcot–Marie–Tooth disease neuropathy score version 1 or 2 and slower nerve conductions than the other groups, and severity increased with age. Twenty-three patients had no family history of Charcot–Marie–Tooth disease. Sixty-one patients wore foot/ankle orthoses, 19 required walking assistance or support, and 10 required wheelchairs. There was hearing loss in 21 and scoliosis in 17. Forty-two patients did not begin walking until after 15 months of age. Half of the infantile onset patients then required

Understanding the molecular mechanisms of rice blast resistance using rice mutants

USDA-ARS?s Scientific Manuscript database

Induced mutation can be useful for studying resistance gene controlled plant immunity. Resulting knowledge should benefit the development of strategies for crop protection. The Pi-ta gene in rice has been effectively deployed for preventing rice blast disease-the most devastating disease of rice wo...

The role of Bh4 in parallel evolution of hull colour in domesticated and weedy rice.

PubMed

Vigueira, C C; Li, W; Olsen, K M

2013-08-01

The two independent domestication events in the genus Oryza that led to African and Asian rice offer an extremely useful system for studying the genetic basis of parallel evolution. This system is also characterized by parallel de-domestication events, with two genetically distinct weedy rice biotypes in the US derived from the Asian domesticate. One important trait that has been altered by rice domestication and de-domestication is hull colour. The wild progenitors of the two cultivated rice species have predominantly black-coloured hulls, as does one of the two U.S. weed biotypes; both cultivated species and one of the US weedy biotypes are characterized by straw-coloured hulls. Using Black hull 4 (Bh4) as a hull colour candidate gene, we examined DNA sequence variation at this locus to study the parallel evolution of hull colour variation in the domesticated and weedy rice system. We find that independent Bh4-coding mutations have arisen in African and Asian rice that are correlated with the straw hull phenotype, suggesting that the same gene is responsible for parallel trait evolution. For the U.S. weeds, Bh4 haplotype sequences support current hypotheses on the phylogenetic relationship between the two biotypes and domesticated Asian rice; straw hull weeds are most similar to indica crops, and black hull weeds are most similar to aus crops. Tests for selection indicate that Asian crops and straw hull weeds deviate from neutrality at this gene, suggesting possible selection on Bh4 during both rice domestication and de-domestication. © 2013 The Authors. Journal of Evolutionary Biology © 2013 European Society For Evolutionary Biology.

Inactivating Mutations in ESCO2 Cause SC Phocomelia and Roberts Syndrome: No Phenotype-Genotype Correlation

PubMed Central

Schüle, Birgitt; Oviedo, Angelica; Johnston, Kathreen; Pai, Shashidhar; Francke, Uta

2005-01-01

The rare, autosomal recessive Roberts syndrome (RBS) is characterized by tetraphocomelia, profound growth deficiency of prenatal onset, craniofacial anomalies, microcephaly, and mental deficiency. SC phocomelia (SC) has a milder phenotype, with a lesser degree of limb reduction and with survival to adulthood. Since heterochromatin repulsion (HR) is characteristic for both disorders and is not complemented in somatic-cell hybrids, it has been hypothesized that the disorders are allelic. Recently, mutations in ESCO2 (establishment of cohesion 1 homolog 2) on 8p21.1 have been reported in RBS. To determine whether ESCO2 mutations are also responsible for SC, we studied three families with SC and two families in which variable degrees of limb and craniofacial abnormalities, detected by fetal ultrasound, led to pregnancy terminations. All cases were positive for HR. We identified seven novel mutations in exons 3–8 of ESCO2. In two families, affected individuals were homozygous—for a 5-nucleotide deletion in one family and a splice-site mutation in the other. In three nonconsanguineous families, probands were compound heterozygous for a single-nucleotide insertion or deletion, a nonsense mutation, or a splice-site mutation. Abnormal splice products were characterized at the RNA level. Since only protein-truncating mutations were identified, regardless of clinical severity, we conclude that genotype does not predict phenotype. Having established that RBS and SC are caused by mutations in the same gene, we delineated the clinical phenotype of the tetraphocomelia spectrum that is associated with HR and ESCO2 mutations and differentiated it from other types of phocomelia that are negative for HR. PMID:16380922

In silico analysis of a disease-causing mutation in PCDH15 gene in a consanguineous Pakistani family with Usher phenotype.

PubMed

Saleha, Shamim; Ajmal, Muhammad; Jamil, Muhammad; Nasir, Muhammad; Hameed, Abdul

2016-01-01

To map Usher phenotype in a consanguineous Pakistani family and identify disease-associated mutation in a causative gene to establish phenotype-genotype correlation. A consanguineous Pakistani family in which Usher phenotype was segregating as an autosomal recessive trait was ascertained. On the basis of results of clinical investigations of affected members of this family disease was diagnosed as Usher syndrome (USH). To identify the locus responsible for the Usher phenotype in this family, genomic DNA from blood sample of each individual was genotyped using microsatellite Short Tandem Repeat (STR) markers for the known Usher syndrome loci. Then direct sequencing was performed to find out disease associated mutations in the candidate gene. By genetic linkage analysis, the USH phenotype of this family was mapped to PCDH15 locus on chromosome 10q21.1. Three different point mutations in exon 11 of PCDH15 were identified and one of them, c.1304A>C was found to be segregating with the disease phenotype in Pakistani family with Usher phenotype. This, c.1304A>C transversion mutation predicts an amino-acid substitution of aspartic acid with an alanine at residue number 435 (p.D435A) of its protein product. Moreover, in silico analysis revealed conservation of aspartic acid at position 435 and predicated this change as pathogenic. The identification of c.1304A>C pathogenic mutation in PCDH15 gene and its association with Usher syndrome in a consanguineous Pakistani family is the first example of a missense mutation of PCDH15 causing USH1 phenotype. In previous reports, it was hypothesized that severe mutations such as truncated protein of PCDH15 led to the Usher I phenotype and that missense variants are mainly responsible for non-syndromic hearing impairment.

Protein model discrimination using mutational sensitivity derived from deep sequencing.

PubMed

Adkar, Bharat V; Tripathi, Arti; Sahoo, Anusmita; Bajaj, Kanika; Goswami, Devrishi; Chakrabarti, Purbani; Swarnkar, Mohit K; Gokhale, Rajesh S; Varadarajan, Raghavan

2012-02-08

A major bottleneck in protein structure prediction is the selection of correct models from a pool of decoys. Relative activities of ∼1,200 individual single-site mutants in a saturation library of the bacterial toxin CcdB were estimated by determining their relative populations using deep sequencing. This phenotypic information was used to define an empirical score for each residue (RankScore), which correlated with the residue depth, and identify active-site residues. Using these correlations, ∼98% of correct models of CcdB (RMSD ≤ 4Å) were identified from a large set of decoys. The model-discrimination methodology was further validated on eleven different monomeric proteins using simulated RankScore values. The methodology is also a rapid, accurate way to obtain relative activities of each mutant in a large pool and derive sequence-structure-function relationships without protein isolation or characterization. It can be applied to any system in which mutational effects can be monitored by a phenotypic readout. Copyright © 2012 Elsevier Ltd. All rights reserved.

Mutation of the Diamond-Blackfan Anemia Gene Rps7 in Mouse Results in Morphological and Neuroanatomical Phenotypes

PubMed Central

Watkins-Chow, Dawn E.; Cooke, Joanna; Pidsley, Ruth; Edwards, Andrew; Slotkin, Rebecca; Leeds, Karen E.; Mullen, Raymond; Baxter, Laura L.; Campbell, Thomas G.; Salzer, Marion C.; Biondini, Laura; Gibney, Gretchen; Phan Dinh Tuy, Françoise; Chelly, Jamel; Morris, H. Douglas; Riegler, Johannes; Lythgoe, Mark F.; Arkell, Ruth M.; Loreni, Fabrizio; Flint, Jonathan

2013-01-01

The ribosome is an evolutionarily conserved organelle essential for cellular function. Ribosome construction requires assembly of approximately 80 different ribosomal proteins (RPs) and four different species of rRNA. As RPs co-assemble into one multi-subunit complex, mutation of the genes that encode RPs might be expected to give rise to phenocopies, in which the same phenotype is associated with loss-of-function of each individual gene. However, a more complex picture is emerging in which, in addition to a group of shared phenotypes, diverse RP gene-specific phenotypes are observed. Here we report the first two mouse mutations (Rps7Mtu and Rps7Zma) of ribosomal protein S7 (Rps7), a gene that has been implicated in Diamond-Blackfan anemia. Rps7 disruption results in decreased body size, abnormal skeletal morphology, mid-ventral white spotting, and eye malformations. These phenotypes are reported in other murine RP mutants and, as demonstrated for some other RP mutations, are ameliorated by Trp53 deficiency. Interestingly, Rps7 mutants have additional overt malformations of the developing central nervous system and deficits in working memory, phenotypes that are not reported in murine or human RP gene mutants. Conversely, Rps7 mouse mutants show no anemia or hyperpigmentation, phenotypes associated with mutation of human RPS7 and other murine RPs, respectively. We provide two novel RP mouse models and expand the repertoire of potential phenotypes that should be examined in RP mutants to further explore the concept of RP gene-specific phenotypes. PMID:23382688

A novel missense mutation in the gene EDARADD associated with an unusual phenotype of hypohidrotic ectodermal dysplasia.

PubMed

Wohlfart, Sigrun; Söder, Stephan; Smahi, Asma; Schneider, Holm

2016-01-01

Hypohidrotic ectodermal dysplasia (HED) is a rare disorder characterized by deficient development of structures derived from the ectoderm including hair, nails, eccrine glands, and teeth. HED forms that are caused by mutations in the genes EDA, EDAR, or EDARADD may show almost identical phenotypes, explained by a common signaling pathway. Proper interaction of the proteins encoded by these three genes is important for the activation of the NF-κB signaling pathway and subsequent transcription of the target genes. Mutations in the gene EDARADD are most rarely implicated in HED. Here we describe a novel missense mutation, c.367G>A (p.Asp123Asn), in this gene which did not appear to influence the interaction between EDAR and EDARADD proteins, but led to an impaired ability to activate NF-κB signaling. Female members of the affected family showed either unilateral or bilateral amazia. In addition, an affected girl developed bilateral ovarian teratomas, possibly associated with her genetic condition. © 2015 Wiley Periodicals, Inc.

Molecular spectrum of somaclonal variation in regenerated rice revealed by whole-genome sequencing.

PubMed

Miyao, Akio; Nakagome, Mariko; Ohnuma, Takako; Yamagata, Harumi; Kanamori, Hiroyuki; Katayose, Yuichi; Takahashi, Akira; Matsumoto, Takashi; Hirochika, Hirohiko

2012-01-01

Somaclonal variation is a phenomenon that results in the phenotypic variation of plants regenerated from cell culture. One of the causes of somaclonal variation in rice is the transposition of retrotransposons. However, many aspects of the mechanisms that result in somaclonal variation remain undefined. To detect genome-wide changes in regenerated rice, we analyzed the whole-genome sequences of three plants independently regenerated from cultured cells originating from a single seed stock. Many single-nucleotide polymorphisms (SNPs) and insertions and deletions (indels) were detected in the genomes of the regenerated plants. The transposition of only Tos17 among 43 transposons examined was detected in the regenerated plants. Therefore, the SNPs and indels contribute to the somaclonal variation in regenerated rice in addition to the transposition of Tos17. The observed molecular spectrum was similar to that of the spontaneous mutations in Arabidopsis thaliana. However, the base change ratio was estimated to be 1.74 × 10(-6) base substitutions per site per regeneration, which is 248-fold greater than the spontaneous mutation rate of A. thaliana.

Phenotypic Variability of Osteogenesis Imperfecta Type V Caused by an IFITM5 Mutation

PubMed Central

Shapiro, Jay R; Lietman, Caressa; Grover, Monica; Lu, James T; Nagamani, Sandesh CS; Dawson, Brian C; Baldridge, Dustin M; Bainbridge, Matthew N; Cohn, Dan H; Blazo, Maria; Roberts, Timothy T; Brennen, Feng-Shu; Wu, Yimei; Gibbs, Richard A; Melvin, Pamela; Campeau, Philippe M; Lee, Brendan H

2013-01-01

In a large cohort of osteogenesis imperfecta type V (OI type V) patients (17 individuals from 12 families), we identified the same mutation in the 5′ untranslated region (5′UTR) of the interferon-induced transmembrane protein 5 (IFITM5) gene by whole exome and Sanger sequencing (IFITM5 c.–14C > T) and provide a detailed description of their phenotype. This mutation leads to the creation of a novel start codon adding five residues to IFITM5 and was recently reported in several other OI type V families. The variability of the phenotype was quite large even within families. Whereas some patients presented with the typical calcification of the forearm interosseous membrane, radial head dislocation and hyperplastic callus (HPC) formation following fractures, others had only some of the typical OI type V findings. Thirteen had calcification of interosseous membranes, 14 had radial head dislocations, 10 had HPC, 9 had long bone bowing, 11 could ambulate without assistance, and 1 had mild unilateral mixed hearing loss. The bone mineral density varied greatly, even within families. Our study thus highlights the phenotypic variability of OI type V caused by the IFITM5 mutation. PMID:23408678

Phenotype diversity analysis of red-grained rice landraces from Yuanyang Hani's terraced fields, China

NASA Astrophysics Data System (ADS)

Li, Lianjie; Cheng, Long

2017-10-01

There are many areas in the world have terraced fields, Yuanyang Rani's terraced fields are examples in the world, and their unique ecological diversity is beyond other terraced fields, rice landraces are very rich. In order to provide useful information for protection and utilization of red-grained rice landraces from Rani's terraced fields, 61 red-grained rice landraces were assessed based 20 quantitative traits. Principal component analysis (PCA) suggested that 20 quantitative characters could be simplified to seven principal components, and their accumulative contribution ration amounted to 78.699%. The first principal component (PC1) explained 18.375% of the total variance, which was contributed by filled grain number, 1000-grain weight, spikelets per panicle, secondary branch number, grain length, and grain thickness. PC2 accounted for 16.548% of the variance and featured flag leaf width, flag leaf area, panicle neck length and primary branch number. These traits were the most effective parameters to discriminate individuals. At the request of the proceedings editor and with the approval of all authors, article 040111 titled, "Phenotype diversity analysis of red-grained rice landraces from Yuanyang Hani's terraced fields, China," is being retracted from the public record due to the fact that it is a duplication of article 040110 published in the same volume.

Three new PAX6 mutations including one causing an unusual ophthalmic phenotype associated with neurodevelopmental abnormalities.

PubMed

Dansault, Anouk; David, Gabriel; Schwartz, Claire; Jaliffa, Carolina; Vieira, Véronique; de la Houssaye, Guillaume; Bigot, Karine; Catin, Françise; Tattu, Laurent; Chopin, Catherine; Halimi, Philippe; Roche, Olivier; Van Regemorter, Nicole; Munier, Francis; Schorderet, Daniel; Dufier, Jean-Louis; Marsac, Cécile; Ricquier, Daniel; Menasche, Maurice; Penfornis, Alfred; Abitbol, Marc

2007-04-02

The PAX6 gene was first described as a candidate for human aniridia. However, PAX6 expression is not restricted to the eye and it appears to be crucial for brain development. We studied PAX6 mutations in a large spectrum of patients who presented with aniridia phenotypes, Peters' anomaly, and anterior segment malformations associated or not with neurological anomalies. Patients and related families were ophthalmologically phenotyped, and in some cases neurologically and endocrinologically examined. We screened the PAX6 gene by direct sequencing in three groups of patients: those affected by aniridia; those with diverse ocular manifestations; and those with Peters' anomaly. Two mutations were investigated by generating crystallographic representations of the amino acid changes. Three novel heterozygous mutations affecting three unrelated families were identified: the g.572T>C nucleotide change, located in exon 5, and corresponding to the Leucine 46 Proline amino-acid mutation (L46P); the g.655A>G nucleotide change, located in exon 6, and corresponding to the Serine 74 Glycine amino-acid mutation (S74G); and the nucleotide deletion 579delG del, located in exon 6, which induces a frameshift mutation leading to a stop codon (V48fsX53). The L46P mutation was identified in affected patients presenting bilateral microphthalmia, cataracts, and nystagmus. The S74G mutation was found in a large family that had congenital ocular abnormalities, diverse neurological manifestations, and variable cognitive impairments. The 579delG deletion (V48fsX53) caused in the affected members of the same family bilateral aniridia associated with congenital cataract, foveal hypolasia, and nystagmus. We also detected a novel intronic nucleotide change, IVS2+9G>A (very likely a mutation) in an apparently isolated patient affected by a complex ocular phenotype, characterized primarily by a bilateral microphthalmia. Whether this nucleotide change is indeed pathogenic remains to be demonstrated

Three new PAX6 mutations including one causing an unusual ophthalmic phenotype associated with neurodevelopmental abnormalities

PubMed Central

Dansault, Anouk; David, Gabriel; Schwartz, Claire; Jaliffa, Carolina; Vieira, Véronique; de la Houssaye, Guillaume; Bigot, Karine; Catin, Françise; Tattu, Laurent; Chopin, Catherine; Halimi, Philippe; Roche, Olivier; Van Regemorter, Nicole; Munier, Francis; Schorderet, Daniel; Dufier, Jean-Louis; Marsac, Cécile; Ricquier, Daniel; Menasche, Maurice; Penfornis, Alfred

2007-01-01

Purpose The PAX6 gene was first described as a candidate for human aniridia. However, PAX6 expression is not restricted to the eye and it appears to be crucial for brain development. We studied PAX6 mutations in a large spectrum of patients who presented with aniridia phenotypes, Peters' anomaly, and anterior segment malformations associated or not with neurological anomalies. Methods Patients and related families were ophthalmologically phenotyped, and in some cases neurologically and endocrinologically examined. We screened the PAX6 gene by direct sequencing in three groups of patients: those affected by aniridia; those with diverse ocular manifestations; and those with Peters' anomaly. Two mutations were investigated by generating crystallographic representations of the amino acid changes. Results Three novel heterozygous mutations affecting three unrelated families were identified: the g.572T>C nucleotide change, located in exon 5, and corresponding to the Leucine 46 Proline amino-acid mutation (L46P); the g.655A>G nucleotide change, located in exon 6, and corresponding to the Serine 74 Glycine amino-acid mutation (S74G); and the nucleotide deletion 579delG del, located in exon 6, which induces a frameshift mutation leading to a stop codon (V48fsX53). The L46P mutation was identified in affected patients presenting bilateral microphthalmia, cataracts, and nystagmus. The S74G mutation was found in a large family that had congenital ocular abnormalities, diverse neurological manifestations, and variable cognitive impairments. The 579delG deletion (V48fsX53) caused in the affected members of the same family bilateral aniridia associated with congenital cataract, foveal hypolasia, and nystagmus. We also detected a novel intronic nucleotide change, IVS2+9G>A (very likely a mutation) in an apparently isolated patient affected by a complex ocular phenotype, characterized primarily by a bilateral microphthalmia. Whether this nucleotide change is indeed pathogenic

Isolation and characterisation of a dwarf rice mutant exhibiting defective gibberellins biosynthesis.

PubMed

Ji, S H; Gururani, M A; Lee, J W; Ahn, B-O; Chun, S-C

2014-03-01

We have isolated a severe dwarf mutant derived from a Ds (Dissociation) insertion mutant rice (Oryza sativa var. japonica c.v. Dongjin). This severe dwarf phenotype, has short and dark green leaves, reduced shoot growth early in the seedling stage, and later severe dwarfism with failure to initiate flowering. When treated with bioactive GA3 , mutants are restored to the normal wild-type phenotype. Reverse transcription PCR analyses of 22 candidate genes related to the gibberellin (GA) biosynthesis pathway revealed that among 22 candidate genes tested, a dwarf mutant transcript was not expressed only in one OsKS2 gene. Genetic analysis revealed that the severe dwarf phenotype was controlled by recessive mutation of a single nuclear gene. The putative OsKS2 gene was a chromosome 4-located ent-kaurene synthase (KS), encoding the enzyme that catalyses an early step of the GA biosynthesis pathway. Sequence analysis revealed that osks2 carried a 1-bp deletion in the ORF region of OsKS2, which led to a loss-of-function mutation. The expression pattern of OsKS2 in wild-type cv Dongjin, showed that it is expressed in all organs, most prominently in the stem and floral organs. Morphological characteristics of the dwarf mutant showed dramatic modifications in internal structure and external morphology. We propose that dwarfism in this mutant is caused by a point mutation in OsKS2, which plays a significant role in growth and development of higher plants. Further investigation on OsKS2 and other OsKS-like proteins is underway and may yield better understanding of the putative role of OsKS in severe dwarf mutants. © 2013 German Botanical Society and The Royal Botanical Society of the Netherlands.

Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype.

PubMed

Tatton-Brown, Katrina; Murray, Anne; Hanks, Sandra; Douglas, Jenny; Armstrong, Ruth; Banka, Siddharth; Bird, Lynne M; Clericuzio, Carol L; Cormier-Daire, Valerie; Cushing, Tom; Flinter, Frances; Jacquemont, Marie-Line; Joss, Shelagh; Kinning, Esther; Lynch, Sally Ann; Magee, Alex; McConnell, Vivienne; Medeira, Ana; Ozono, Keiichi; Patton, Michael; Rankin, Julia; Shears, Debbie; Simon, Marleen; Splitt, Miranda; Strenger, Volker; Stuurman, Kyra; Taylor, Clare; Titheradge, Hannah; Van Maldergem, Lionel; Temple, I Karen; Cole, Trevor; Seal, Sheila; Rahman, Nazneen

2013-12-01

Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with EZH2 mutations. The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain. Through analyses of clinical data and facial photographs of EZH2 mutation-positive individuals, we have shown that the facial features can be subtle and the clinical diagnosis of Weaver syndrome is thus challenging, especially in older individuals. However, tall stature is very common, reported in >90% of affected individuals. Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild. Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry. Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. As mutation testing becomes increasingly accessible and larger numbers of EZH2 mutation-positive individuals are identified, knowledge of the clinical spectrum and prognostic implications of EZH2 mutations should improve. © 2013 Wiley Periodicals, Inc.

Somatic frameshift mutations in the Bloom syndrome BLM gene are frequent in sporadic gastric carcinomas with microsatellite mutator phenotype

PubMed Central

Calin, George; Ranzani, Guglielmina N; Amadori, Dino; Herlea, Vlad; Matei, Irina; Barbanti-Brodano, Giuseppe; Negrini, Massimo

2001-01-01

Background Genomic instability has been reported at microsatellite tracts in few coding sequences. We have shown that the Bloom syndrome BLM gene may be a target of microsatelliteinstability (MSI) in a short poly-adenine repeat located in its coding region. To further characterize the involvement of BLM in tumorigenesis, we have investigated mutations in nine genes containing coding microsatellites in microsatellite mutator phenotype (MMP) positive and negative gastric carcinomas (GCs). Methods We analyzed 50 gastric carcinomas (GCs) for mutations in the BLM poly(A) tract aswell as in the coding microsatellites of the TGFβ1-RII, IGFIIR, hMSH3, hMSH6, BAX, WRN, RECQL and CBL genes. Results BLM mutations were found in 27% of MMP+ GCs (4/15 cases) but not in any of the MMP negative GCs (0/35 cases). The frequency of mutations in the other eight coding regions microsatellite was the following: TGFβ1-RII (60 %), BAX (27%), hMSH6 (20%),hMSH3 (13%), CBL (13%), IGFIIR (7%), RECQL (0%) and WRN (0%). Mutations in BLM appear to be more frequently associated with frameshifts in BAX and in hMSH6and/or hMSH3. Tumors with BLM alterations present a higher frequency of unstable mono- and trinucleotide repeats located in coding regions as compared with mutator phenotype tumors without BLM frameshifts. Conclusions BLM frameshifts are frequent alterations in GCs specifically associated with MMP+tumors. We suggest that BLM loss of function by MSI may increase the genetic instability of a pre-existent unstable genotype in gastric tumors. PMID:11532193

Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU.

PubMed

Depienne, Christel; Nava, Caroline; Keren, Boris; Heide, Solveig; Rastetter, Agnès; Passemard, Sandrine; Chantot-Bastaraud, Sandra; Moutard, Marie-Laure; Agrawal, Pankaj B; VanNoy, Grace; Stoler, Joan M; Amor, David J; Billette de Villemeur, Thierry; Doummar, Diane; Alby, Caroline; Cormier-Daire, Valérie; Garel, Catherine; Marzin, Pauline; Scheidecker, Sophie; de Saint-Martin, Anne; Hirsch, Edouard; Korff, Christian; Bottani, Armand; Faivre, Laurence; Verloes, Alain; Orzechowski, Christine; Burglen, Lydie; Leheup, Bruno; Roume, Joelle; Andrieux, Joris; Sheth, Frenny; Datar, Chaitanya; Parker, Michael J; Pasquier, Laurent; Odent, Sylvie; Naudion, Sophie; Delrue, Marie-Ange; Le Caignec, Cédric; Vincent, Marie; Isidor, Bertrand; Renaldo, Florence; Stewart, Fiona; Toutain, Annick; Koehler, Udo; Häckl, Birgit; von Stülpnagel, Celina; Kluger, Gerhard; Møller, Rikke S; Pal, Deb; Jonson, Tord; Soller, Maria; Verbeek, Nienke E; van Haelst, Mieke M; de Kovel, Carolien; Koeleman, Bobby; Monroe, Glen; van Haaften, Gijs; Attié-Bitach, Tania; Boutaud, Lucile; Héron, Delphine; Mignot, Cyril

2017-04-01

Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans.

Gene flow from transgenic rice to red rice (Oryza sativa L.) in the field.

PubMed

Busconi, M; Baldi, G; Lorenzoni, C; Fogher, C

2014-01-01

In this study, we simulate a transgenic rice crop highly infested with red rice to examine transgene transfer from a transgenic line (A2504) resistant to glufosinate ammonium to cohabitant red rice. The red rice was sown along with the transgenic line at the highest density found in naturally infested crops in the region. Agricultural practices similar to those used to control red rice infestation in northern Italy rice fields were used to reproduce the local rice production system. During the first 2 years, the field was treated with herbicide at the appropriate time; in the first year the dosage of herbicide was three times the recommended amount. In this first year, detectable red rice plants that escaped herbicide treatment were manually removed. Nevertheless, two herbicide-resistant hybrid plants (named 101 and 104) were identified in the experimental field during the second year of cultivation. Phenotypic and molecular characterisation suggests the hybrid nature of these two plants, deriving from crossing events involving A2504, respectively, with red rice (plant 101) and the buffer cultivar Gladio (plant 104). The progeny of two subsequent generations of the two plants were examined and the presence of the transgene detected, indicating stable transfer of the transgene across generations. In conclusion, despite control methods, red rice progeny tolerant to the herbicide can be expected following use of transgenic rice and, consequently, difficulties in controlling this weed with chemicals will emerge in a relatively short time. © 2013 German Botanical Society and The Royal Botanical Society of the Netherlands.

A homozygous PMS2 founder mutation with an attenuated constitutional mismatch repair deficiency phenotype.

PubMed

Li, Lili; Hamel, Nancy; Baker, Kristi; McGuffin, Michael J; Couillard, Martin; Gologan, Adrian; Marcus, Victoria A; Chodirker, Bernard; Chudley, Albert; Stefanovici, Camelia; Durandy, Anne; Hegele, Robert A; Feng, Bing-Jian; Goldgar, David E; Zhu, Jun; De Rosa, Marina; Gruber, Stephen B; Wimmer, Katharina; Young, Barbara; Chong, George; Tischkowitz, Marc D; Foulkes, William D

2015-05-01

Inherited mutations in DNA mismatch repair genes predispose to different cancer syndromes depending on whether they are mono-allelic or bi-allelic. This supports a causal relationship between expression level in the germline and phenotype variation. As a model to study this relationship, our study aimed to define the pathogenic characteristics of a recurrent homozygous coding variant in PMS2 displaying an attenuated phenotype identified by clinical genetic testing in seven Inuit families from Northern Quebec. Pathogenic characteristics of the PMS2 mutation NM_000535.5:c.2002A>G were studied using genotype-phenotype correlation, single-molecule expression detection and single genome microsatellite instability analysis. This PMS2 mutation generates a de novo splice site that competes with the authentic site. In homozygotes, expression of the full-length protein is reduced to a level barely detectable by conventional diagnostics. Median age at primary cancer diagnosis is 22 years among 13 NM_000535.5:c.2002A>G homozygotes, versus 8 years in individuals carrying bi-allelic truncating mutations. Residual expression of full-length PMS2 transcript was detected in normal tissues from homozygotes with cancers in their 20s. Our genotype-phenotype study of c.2002A>G illustrates that an extremely low level of PMS2 expression likely delays cancer onset, a feature that could be exploited in cancer preventive intervention. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Characterization and genetic mapping of a Photoperiod-sensitive dwarf 1 locus in rice (Oryza sativa L.).

PubMed

Li, Riqing; Xia, Jixing; Xu, Yiwei; Zhao, Xiucai; Liu, Yao-Guang; Chen, Yuanling

2014-01-01

Plant height is an important agronomic trait for crop architecture and yield. Most known factors determining plant height function in gibberellin or brassinosteroid biosynthesis or signal transduction. Here, we report a japonica rice (Oryza sativa ssp. japonica) dominant dwarf mutant, Photoperiod-sensitive dwarf 1 (Psd1). The Psd1 mutant showed impaired cell division and elongation, and a severe dwarf phenotype under long-day conditions, but nearly normal growth in short-day. The plant height of Psd1 mutant could not be rescued by gibberellin or brassinosteroid treatment. Genetic analysis with R1 and F2 populations determined that Psd1 phenotype was controlled by a single dominant locus. Linkage analysis with 101 tall F2 plants grown in a long-day season, which were derived from a cross between Psd1 and an indica cultivar, located Psd1 locus on chromosome 1. Further fine-mapping with 1017 tall F2 plants determined this locus on an 11.5-kb region. Sequencing analysis of this region detected a mutation site in a gene encoding a putative lipid transfer protein; the mutation produces a truncated C-terminus of the protein. This study establishes the genetic foundation for understanding the molecular mechanisms regulating plant cell division and elongation mediated by interaction between genetic and environmental factors.

Binge eating as a major phenotype of melanocortin 4 receptor gene mutations.

PubMed

Branson, Ruth; Potoczna, Natascha; Kral, John G; Lentes, Klaus-Ulrich; Hoehe, Margret R; Horber, Fritz F

2003-03-20

Obesity, a multifactorial disease caused by the interaction of genetic factors with the environment, is largely polygenic. A few mutations in these genes, such as in the leptin receptor (LEPR) gene and melanocortin 4 receptor (MC4R) gene, have been identified as causes of monogenic obesity. We sequenced the complete MC4R coding region, the region of the proopiomelanocortin gene (POMC) encoding the alpha melanocyte-stimulating hormone, and the leptin-binding domain of LEPR in 469 severely obese white subjects (370 women and 99 men; mean [+/-SE] age, 41.0+/-0.5 years; body-mass index [the weight in kilograms divided by the square of the height in meters], 44.1+/-2.0). Fifteen women and 10 men without a history of dieting or a family history of obesity served as normal-weight controls (age, 47.7+/-2.0 years; body-mass index, 21.6+/-0.4). Detailed phenotypic data, including information on body fat, resting energy expenditure, diet-induced thermogenesis, serum concentrations of leptin, and eating behavior, were collected. Twenty-four obese subjects (5.1 percent) and one control subject (4 percent) had MC4R mutations, including five novel variants. Twenty of the 24 obese subjects with an MC4R mutation were matched for age, sex, and body-mass index with 120 of the 445 obese subjects without an MC4R mutation. All mutation carriers reported binge eating, as compared with 14.2 percent of obese subjects without mutations (P<0.001) and 0 percent of the normal-weight subjects without mutations. The prevalence of binge eating was similar among carriers of mutations in the leptin-binding domain of LEPR and noncarriers. No mutations were found in the region of POMC encoding alpha melanocyte-stimulating hormone. Binge eating is a major phenotypic characteristic of subjects with a mutation in MC4R, a candidate gene for the control of eating behavior. Copyright 2003 Massachusetts Medical Society

Linkage Mapping of Stem Saccharification Digestibility in Rice

PubMed Central

Hua, Cangmei; Sun, Lili; Ali, Imran; Huang, Linli; Yu, Chunyan; Simister, Rachael; Steele-King, Clare; Gan, Yinbo; McQueen-Mason, Simon J.

2016-01-01

Rice is the staple food of almost half of the world population, and in excess 90% of it is grown and consumed in Asia, but the disposal of rice straw poses a problem for farmers, who often burn it in the fields, causing health and environmental problems. However, with increased focus on the development of sustainable biofuel production, rice straw has been recognized as a potential feedstock for non-food derived biofuel production. Currently, the commercial realization of rice as a biofuel feedstock is constrained by the high cost of industrial saccharification processes needed to release sugar for fermentation. This study is focused on the alteration of lignin content, and cell wall chemotypes and structures, and their effects on the saccharification potential of rice lignocellulosic biomass. A recombinant inbred lines (RILs) population derived from a cross between the lowland rice variety IR1552 and the upland rice variety Azucena with 271 molecular markers for quantitative trait SNP (QTS) analyses was used. After association analysis of 271 markers for saccharification potential, 1 locus and 4 pairs of epistatic loci were found to contribute to the enzymatic digestibility phenotype, and an inverse relationship between reducing sugar and lignin content in these recombinant inbred lines was identified. As a result of QTS analyses, several cell-wall associated candidate genes are proposed that may be useful for marker-assisted breeding and may aid breeders to produce potential high saccharification rice varieties. PMID:27415441

Interplay between DMD Point Mutations and Splicing Signals in Dystrophinopathy Phenotypes

PubMed Central

Juan-Mateu, Jonàs; González-Quereda, Lidia; Rodríguez, Maria José; Verdura, Edgard; Lázaro, Kira; Jou, Cristina; Nascimento, Andrés; Jiménez-Mallebrera, Cecilia; Colomer, Jaume; Monges, Soledad; Lubieniecki, Fabiana; Foncuberta, Maria Eugenia; Pascual-Pascual, Samuel Ignacio; Molano, Jesús; Baiget, Montserrat; Gallano, Pia

2013-01-01

DMD nonsense and frameshift mutations lead to severe Duchenne muscular dystrophy while in-frame mutations lead to milder Becker muscular dystrophy. Exceptions are found in 10% of cases and the production of alternatively spliced transcripts is considered a key modifier of disease severity. Several exonic mutations have been shown to induce exon-skipping, while splice site mutations result in exon-skipping or activation of cryptic splice sites. However, factors determining the splicing pathway are still unclear. Point mutations provide valuable information regarding the regulation of pre-mRNA splicing and elements defining exon identity in the DMD gene. Here we provide a comprehensive analysis of 98 point mutations related to clinical phenotype and their effect on muscle mRNA and dystrophin expression. Aberrant splicing was found in 27 mutations due to alteration of splice sites or splicing regulatory elements. Bioinformatics analysis was performed to test the ability of the available algorithms to predict consequences on mRNA and to investigate the major factors that determine the splicing pathway in mutations affecting splicing signals. Our findings suggest that the splicing pathway is highly dependent on the interplay between splice site strength and density of regulatory elements. PMID:23536893

Gibberellin regulates pollen viability and pollen tube growth in rice.

PubMed

Chhun, Tory; Aya, Koichiro; Asano, Kenji; Yamamoto, Eiji; Morinaka, Yoichi; Watanabe, Masao; Kitano, Hidemi; Ashikari, Motoyuki; Matsuoka, Makoto; Ueguchi-Tanaka, Miyako

2007-12-01

Gibberellins (GAs) play many biological roles in higher plants. We collected and performed genetic analysis on rice (Oryza sativa) GA-related mutants, including GA-deficient and GA-insensitive mutants. Genetic analysis of the mutants revealed that rice GA-deficient mutations are not transmitted as Mendelian traits to the next generation following self-pollination of F1 heterozygous plants, although GA-insensitive mutations are transmitted normally. To understand these differences in transmission, we examined the effect of GA on microsporogenesis and pollen tube elongation in rice using new GA-deficient and GA-insensitive mutants that produce semifertile flowers. Phenotypic analysis revealed that the GA-deficient mutant reduced pollen elongation1 is defective in pollen tube elongation, resulting in a low fertilization frequency, whereas the GA-insensitive semidominant mutant Slr1-d3 is mainly defective in viable pollen production. Quantitative RT-PCR revealed that GA biosynthesis genes tested whose mutations are transmitted to the next generation at a lower frequency are preferentially expressed after meiosis during pollen development, but expression is absent or very low before the meiosis stage, whereas GA signal-related genes are actively expressed before meiosis. Based on these observations, we predict that the transmission of GA-signaling genes occurs in a sporophytic manner, since the protein products and/or mRNA transcripts of these genes may be introduced into pollen-carrying mutant alleles, whereas GA synthesis genes are transmitted in a gametophytic manner, since these genes are preferentially expressed after meiosis.

Novel mutations and phenotypic associations identified through APC, MUTYH, NTHL1, POLD1, POLE gene analysis in Indian Familial Adenomatous Polyposis cohort.

PubMed

Khan, Nikhat; Lipsa, Anuja; Arunachal, Gautham; Ramadwar, Mukta; Sarin, Rajiv

2017-05-22

Colo-Rectal Cancer is a common cancer worldwide with 5-10% cases being hereditary. Familial Adenomatous Polyposis (FAP) syndrome is due to germline mutations in the APC or rarely MUTYH gene. NTHL1, POLD1, POLE have been recently reported in previously unexplained FAP cases. Unlike the Caucasian population, FAP phenotype and its genotypic associations have not been widely studied in several geoethnic groups. We report the first FAP cohort from South Asia and the only non-Caucasian cohort with comprehensive analysis of APC, MUTYH, NTHL1, POLD1, POLE genes. In this cohort of 112 individuals from 53 FAP families, we detected germline APC mutations in 60 individuals (45 families) and biallelic MUTYH mutations in 4 individuals (2 families). No NTHL1, POLD1, POLE mutations were identified. Fifteen novel APC mutations and a new Indian APC mutational hotspot at codon 935 were identified. Eight very rare FAP phenotype or phenotypes rarely associated with mutations outside specific APC regions were observed. APC genotype-phenotype association studies in different geo-ethnic groups can enrich the existing knowledge about phenotypic consequences of distinct APC mutations and guide counseling and risk management in different populations. A stepwise cost-effective mutation screening approach is proposed for genetic testing of south Asian FAP patients.

Structural phenotyping of stem cell-derived cardiomyocytes.

PubMed

Pasqualini, Francesco Silvio; Sheehy, Sean Paul; Agarwal, Ashutosh; Aratyn-Schaus, Yvonne; Parker, Kevin Kit

2015-03-10

Structural phenotyping based on classical image feature detection has been adopted to elucidate the molecular mechanisms behind genetically or pharmacologically induced changes in cell morphology. Here, we developed a set of 11 metrics to capture the increasing sarcomere organization that occurs intracellularly during striated muscle cell development. To test our metrics, we analyzed the localization of the contractile protein α-actinin in a variety of primary and stem-cell derived cardiomyocytes. Further, we combined these metrics with data mining algorithms to unbiasedly score the phenotypic maturity of human-induced pluripotent stem cell-derived cardiomyocytes. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

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

PubMed Central

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

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 μmol/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

Functional Inactivation of Putative Photosynthetic Electron Acceptor Ferredoxin C2 (FdC2) Induces Delayed Heading Date and Decreased Photosynthetic Rate in Rice

PubMed Central

Ruan, Banpu; Kang, Shujing; He, Lei; Zhang, Sen; Dong, Guojun; Hu, Jiang; Zeng, Dali; Zhang, Guangheng; Gao, Zhenyu; Ren, Deyong; Hu, Xingming; Chen, Guang; Guo, Longbiao; Qian, Qian; Zhu, Li

2015-01-01

Ferredoxin (Fd) protein as unique electron acceptor, involved in a variety of fundamental metabolic and signaling processes, which is indispensable for plant growth. The molecular mechanisms of Fd such as regulation of electron partitioning, impact of photosynthetic rate and involvement in the carbon fixing remain elusive in rice. Here we reported a heading date delay and yellowish leaf 1 (hdy1) mutant derived from Japonica rice cultivar “Nipponbare” subjected to EMS treatment. In the paddy field, the hdy1 mutant appeared at a significantly late heading date and had yellow-green leaves during the whole growth stage. Further investigation indicated that the abnormal phenotype of hdy1 was connected with depressed pigment content and photosynthetic rate. Genetic analysis results showed that the hdy1 mutant phenotype was caused by a single recessive nuclear gene mutation. Map-based cloning revealed that OsHDY1 is located on chromosome 3 and encodes an ortholog of the AtFdC2 gene. Complementation and overexpression, transgenic plants exhibited the mutant phenotype including head date, leaf color and the transcription levels of the FdC2 were completely rescued by transformation with OsHDY1. Real-time PCR revealed that the expression product of OsHDY1 was detected in almost all of the organs except root, whereas highest expression levels were observed in seeding new leaves. The lower expression levels of HDY1 and content of iron were detected in hdy1 than WT’s. The FdC2::GFP was detected in the chloroplasts of rice. Real-time PCR results showed that the expression of many photosynthetic electron transfer related genes in hdy1 were higher than WT. Our results suggest that OsFdC2 plays an important role in photosynthetic rate and development of heading date by regulating electron transfer and chlorophyll content in rice. PMID:26598971

Truncating mutations of HIBCH tend to cause severe phenotypes in cases with HIBCH deficiency: a case report and brief literature review.

PubMed

Tan, Hu; Chen, Xin; Lv, Weigang; Linpeng, Siyuan; Liang, Desheng; Wu, Lingqian

2018-04-27

3-hydroxyisobutryl-CoA hydrolase (HIBCH) deficiency is a rare inborn error of valine metabolism characterized by neurodegenerative symptoms and caused by recessive mutations in the HIBCH gene. In this study, utilizing whole exome sequencing, we identified two novel splicing mutations of HIBCH (c.304+3A>G; c.1010_1011+3delTGGTA) in a Chinese patient with characterized neurodegenerative features of HIBCH deficiency and bilateral syndactyly which was not reported in previous studies. Functional tests showed that both of these two mutations destroyed the normal splicing and reduced the expression of HIBCH protein. Through a literature review, a potential phenotype-genotype correlation was found that patients carrying truncating mutations tended to have more severe phenotypes compared with those with missense mutations. Our findings would widen the mutation spectrum of HIBCH causing HIBCH deficiency and the phenotypic spectrum of the disease. The potential genotype-phenotype correlation would be profitable for the treatment and management of patients with HIBCH deficiency.

Mutations in RIT1 cause Noonan syndrome - additional functional evidence and expanding the clinical phenotype.

PubMed

Koenighofer, M; Hung, C Y; McCauley, J L; Dallman, J; Back, E J; Mihalek, I; Gripp, K W; Sol-Church, K; Rusconi, P; Zhang, Z; Shi, G-X; Andres, D A; Bodamer, O A

2016-03-01

RASopathies are a clinically heterogeneous group of conditions caused by mutations in 1 of 16 proteins in the RAS-mitogen activated protein kinase (RAS-MAPK) pathway. Recently, mutations in RIT1 were identified as a novel cause for Noonan syndrome. Here we provide additional functional evidence for a causal role of RIT1 mutations and expand the associated phenotypic spectrum. We identified two de novo missense variants p.Met90Ile and p.Ala57Gly. Both variants resulted in increased MEK-ERK signaling compared to wild-type, underscoring gain-of-function as the primary functional mechanism. Introduction of p.Met90Ile and p.Ala57Gly into zebrafish embryos reproduced not only aspects of the human phenotype but also revealed abnormalities of eye development, emphasizing the importance of RIT1 for spatial and temporal organization of the growing organism. In addition, we observed severe lymphedema of the lower extremity and genitalia in one patient. We provide additional evidence for a causal relationship between pathogenic mutations in RIT1, increased RAS-MAPK/MEK-ERK signaling and the clinical phenotype. The mutant RIT1 protein may possess reduced GTPase activity or a diminished ability to interact with cellular GTPase activating proteins; however the precise mechanism remains unknown. The phenotypic spectrum is likely to expand and includes lymphedema of the lower extremities in addition to nuchal hygroma. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Autosomal dominant SCN8A mutation with an unusually mild phenotype.

PubMed

Anand, G; Collett-White, F; Orsini, A; Thomas, S; Jayapal, S; Trump, N; Zaiwalla, Z; Jayawant, S

2016-09-01

Mutations in SCN8A, coding for the voltage-gated sodium channel Nav 1.6, have been described in relation to infantile onset epilepsy with developmental delay and cognitive impairment, in particular early onset epileptic encephalopathy (EIEE) type 13. Here we report an infant and his father with early onset focal epileptic seizures but without cognitive or neurological impairment in whom next generation sequence analysis identified a heterozygous mutation (c.5630A > G, p. (Asn1877Ser)) in the SCN8A gene. This mutation, confirmed by Sanger sequence analysis, affects a highly conserved amino acid and in silico tools predicts that it may be pathogenic. The reported infant has a normal developmental profile at 16-month follow-up. His father also had normal development and has no cognitive impairment at 42 years. This is the second known SCN8A mutation associated with a phenotype of benign familial infantile epilepsy. Good seizure control was achieved in our patients with sodium channel blockers. Based on our proband and a recently described group of families with benign familial infantile epilepsy and SCN8A variant we suggest expanding testing to patients with infantile epilepsy and no cognitive impairment. In addition, the same SCN8A variant (c.5630A > G, p. (Asn1877Ser)) is also found in patients with epilepsy and developmental delay highlighting the phenotypic variability and the possible role of other protective genetic factors. Copyright © 2016. Published by Elsevier Ltd.

Phenotypical, physiological and biochemical analyses provide insight into selenium-induced phytotoxicity in rice plants.

PubMed

Mostofa, Mohammad Golam; Hossain, Mohammad Anwar; Siddiqui, Md Nurealam; Fujita, Masayuki; Tran, Lam-Son

2017-07-01

The present study investigated the phenotypical, physiological and biochemical changes of rice plants exposed to high selenium (Se) concentrations to gain an insight into Se-induced phytotoxicity. Results showed that exposure of rice plants to excessive Se resulted in growth retardation and biomass reduction in connection with the decreased levels of chlorophyll, carotenoids and soluble proteins. The reduced water status and an associated increase in sugar and proline levels indicated Se-induced osmotic stress in rice plants. Measurements of Se contents in roots, leaf sheaths and leaves revealed that Se was highly accumulated in leaves followed by leaf sheaths and roots. Se also potentiated its toxicity by impairing oxidative metabolism, as evidenced by enhanced accumulation of hydrogen peroxide, superoxide and lipid peroxidation product. Se toxicity also displayed a desynchronized antioxidant system by elevating the level of glutathione and the activities of superoxide dismutase, glutathione-S-transferase and glutathione peroxidase, whereas decreasing the level of ascorbic acid and the activities of catalase, glutathione reductase and dehydroascorbate reductase. Furthermore, Se triggered methylglyoxal toxicity by inhibiting the activities of glyoxalases I and II, particularly at higher concentrations of Se. Collectively, our results suggest that excessive Se caused phytotoxic effects on rice plants by inducing chlorosis, reducing sugar, protein and antioxidant contents, and exacerbating oxidative stress and methylglyoxal toxicity. Accumulation levels of Se, proline and glutathione could be considered as efficient biomarkers to indicate degrees of Se-induced phytotoxicity in rice, and perhaps in other crops. Copyright © 2017 Elsevier Ltd. All rights reserved.

De novo truncating mutations in ASXL3 are associated with a novel clinical phenotype with similarities to Bohring-Opitz syndrome

PubMed Central

2013-01-01

Background Molecular diagnostics can resolve locus heterogeneity underlying clinical phenotypes that may otherwise be co-assigned as a specific syndrome based on shared clinical features, and can associate phenotypically diverse diseases to a single locus through allelic affinity. Here we describe an apparently novel syndrome, likely caused by de novo truncating mutations in ASXL3, which shares characteristics with Bohring-Opitz syndrome, a disease associated with de novo truncating mutations in ASXL1. Methods We used whole-genome and whole-exome sequencing to interrogate the genomes of four subjects with an undiagnosed syndrome. Results Using genome-wide sequencing, we identified heterozygous, de novo truncating mutations in ASXL3, a transcriptional repressor related to ASXL1, in four unrelated probands. We found that these probands shared similar phenotypes, including severe feeding difficulties, failure to thrive, and neurologic abnormalities with significant developmental delay. Further, they showed less phenotypic overlap with patients who had de novo truncating mutations in ASXL1. Conclusion We have identified truncating mutations in ASXL3 as the likely cause of a novel syndrome with phenotypic overlap with Bohring-Opitz syndrome. PMID:23383720

Embryonic left-right separation mechanism allows confinement of mutation-induced phenotypes to one lateral body half of bilaterians.

PubMed

Ma, Kun

2013-12-01

A fundamental question in developmental biology is how a chimeric animal such as a bilateral gynandromorphic animal can have different phenotypes confined to different lateral body halves, and how mutation-induced phenotypes, such as genetic diseases, can be confined to one lateral body half in patients. Here, I propose that embryos of many, if not all, bilaterian animals are divided into left and right halves at a very early stage (which may vary among different types of animals), after which the descendants of the left-sided and right-sided cells will almost exclusively remain on their original sides, respectively, throughout the remaining development. This embryonic left-right separation mechanism allows (1) mutations and the mutation-induced phenotypes to be strictly confined to one lateral body half in animals and humans; (2) mothers with bilateral hereditary primary breast cancer to transmit their disease to their offspring at twofold of the rate compared to mothers with unilateral hereditary breast cancer; and (3) a mosaic embryo carrying genetic or epigenetic mutations to develop into either an individual with the mutation-induced phenotype confined unilaterally, or a pair of twins displaying complete, partial, or mirror-image discordance for the phenotype. Further, this left-right separation mechanism predicts that the two lateral halves of a patient carrying a unilateral genetic disease can each serve as a case and an internal control, respectively, for genetic and epigenetic comparative studies to identify the disease causations. © 2013 Wiley Periodicals, Inc.

Autism Spectrum Phenotype in Males and Females with Fragile X Full Mutation and Premutation

ERIC Educational Resources Information Center

Clifford, Sally; Dissanayake, Cheryl; Bui, Quang M.; Huggins, Richard; Taylor, Annette K.; Loesch, Danuta Z.

2007-01-01

The behavioural phenotype of autism was assessed in individuals with full mutation and premutation fragile X syndrome (FXS) using the Autism Diagnostic Observation Scale-Generic (ADOS-G) and the Autism Diagnostic Interview (ADI-R). The participants, aged 5-80 years, comprised 33 males and 31 females with full mutation, 7 males and 43 females with…

Map-based cloning and characterization of the novel yellow-green leaf gene ys83 in rice (Oryza sativa).

PubMed

Ma, Xiaozhi; Sun, Xiaoqiu; Li, Chunmei; Huan, Rui; Sun, Changhui; Wang, Yang; Xiao, Fuliang; Wang, Qian; Chen, Purui; Ma, Furong; Zhang, Kuan; Wang, Pingrong; Deng, Xiaojian

2017-02-01

Leaf-color mutants have been extensively studied in rice, and many corresponding genes have been identified up to now. However, leaf-color mutation mechanisms are diverse and still need further research through identification of novel genes. In the present paper, we isolated a leaf-color mutant, ys83, in rice (Oryza sativa). The mutant displayed a yellow-green leaf phenotype at seedling stage, and then slowly turned into light-green leaf from late tillering stage. In its yellow leaves, photosynthetic pigment contents significantly decreased and the chloroplast development was retarded. The mutant phenotype was controlled by a recessive mutation in a nuclear gene on the short arm of rice chromosome 2. Map-based cloning and sequencing analysis suggested that the candidate gene was YS83 (LOC_Os02g05890) encoding a protein containing 165 amino acid residues. Gene YS83 was expressed in a wide range of tissues, and its encoded protein was targeted to the chloroplast. In the mutant, a T-to-A substitution occurred in coding sequence of gene YS83, which caused a premature translation of its encoded product. By introduction of the wild-type gene, the ys83 mutant recovered to normal green-leaf phenotype. Taken together, we successfully identified a novel yellow-green leaf gene YS83. In addition, number of productive panicles per plant and number of spikelets per panicle only reduced by 6.7% and 7.6%, respectively, meanwhile its seed setting rate and 1000-grain weight (seed size) were not significantly affected in the mutant, so leaf-color mutant gene ys83 could be used as a trait marker gene in commercial hybrid rice production. Copyright © 2016. Published by Elsevier Masson SAS.

Neurons generated by direct conversion of fibroblasts reproduce synaptic phenotype caused by autism-associated neuroligin-3 mutation.

PubMed

Chanda, Soham; Marro, Samuele; Wernig, Marius; Südhof, Thomas C

2013-10-08

Recent studies suggest that induced neuronal (iN) cells that are directly transdifferentiated from nonneuronal cells provide a powerful opportunity to examine neuropsychiatric diseases. However, the validity of using this approach to examine disease-specific changes has not been demonstrated. Here, we analyze the phenotypes of iN cells that were derived from murine embryonic fibroblasts cultured from littermate wild-type and mutant mice carrying the autism-associated R704C substitution in neuroligin-3. We show that neuroligin-3 R704C-mutant iN cells exhibit a large and selective decrease in AMPA-type glutamate receptor-mediated synaptic transmission without changes in NMDA-type glutamate receptor- or in GABAA receptor-mediated synaptic transmission. Thus, the synaptic phenotype observed in R704C-mutant iN cells replicates the previously observed phenotype of R704C-mutant neurons. Our data show that the effect of the R704C mutation is applicable even to neurons transdifferentiated from fibroblasts and constitute a proof-of-concept demonstration that iN cells can be used for cellular disease modeling.

Neurons generated by direct conversion of fibroblasts reproduce synaptic phenotype caused by autism-associated neuroligin-3 mutation

PubMed Central

Chanda, Soham; Marro, Samuele; Wernig, Marius; Südhof, Thomas C.

2013-01-01

Recent studies suggest that induced neuronal (iN) cells that are directly transdifferentiated from nonneuronal cells provide a powerful opportunity to examine neuropsychiatric diseases. However, the validity of using this approach to examine disease-specific changes has not been demonstrated. Here, we analyze the phenotypes of iN cells that were derived from murine embryonic fibroblasts cultured from littermate wild-type and mutant mice carrying the autism-associated R704C substitution in neuroligin-3. We show that neuroligin-3 R704C-mutant iN cells exhibit a large and selective decrease in AMPA-type glutamate receptor-mediated synaptic transmission without changes in NMDA-type glutamate receptor- or in GABAA receptor-mediated synaptic transmission. Thus, the synaptic phenotype observed in R704C-mutant iN cells replicates the previously observed phenotype of R704C-mutant neurons. Our data show that the effect of the R704C mutation is applicable even to neurons transdifferentiated from fibroblasts and constitute a proof-of-concept demonstration that iN cells can be used for cellular disease modeling. PMID:24046374

Further insight into the phenotype associated with a mutation in the ORC6 gene, causing Meier-Gorlin syndrome 3.

PubMed

Shalev, Stavit Allon; Khayat, Morad; Etty, Daniel-Spiegl; Elpeleg, Orly

2015-03-01

Mutations in genes encoding the origin recognition complex subunits cause Meier-Gorlin syndrome. The disease manifests a triad of short stature, small ears, and small and/or absent patellae with variable expressivity. We report on the identification of a homozygous deleterious mutation in the ORC6 gene in previously described fetuses at the severe end of the Meier-Gorlin spectrum. The phenotype included severe intrauterine growth retardation, dislocation of knees, gracile bones, clubfeet, and small mandible and chest. To date, the clinical presentation of ORC6-associated Meier-Gorlin syndrome has been mild compared to other the phenotype associated with other loci. The present report expands the clinical phenotype associated with ORC6 mutations to include severely abnormal embryological development suggesting a possible genotype-phenotype correlation. © 2015 Wiley Periodicals, Inc.

Increasing leaf vein density by mutagenesis: laying the foundations for C4 rice.

PubMed

Feldman, Aryo B; Murchie, Erik H; Leung, Hei; Baraoidan, Marietta; Coe, Robert; Yu, Su-May; Lo, Shuen-Fang; Quick, William P

2014-01-01

A high leaf vein density is both an essential feature of C4 photosynthesis and a foundation trait to C4 evolution, ensuring the optimal proportion and proximity of mesophyll and bundle sheath cells for permitting the rapid exchange of photosynthates. Two rice mutant populations, a deletion mutant library with a cv. IR64 background (12,470 lines) and a T-DNA insertion mutant library with a cv. Tainung 67 background (10,830 lines), were screened for increases in vein density. A high throughput method with handheld microscopes was developed and its accuracy was supported by more rigorous microscopy analysis. Eight lines with significantly increased leaf vein densities were identified to be used as genetic stock for the global C4 Rice Consortium. The candidate population was shown to include both shared and independent mutations and so more than one gene controlled the high vein density phenotype. The high vein density trait was found to be linked to a narrow leaf width trait but the linkage was incomplete. The more genetically robust narrow leaf width trait was proposed to be used as a reliable phenotypic marker for finding high vein density variants in rice in future screens.

MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study.

PubMed

Makrythanasis, P; van Bon, B W; Steehouwer, M; Rodríguez-Santiago, B; Simpson, M; Dias, P; Anderlid, B M; Arts, P; Bhat, M; Augello, B; Biamino, E; Bongers, E M H F; Del Campo, M; Cordeiro, I; Cueto-González, A M; Cuscó, I; Deshpande, C; Frysira, E; Izatt, L; Flores, R; Galán, E; Gener, B; Gilissen, C; Granneman, S M; Hoyer, J; Yntema, H G; Kets, C M; Koolen, D A; Marcelis, C l; Medeira, A; Micale, L; Mohammed, S; de Munnik, S A; Nordgren, A; Psoni, S; Reardon, W; Revencu, N; Roscioli, T; Ruiterkamp-Versteeg, M; Santos, H G; Schoumans, J; Schuurs-Hoeijmakers, J H M; Silengo, M C; Toledo, L; Vendrell, T; van der Burgt, I; van Lier, B; Zweier, C; Reymond, A; Trembath, R C; Perez-Jurado, L; Dupont, J; de Vries, B B A; Brunner, H G; Veltman, J A; Merla, G; Antonarakis, S E; Hoischen, A

2013-12-01

Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa-Kuroki) syndrome (MIM#147920). To further elucidate the genotype-phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2-Kabuki score 0-10). Sequencing of the full coding region and intron-exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice-site mutations, 34 of which were novel. In five additional patients, novel, i.e. non-dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median 'MLL2-Kabuki score' of 6) as compared to the patients without MLL2 mutations (median 'MLL2-Kabuki score' of 5), a significant difference (p < 0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Confounders of mutation-rate estimators: selection and phenotypic lag in Thermus thermophilus

PubMed Central

Kissling, Grace E.; Grogan, Dennis W.; Drake, John W.

2015-01-01

In a recent description of the rate and character of spontaneous mutation in the hyperthermophilic bacterium Thermus thermophilus, the mutation rate was observed to be substantially lower than seen in several mesophiles. Subsequently, a report appeared indicating that this bacterium maintains an average of about 4.5 genomes per cell. This number of genomes might result in a segregation lag for the expression of a recessive mutation and might therefore lead to an underestimate of the rate of mutation. Here we describe some kinds of problems that may arise when estimating mutation rates and outline ways to adjust the rates accordingly. The emphasis is mainly on differential rates of growth of mutants versus their parents and on various kinds of phenotypic lag. We then apply these methods to the T. thermophilus data and conclude that there is as yet no reliable impact on a previously described rate. PMID:23916418

Mutations in chromatin regulators functionally link Cornelia de Lange syndrome and clinically overlapping phenotypes.

PubMed

Parenti, Ilaria; Teresa-Rodrigo, María E; Pozojevic, Jelena; Ruiz Gil, Sara; Bader, Ingrid; Braunholz, Diana; Bramswig, Nuria C; Gervasini, Cristina; Larizza, Lidia; Pfeiffer, Lutz; Ozkinay, Ferda; Ramos, Feliciano; Reiz, Benedikt; Rittinger, Olaf; Strom, Tim M; Watrin, Erwan; Wendt, Kerstin; Wieczorek, Dagmar; Wollnik, Bernd; Baquero-Montoya, Carolina; Pié, Juan; Deardorff, Matthew A; Gillessen-Kaesbach, Gabriele; Kaiser, Frank J

2017-03-01

The coordinated tissue-specific regulation of gene expression is essential for the proper development of all organisms. Mutations in multiple transcriptional regulators cause a group of neurodevelopmental disorders termed "transcriptomopathies" that share core phenotypical features including growth retardation, developmental delay, intellectual disability and facial dysmorphism. Cornelia de Lange syndrome (CdLS) belongs to this class of disorders and is caused by mutations in different subunits or regulators of the cohesin complex. Herein, we report on the clinical and molecular characterization of seven patients with features overlapping with CdLS who were found to carry mutations in chromatin regulators previously associated to other neurodevelopmental disorders that are frequently considered in the differential diagnosis of CdLS. The identified mutations affect the methyltransferase-encoding genes KMT2A and SETD5 and different subunits of the SWI/SNF chromatin-remodeling complex. Complementary to this, a patient with Coffin-Siris syndrome was found to carry a missense substitution in NIPBL. Our findings indicate that mutations in a variety of chromatin-associated factors result in overlapping clinical phenotypes, underscoring the genetic heterogeneity that should be considered when assessing the clinical and molecular diagnosis of neurodevelopmental syndromes. It is clear that emerging molecular mechanisms of chromatin dysregulation are central to understanding the pathogenesis of these clinically overlapping genetic disorders.

Distinct distal myopathy phenotype caused by VCP gene mutation in a Finnish family.

PubMed

Palmio, Johanna; Sandell, Satu; Suominen, Tiina; Penttilä, Sini; Raheem, Olayinka; Hackman, Peter; Huovinen, Sanna; Haapasalo, Hannu; Udd, Bjarne

2011-08-01

Inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD) is caused by mutations in the valosin-containing protein (VCP) gene. We report a new distal phenotype caused by VCP gene mutation in a Finnish family with nine affected members in three generations. Patients had onset of distal leg muscle weakness and atrophy in the anterior compartment muscles after age 35, which caused a foot drop at age 50. None of the siblings had scapular winging, proximal myopathy, cardiomyopathy or respiratory problems during long-term follow-up. Three distal myopathy patients developed rapidly progressive dementia, became bedridden and died of cachexia and pneumonia and VCP gene mutation P137L (c.410C>T) was then identified in the family. Late onset autosomal dominant distal myopathy with rimmed vacuolar muscle pathology was not sufficient for exact diagnosis in this family until late-occurring dementia provided the clue for molecular diagnosis. VCP needs to be considered in the differential diagnostic work-up in patients with distal myopathy phenotype. Copyright © 2011 Elsevier B.V. All rights reserved.

Phenotypic variability in familial prion diseases due to the D178N mutation

PubMed Central

Zarranz, J; Digon, A; Atares, B; Rodriguez-Martine..., A; Arce, A; Carrera, N; Fernandez-Manchol..., I; Fernandez-Martine..., M; Fernandez-Maizteg..., C; Forcadas, I; Galdos, L; Gomez-Esteban, J; Ibanez, A; Lezcano, E; d Lopez; Marti-Masso, J; Mendibe, M; Urtasun, M; Uterga, J; Saracibar, N; Velasco, F; de Pancorbo, M M

2005-01-01

Background: Between January 1993 and December 2003, 19 patients with familial prion diseases due to the D178N mutation were referred to the regional epidemiological registry for spongiform encephalopathies in the Basque Country in Spain, a small community of some 2 100 000 inhabitants. Methods: Ten further patients belonging to the same pedigrees were retrospectively ascertained through neurological or neuropathological records. In four of the patients, the diagnosis was confirmed by analysing DNA obtained from paraffin blocks. In this article, we report on the clinical, genetic, and pathological features of the 23 patients carrying the D178N mutation confirmed by genetic molecular analysis. Haplotyping studies suggest a founder effect among Basque born families, explaining in part this unusually high incidence of the D178N mutation in a small community. Only two patients (8%) lack familial antecedents. Results: We have observed a phenotypic variability even among homozygous 129MM patients. Our findings challenge the currently accepted belief that MM homozygosity in codon 129 is always related to a fatal familial insomnia (FFI) phenotype. Indeed, seven out of 17 patients with a 129MM genotype in this series presented with a Creutzfeldt-Jakob disease (CJD) clinicopathological picture. Conclusions: The considerable clinical and pathological overlapping observed among homozygous 129MM patients favours the view that FFI and CJD178 are the extremes of a spectrum rather than two discrete and separate entities. Other genetic or environmental factors apart from the polymorphism in codon 129 may play a role in determining the phenotypic expression of the D178N mutation in the PRNP gene. PMID:16227536

Recombination activity of human RAG2 mutations and correlation with the clinical phenotype.

PubMed

Tirosh, Irit; Yamazaki, Yasuhiro; Frugoni, Francesco; Ververs, Francesca A; Allenspach, Eric J; Zhang, Yu; Burns, Siobhan; Al-Herz, Waleed; Noroski, Lenora; Walter, Jolan E; Gennery, Andrew R; van der Burg, Mirjam; Notarangelo, Luigi D; Lee, Yu Nee

2018-05-14

Mutations in the Recombinase Activating Gene 1 and 2 (RAG1, RAG2) are associated with a broad range of clinical and immunological phenotypes in humans. Using a flow cytometry-based assay, we aimed to measure the recombinase activity of naturally occurring RAG2 mutant proteins, and to correlate results with the severity of the clinical and immunological phenotype. Abelson virus-transformed Rag2 -/- pro-B cells engineered to contain an inverted GFP cassette flanked by recombination signal sequences (RSS) were transduced with retroviruses encoding either wild-type or 41 naturally occurring RAG2 variants. Bicistronic vectors were used to introduce compound heterozygous RAG2 variants.The percentage of GFP-expressing cells was evaluated by flow cytometry, and high throughput sequencing was used to analyze rearrangements at the endogenous Igh locus.. The RAG2 variants showed a wide range of recombination activity. Mutations associated with severe combined immune deficiency (SCID) and Omenn syndrome had significantly lower activity than those detected in patients with less severe clinical presentations. Four variants (P253R, F386L, N474S, and M502V) previously thought to be pathogenic were found to have wild-type levels of activity. Use of bicistronic vectors permitted to assess more carefully the effect of compound heterozygous mutations, with good correlation between GFP expression and number and diversity of Igh rearrangements. Our data support genotype-phenotype correlation in RAG2 deficiency. The assay described can be used to define the possible disease-causing role of novel RAG2 variants and may help predict the severity of the clinical phenotype. Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

JP-HHT phenotype in Danish patients with SMAD4 mutations.

PubMed

Jelsig, A M; Tørring, P M; Kjeldsen, A D; Qvist, N; Bojesen, A; Jensen, U B; Andersen, M K; Gerdes, A M; Brusgaard, K; Ousager, L B

2016-07-01

Patients with germline mutations in SMAD4 can present symptoms of both juvenile polyposis syndrome (JPS) and hereditary hemorrhagic telangiectasia (HHT): the JP-HHT syndrome. The complete phenotypic picture of this syndrome is only just emerging. We describe the clinical characteristics of 14 patients with SMAD4-mutations. The study was a retrospective, register-based study. SMAD4 mutations carriers were identified through the Danish HHT-registry, the genetic laboratories - and the genetic departments in Denmark. The medical files from relevant departments were reviewed and symptoms of HHT, JPS, aortopathy and family history were noted. We detected 14 patients with SMAD4 mutations. All patients had polyps removed and 11 of 14 fulfilled the diagnostic criteria for JPS. Eight patients were screened for HHT-symptoms and seven of these fulfilled the Curaçao criteria. One patient had aortic root dilation. Our findings support that SMAD4 mutations carriers have symptoms of both HHT and JPS and that the frequency of PAVM and gastric involvement with polyps is higher than in patients with HHT or JPS not caused by a SMAD4 mutation. Out of eight patients screened for aortopathy, one had aortic root dilatation, highlighting the need for additional screening for aortopathy. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Arylamine N-acetyltransferase (NAT2) mutations and their allelic linkage in unrelated caucasian individuals: Correlation with phenotypic activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cascorbi, I.; Drakoulis, N.; Brockmoeller, J.

1995-09-01

The polymorphic arylamine N-acetyltransferase (NAT2; EC2.3.1.5) is supposed to be a susceptibility factor for several drug side effects and certain malignancies. A group of 844 unrelated German subjects was genotyped for their acetylation type, and 563 of them were also phenotyped. Seven mutations of the NAT2 gene were evaluated by allele-specific PCR (mutation 341C to T) and PCR-RFLP for mutations at nt positions 191, 282, 481, 590, 803, and 857. From the mutation pattern eight different alleles, including the wild type coding for rapid acetylation and seven alleles coding for slow phenotype, were determined. Four hundred ninety-seven subjects had amore » genotype of slow acetylation (58.9%; 95% confidence limits 55.5%-62.2%). Phenotypic acetylation capacity was expressed as the ratio of 5-acetylamino-6-formylamino-3-methyluracil and 1-methylxanthine in urine after caffeine intake. Some 6.7% of the cases deviated in genotype and phenotype, but sequencing DNA of these probands revealed no new mutations. Furthermore, linkage pattern of the mutations was always confirmed, as tested in 533 subjects. In vivo acetylation capacity of homozygous wild-type subjects (NAT2{sup *}4/{sup *}4) was significantly higher than in heterozygous genotypes (P = .001). All mutant alleles showed low in vivo acetylation capacities, including the previously not-yet-defined alleles {sup *}5A, {sup *}5C, and {sup *}13. Moreover, distinct slow genotypes differed significantly among each other, as reflected in lower acetylation capacity of {sup *}6A, {sup *}7B, and {sup *}13 alleles than the group of {sup *}5 alleles. The study demonstrated differential phenotypic activity of various NAT2 genes and gives a solid basis for clinical and molecular-epidemiological investigations. 34 refs., 4 figs., 7 tabs.« less

Highly Prevalent LIPH Founder Mutations Causing Autosomal Recessive Woolly Hair/Hypotrichosis in Japan and the Genotype/Phenotype Correlations

PubMed Central

Kono, Michihiro; Takama, Hiromichi; Hamajima, Nobuyuki; Akiyama, Masashi

2014-01-01

Mutations in LIPH cause of autosomal recessive woolly hair/hypotrichosis (ARWH), and the 2 missense mutations c.736T>A (p.Cys246Ser) and c.742C>A (p.His248Asn) are considered prevalent founder mutations for ARWH in the Japanese population. To reveal genotype/phenotype correlations in ARWH cases in Japan and the haplotypes in 14 Japanese patients from 14 unrelated Japanese families. 13 patients had woolly hair, and 1 patient had complete baldness since birth. An LIPH mutation search revealed homozygous c.736T>A mutations in 10 of the patients. Compound heterozygous c.736T>A and c.742C>A mutations were found in 3 of the patients, and homozygous c.742C>A mutation in 1 patient. The phenotype of mild hypotrichosis with woolly hair was restricted to the patients with the homozygous c.736T>A mutation. The severe phenotype of complete baldness was seen in only 1 patient with homozygous c.742C>A. Haplotype analysis revealed that the alleles containing the LIPH c.736T>A mutation had a haplotype identical to that reported previously, although 4 alleles out of 5 chromosomes containing the LIPH c.742C>A mutation had a different haplotype from the previously reported founder allele. These alleles with c.742C>A are thought to be the third founder LIPH mutation causing ARWH. To accurately determine the prevalence of the founder mutations, we investigated allele frequencies of those mutations in 819 Japanese controls. Heterozygous c.736T>A mutations were found in 13 controls (allele frequency: 0.0079; carrier rate: 0.016), and heterozygous c.742C>A mutations were found in 2 controls (allele frequency: 0.0012; carrier rate: 0.0024). In conclusion, this study confirms the more accurate allele frequencies of the pathogenic founder mutations of LIPH and shows that there is a third founder mutation in Japan. In addition, the present findings suggest that the mutation patterns of LIPH might be associated with hypotrichosis severity in ARWH. PMID:24586639

Suppression of the heterotrimeric G protein causes abnormal morphology, including dwarfism, in rice

PubMed Central

Fujisawa, Yukiko; Kato, Teruhisa; Ohki, Shizuka; Ishikawa, Atsushi; Kitano, Hidemi; Sasaki, Takuji; Asahi, Tadashi; Iwasaki, Yukimoto

1999-01-01

Transgenic rice containing an antisense cDNA for the α subunit of rice heterotrimeric G protein produced little or no mRNA for the subunit and exhibited abnormal morphology, including dwarf traits and the setting of small seeds. In normal rice, the mRNA for the α subunit was abundant in the internodes and florets, the tissues closely related to abnormality in the dwarf transformants. The position of the α-subunit gene was mapped on rice chromosome 5 by mapping with the restriction fragment length polymorphism. The position was closely linked to the locus of a rice dwarf mutant, Daikoku dwarf (d-1), which is known to exhibit abnormal phenotypes similar to those of the transformants that suppressed the endogenous mRNA for the α subunit by antisense technology. Analysis of the cDNAs for the α subunits of five alleles of Daikoku dwarf (d-1), ID-1, DK22, DKT-1, DKT-2, and CM1361–1, showed that these dwarf mutants had mutated in the coding region of the α-subunit gene. These results show that the G protein functions in the formation of normal internodes and seeds in rice. PMID:10377457

Identification of novel FBN1 and TGFBR2 mutations in 65 probands with Marfan syndrome or Marfan-like phenotypes.

PubMed

Chung, Brian Hon-Yin; Lam, Stephen Tak-Sum; Tong, Tony Ming-For; Li, Susanna Yuk-Han; Lun, Kin-Shing; Chan, Daniel Hon-Chuen; Fok, Susanna Fung-Shan; Or, June Siu-Fong; Smith, David Keith; Yang, Wanling; Lau, Yu-Lung

2009-07-01

Marfan syndrome is an autosomal dominant connective tissue disorder, and mutations in the FBN1 and TGFBR2 genes have been identified in probands with MFS and related phenotypes. Using DHPLC and sequencing, we studied the mutation spectrum in 65 probands with Marfan syndrome and related phenotypes. A total of 24 mutations in FBN1 were identified, of which 19 (nine missense, six frameshift, two nonsense and two affecting splice junctions) were novel. In the remaining 41 probands, six were identified to have novel TGFBR2 mutations (one frameshift and five missense mutations). All novel mutations found in this study were confirmed to be absent in 50 unrelated normal individuals of the same ethnic background. In probands who fulfilled the Ghent criteria (n = 16), mutations in FBN1 were found in 81% of cases. None of those with TGFBR2 mutations fulfilled the Ghent criteria. Novel missense mutations of unknown significance were classified according to the latest ACMG guidelines and their likelihood to be causative was evaluated.

Phenotypic diversity identified by cardiac magnetic resonance in a large hypertrophic cardiomyopathy family with a single MYH7 mutation.

PubMed

Wang, Jie; Wan, Ke; Sun, Jiayu; Li, Weihao; Liu, Hong; Han, Yuchi; Chen, Yucheng

2018-01-17

Limited data is available on phenotypic variations with the same genotype in hypertrophic cardiomyopathy (HCM). The present study aims to explore the relationship between genotype and phenotype characterized by cardiovascular magnetic resonance (CMR) in a large Chinese family. A proband diagnosed with HCM from a multigenerational family underwent next-generation sequencing based on a custom sureSelect panel, including 117 candidate pathogenic genes associated with cardiomyopathies. All genetic results were confirmed by the Sanger sequencing method. All confirmed mutation carriers underwent CMR exam and myocardial tissue characterization using T1 mapping and late gadolinium enhancement (LGE) on a 3T scanner (Siemens Trio, Gemany). After clinical and genetic screening of 36 (including the proband) members of a large Chinese family, nineteen family members are determined to carry the single p.T1377M (c.4130C>T) mutation in the MYH7 gene. Of these 19 mutation carriers, eight are diagnosed with HCM, one was considered as borderline affected and ten are not clinically or phenotypically affected. Different HCM phenotypes are present in the nine affected individuals in this family. In addition, we have found different tissue characteristics assessed by T1 mapping and LGE in these individuals. We describe a family that demonstrates the diverse HCM phenotypes associated with a single MYH7 mutation.

Clinical and molecular characterization of a novel INS mutation identified in patients with MODY phenotype.

PubMed

Piccini, Barbara; Artuso, Rosangela; Lenzi, Lorenzo; Guasti, Monica; Braccesi, Giulia; Barni, Federica; Casalini, Emilio; Giglio, Sabrina; Toni, Sonia

2016-11-01

Correct diagnosis of Maturity-Onset Diabetes of the Young (MODY) is based on genetic tests requiring an appropriate subject selection by clinicians. Mutations in the insulin (INS) gene rarely occur in patients with MODY. This study is aimed at determining the genetic background and clinical phenotype in patients with suspected MODY. 34 patients with suspected MODY, negative for mutations in the GCK, HNF1α, HNF4α, HNF1β and PDX1 genes, were screened by next generation sequencing (NGS). A heterozygous INS mutation was identified in 4 members of the same family. First genetic tests performed identified two heterozygous silent nucleotide substitutions in MODY3/HNF1α gene. An ineffective attempt to suspend insulin therapy, administering repaglinide and sulphonylureas, was made. DNA was re-sequenced by NGS investigating a set of 102 genes. Genes implicated in the pathway of pancreatic β-cells, candidate genes for type 2 diabetes mellitus and genes causative of diabetes in mice were selected. A novel heterozygous variant in human preproinsulin INS gene (c.125T > C) was found in the affected family members. The new INS mutation broadens the spectrum of possible INS phenotypes. Screening for INS mutations is warranted not only in neonatal diabetes but also in MODYx patients and in selected patients with type 1 diabetes mellitus negative for autoantibodies. Subjects with complex diseases without a specific phenotype should be studied by NGS because Sanger sequencing is ineffective and time consuming in detecting rare variants. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Cloning of the neurodegeneration gene drop-dead and characterization of additional phenotypes of its mutation.

PubMed

Blumenthal, Edward M

2008-01-01

Mutations in the Drosophila gene drop-dead (drd) result in early adult lethality and neurodegeneration, but the molecular identity of the drd gene and its mechanism of action are not known. This paper describes the characterization of a new X-linked recessive adult-lethal mutation, originally called lot's wife (lwf(1)) but subsequently identified as an allele of drd (drd(lwf)); drd(lwf) mutants die within two weeks of eclosion. Through mapping and complementation, the drd gene has been identified as CG33968, which encodes a putative integral membrane protein of unknown function. The drd(lwf) allele is associated with a nonsense mutation that eliminates nearly 80% of the CG33968 gene product; mutations in the same gene were also found in two previously described drd alleles. Characterization of drd (lwf) flies revealed additional phenotypes of drd, most notably, defects in food processing by the digestive system and in oogenesis. Mutant flies store significantly more food in their crops and defecate less than wild-type flies, suggesting that normal transfer of ingested food from the crop into the midgut is dependent upon the DRD gene product. The defect in oogenesis results in the sterility of homozygous mutant females and is associated with a reduction in the number of vitellogenic egg chambers. The disruption in vitellogenesis is far more severe than that seen in starved flies and so is unlikely to be a secondary consequence of the digestive phenotype. This study demonstrates that mutation of the drd gene CG33968 results in a complex phenotype affecting multiple physiological systems within the fly.

Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844-848.

PubMed

Koczkowska, Magdalena; Chen, Yunjia; Callens, Tom; Gomes, Alicia; Sharp, Angela; Johnson, Sherrell; Hsiao, Meng-Chang; Chen, Zhenbin; Balasubramanian, Meena; Barnett, Christopher P; Becker, Troy A; Ben-Shachar, Shay; Bertola, Debora R; Blakeley, Jaishri O; Burkitt-Wright, Emma M M; Callaway, Alison; Crenshaw, Melissa; Cunha, Karin S; Cunningham, Mitch; D'Agostino, Maria D; Dahan, Karin; De Luca, Alessandro; Destrée, Anne; Dhamija, Radhika; Eoli, Marica; Evans, D Gareth R; Galvin-Parton, Patricia; George-Abraham, Jaya K; Gripp, Karen W; Guevara-Campos, Jose; Hanchard, Neil A; Hernández-Chico, Concepcion; Immken, LaDonna; Janssens, Sandra; Jones, Kristi J; Keena, Beth A; Kochhar, Aaina; Liebelt, Jan; Martir-Negron, Arelis; Mahoney, Maurice J; Maystadt, Isabelle; McDougall, Carey; McEntagart, Meriel; Mendelsohn, Nancy; Miller, David T; Mortier, Geert; Morton, Jenny; Pappas, John; Plotkin, Scott R; Pond, Dinel; Rosenbaum, Kenneth; Rubin, Karol; Russell, Laura; Rutledge, Lane S; Saletti, Veronica; Schonberg, Rhonda; Schreiber, Allison; Seidel, Meredith; Siqveland, Elizabeth; Stockton, David W; Trevisson, Eva; Ullrich, Nicole J; Upadhyaya, Meena; van Minkelen, Rick; Verhelst, Helene; Wallace, Margaret R; Yap, Yoon-Sim; Zackai, Elaine; Zonana, Jonathan; Zurcher, Vickie; Claes, Kathleen; Martin, Yolanda; Korf, Bruce R; Legius, Eric; Messiaen, Ludwine M

2018-01-04

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000-3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons-Leu844, Cys845, Ala846, Leu847, and Gly848-located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844-848 exists and will be valuable in the management and genetic counseling of a significant number of individuals. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Delineation of the Marfan phenotype associated with mutations in exons 23-32 of the FBN1 gene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Putnam, E.A.; Cho, M.; Milewicz, D.M.

Marfan syndrome is a dominantly inherited connective tissue disorder with a wide range of phenotypic severity. The condition is the result of mutations in FBN1, a large gene composed of 65 exons encoding the fibrillin-1 protein. While mutations causing classic manifestations of Marfan syndrome have been identified throughout the FBN1 gene, the six previously characterized mutations resulting in the severe, perinatal lethal form of Marfan syndrome have clustered in exons 24-32 of the gene. We screened 8 patients with either neonatal Marfan syndrome or severe cardiovascular complications of Marfan syndrome for mutations in this region of the gene. Using intron-basedmore » exon-specific primers, we amplified exons 23-32 from genomic DNAs, screened these fragments by single-stranded conformational polymorphism analysis, and sequenced indicated exons. This analysis documented mutations in exons 25-27 of the FBN1 mutations in 6 of these patients. These results, taken together with previously published FBN1 mutations in this region, further define the phenotype associated with mutations in exons 24-32 of the FBN1 gene, information important for the development of possible diagnostic tests and genetic counseling. 49 refs., 4 figs., 2 tabs.« less

Phenotypes of Recessive Pediatric Cataract in a Cohort of Children with Identified Homozygous Gene Mutations (An American Ophthalmological Society Thesis)

PubMed Central

Khan, Arif O.; Aldahmesh, Mohammed A.; Alkuraya, Fowzan S.

2015-01-01

Purpose: To assess for phenotype-genotype correlations in families with recessive pediatric cataract and identified gene mutations. Methods: Retrospective review (2004 through 2013) of 26 Saudi Arabian apparently nonsyndromic pediatric cataract families referred to one of the authors (A.O.K.) and for which recessive gene mutations were identified. Results: Fifteen different homozygous recessive gene mutations were identified in the 26 consanguineous families; two genes and five families are novel to this study. Ten families had a founder CRYBB1 deletion (all with bilateral central pulverulent cataract), two had the same missense mutation in CRYAB (both with bilateral juvenile cataract with marked variable expressivity), and two had different mutations in FYCO1 (both with bilateral posterior capsular abnormality). The remaining 12 families each had mutations in 12 different genes (CRYAA, CRYBA1, AKR1E2, AGK, BFSP2, CYP27A1, CYP51A1, EPHA2, GCNT2, LONP1, RNLS, WDR87) with unique phenotypes noted for CYP27A1 (bilateral juvenile fleck with anterior and/or posterior capsular cataract and later cerebrotendinous xanthomatosis), EPHA2 (bilateral anterior persistent fetal vasculature), and BFSP2 (bilateral flecklike with cloudy cortex). Potential carrier signs were documented for several families. Conclusions: In this recessive pediatric cataract case series most identified genes are noncrystallin. Recessive pediatric cataract phenotypes are generally nonspecific, but some notable phenotypes are distinct and associated with specific gene mutations. Marked variable expressivity can occur from a recessive missense CRYAB mutation. Genetic analysis of apparently isolated pediatric cataract can sometimes uncover mutations in a syndromic gene. Some gene mutations seem to be associated with apparent heterozygous carrier signs. PMID:26622071

A novel frameshift GRN mutation results in frontotemporal lobar degeneration with a distinct clinical phenotype in two siblings: case report and literature review.

PubMed

Hosaka, Takashi; Ishii, Kazuhiro; Miura, Takeshi; Mezaki, Naomi; Kasuga, Kensaku; Ikeuchi, Takeshi; Tamaoka, Akira

2017-09-15

Progranulin gene (GRN) mutations are major causes of frontotemporal lobar degeneration. To date, 68 pathogenic GRN mutations have been identified. However, very few of these mutations have been reported in Asians. Moreover, some GRN mutations manifest with familial phenotypic heterogeneity. Here, we present a novel GRN mutation resulting in frontotemporal lobar degeneration with a distinct clinical phenotype, and we review reports of GRN mutations associated with familial phenotypic heterogeneity. We describe the case of a 74-year-old woman with left frontotemporal lobe atrophy who presented with progressive anarthria and non-fluent aphasia. Her brother had been diagnosed with corticobasal syndrome (CBS) with right-hand limb-kinetic apraxia, aphasia, and a similar pattern of brain atrophy. Laboratory blood examinations did not reveal abnormalities that could have caused cognitive dysfunction. In the cerebrospinal fluid, cell counts and protein concentrations were within normal ranges, and concentrations of tau protein and phosphorylated tau protein were also normal. Since similar familial cases due to mutation of GRN and microtubule-associated protein tau gene (MAPT) were reported, we performed genetic analysis. No pathological mutations of MAPT were identified, but we identified a novel GRN frameshift mutation (c.1118_1119delCCinsG: p.Pro373ArgX37) that resulted in progranulin haploinsufficiency. This is the first report of a GRN mutation associated with familial phenotypic heterogeneity in Japan. Literature review of GRN mutations associated with familial phenotypic heterogeneity revealed no tendency of mutation sites. The role of progranulin has been reported in this and other neurodegenerative diseases, and the analysis of GRN mutations may lead to the discovery of a new therapeutic target.

Meier–Gorlin syndrome genotype–phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis

PubMed Central

de Munnik, Sonja A; Bicknell, Louise S; Aftimos, Salim; Al-Aama, Jumana Y; van Bever, Yolande; Bober, Michael B; Clayton-Smith, Jill; Edrees, Alaa Y; Feingold, Murray; Fryer, Alan; van Hagen, Johanna M; Hennekam, Raoul C; Jansweijer, Maaike C E; Johnson, Diana; Kant, Sarina G; Opitz, John M; Ramadevi, A Radha; Reardon, Willie; Ross, Alison; Sarda, Pierre; Schrander-Stumpel, Constance T R M; Schoots, Jeroen; Temple, I Karen; Terhal, Paulien A; Toutain, Annick; Wise, Carol A; Wright, Michael; Skidmore, David L; Samuels, Mark E; Hoefsloot, Lies H; Knoers, Nine V A M; Brunner, Han G; Jackson, Andrew P; Bongers, Ernie M H F

2012-01-01

Meier–Gorlin syndrome (MGS) is an autosomal recessive disorder characterized by microtia, patellar aplasia/hypoplasia, and short stature. Recently, mutations in five genes from the pre-replication complex (ORC1, ORC4, ORC6, CDT1, and CDC6), crucial in cell-cycle progression and growth, were identified in individuals with MGS. Here, we report on genotype–phenotype studies in 45 individuals with MGS (27 females, 18 males; age 3 months–47 years). Thirty-five individuals had biallelic mutations in one of the five causative pre-replication genes. No homozygous or compound heterozygous null mutations were detected. In 10 individuals, no definitive molecular diagnosis was made. The triad of microtia, absent/hypoplastic patellae, and short stature was observed in 82% of individuals with MGS. Additional frequent clinical features were mammary hypoplasia (100%) and abnormal genitalia (42% predominantly cryptorchidism and hypoplastic labia minora/majora). One individual with ORC1 mutations only had short stature, emphasizing the highly variable clinical spectrum of MGS. Individuals with ORC1 mutations had significantly shorter stature and smaller head circumferences than individuals from other gene categories. Furthermore, compared with homozygous missense mutations, compound heterozygous mutations appeared to have a more severe effect on phenotype, causing more severe growth retardation in ORC4 and more frequently pulmonary emphysema in CDT1. A lethal phenotype was seen in four individuals with compound heterozygous ORC1 and CDT1 mutations. No other clear genotype–phenotype association was observed. Growth hormone and estrogen treatment may be of some benefit, respectively, to growth retardation and breast hypoplasia, though further studies in this patient group are needed. PMID:22333897

Timing is everything: early degradation of abscission layer is associated with increased seed shattering in U.S. weedy rice

PubMed Central

2011-01-01

Background Seed shattering, or shedding, is an important fitness trait for wild and weedy grasses. U.S. weedy rice (Oryza sativa) is a highly shattering weed, thought to have evolved from non-shattering cultivated ancestors. All U.S. weedy rice individuals examined to date contain a mutation in the sh4 locus associated with loss of shattering during rice domestication. Weedy individuals also share the shattering trait with wild rice, but not the ancestral shattering mutation at sh4; thus, how weedy rice reacquired the shattering phenotype is unknown. To establish the morphological basis of the parallel evolution of seed shattering in weedy rice and wild, we examined the abscission layer at the flower-pedicel junction in weedy individuals in comparison with wild and cultivated relatives. Results Consistent with previous work, shattering wild rice individuals possess clear, defined abscission layers at flowering, whereas non-shattering cultivated rice individuals do not. Shattering weedy rice from two separately evolved populations in the U.S. (SH and BHA) show patterns of abscission layer formation and degradation distinct from wild rice. Prior to flowering, the abscission layer has formed in all weedy individuals and by flowering it is already degrading. In contrast, wild O. rufipogon abscission layers have been shown not to degrade until after flowering has occurred. Conclusions Seed shattering in weedy rice involves the formation and degradation of an abscission layer in the flower-pedicel junction, as in wild Oryza, but is a developmentally different process from shattering in wild rice. Weedy rice abscission layers appear to break down earlier than wild abscission layers. The timing of weedy abscission layer degradation suggests that unidentified regulatory genes may play a critical role in the reacquisition of shattering in weedy rice, and sheds light on the morphological basis of parallel evolution for shattering in weedy and wild rice. PMID:21235796

Timing is everything: early degradation of abscission layer is associated with increased seed shattering in U.S. weedy rice.

PubMed

Thurber, Carrie S; Hepler, Peter K; Caicedo, Ana L

2011-01-14

Seed shattering, or shedding, is an important fitness trait for wild and weedy grasses. U.S. weedy rice (Oryza sativa) is a highly shattering weed, thought to have evolved from non-shattering cultivated ancestors. All U.S. weedy rice individuals examined to date contain a mutation in the sh4 locus associated with loss of shattering during rice domestication. Weedy individuals also share the shattering trait with wild rice, but not the ancestral shattering mutation at sh4; thus, how weedy rice reacquired the shattering phenotype is unknown. To establish the morphological basis of the parallel evolution of seed shattering in weedy rice and wild, we examined the abscission layer at the flower-pedicel junction in weedy individuals in comparison with wild and cultivated relatives. Consistent with previous work, shattering wild rice individuals possess clear, defined abscission layers at flowering, whereas non-shattering cultivated rice individuals do not. Shattering weedy rice from two separately evolved populations in the U.S. (SH and BHA) show patterns of abscission layer formation and degradation distinct from wild rice. Prior to flowering, the abscission layer has formed in all weedy individuals and by flowering it is already degrading. In contrast, wild O. rufipogon abscission layers have been shown not to degrade until after flowering has occurred. Seed shattering in weedy rice involves the formation and degradation of an abscission layer in the flower-pedicel junction, as in wild Oryza, but is a developmentally different process from shattering in wild rice. Weedy rice abscission layers appear to break down earlier than wild abscission layers. The timing of weedy abscission layer degradation suggests that unidentified regulatory genes may play a critical role in the reacquisition of shattering in weedy rice, and sheds light on the morphological basis of parallel evolution for shattering in weedy and wild rice.

Phenotype variability in a large Spanish family with Alport syndrome associated with novel mutations in COL4A3 gene.

PubMed

Cervera-Acedo, C; Coloma, A; Huarte-Loza, E; Sierra-Carpio, M; Domínguez-Garrido, E

2017-10-31

Alport syndrome is an inherited renal disorder characterized by glomerular basement membrane lesions with hematuria, proteinuria and frequent hearing defects and ocular abnormalities. The disease is associated with mutations in genes encoding α3, α4, or α5 chains of type IV collagen, namely COL4A3 and COL4A4 in chromosome 2 and COL4A5 in chromosome X. In contrast to the well-known X-linked and autosomal recessive phenotypes, there is very little information about the autosomal dominant. In view of the wide spectrum of phenotypes, an exact diagnosis is sometimes difficult to achieve. We investigated a Spanish family with variable phenotype of autosomal dominant Alport syndrome using clinical, histological, and genetic analysis. Mutational analysis of COL4A3 and COL4A4 genes showed a novel heterozygous mutation (c. 998G > A; p.G333E) in exon 18 of the COL4A3 gene. Among relatives carrying the novel mutation, the clinical phenotype was variable. Two additional COL4A3 mutations were found, a Pro-Leu substitution in exon 48 (p.P1461L) and a Ser-Cys substitution in exon 49 (p.S1492C), non-pathogenics alone. Carriers of p.G333E and p.P1461L or p.S1492C mutations in COL4A3 gene appear to be more severely affected than carriers of only p.G333E mutation, and the clinical findings has an earlier onset. In this way, we could speculate on a synergistic effect of compound heterozygosity that could explain the different phenotype observed in this family.

Targeted next-generation sequencing reveals novel USH2A mutations associated with diverse disease phenotypes: implications for clinical and molecular diagnosis.

PubMed

Chen, Xue; Sheng, Xunlun; Liu, Xiaoxing; Li, Huiping; Liu, Yani; Rong, Weining; Ha, Shaoping; Liu, Wenzhou; Kang, Xiaoli; Zhao, Kanxing; Zhao, Chen

2014-01-01

USH2A mutations have been implicated in the disease etiology of several inherited diseases, including Usher syndrome type 2 (USH2), nonsyndromic retinitis pigmentosa (RP), and nonsyndromic deafness. The complex genetic and phenotypic spectrums relevant to USH2A defects make it difficult to manage patients with such mutations. In the present study, we aim to determine the genetic etiology and to characterize the correlated clinical phenotypes for three Chinese pedigrees with nonsyndromic RP, one with RP sine pigmento (RPSP), and one with USH2. Family histories and clinical details for all included patients were reviewed. Ophthalmic examinations included best corrected visual acuities, visual field measurements, funduscopy, and electroretinography. Targeted next-generation sequencing (NGS) was applied using two sequence capture arrays to reveal the disease causative mutations for each family. Genotype-phenotype correlations were also annotated. Seven USH2A mutations, including four missense substitutions (p.P2762A, p.G3320C, p.R3719H, and p.G4763R), two splice site variants (c.8223+1G>A and c.8559-2T>C), and a nonsense mutation (p.Y3745*), were identified as disease causative in the five investigated families, of which three reported to have consanguineous marriage. Among all seven mutations, six were novel, and one was recurrent. Two homozygous missense mutations (p.P2762A and p.G3320C) were found in one individual family suggesting a potential double hit effect. Significant phenotypic divergences were revealed among the five families. Three families of the five families were affected with early, moderated, or late onset RP, one with RPSP, and the other one with USH2. Our study expands the genotypic and phenotypic variability relevant to USH2A mutations, which would help with a clear insight into the complex genetic and phenotypic spectrums relevant to USH2A defects, and is complementary for a better management of patients with such mutations. We have also

Targeted Next-Generation Sequencing Reveals Novel USH2A Mutations Associated with Diverse Disease Phenotypes: Implications for Clinical and Molecular Diagnosis

PubMed Central

Li, Huiping; Liu, Yani; Rong, Weining; Ha, Shaoping; Liu, Wenzhou; Kang, Xiaoli; Zhao, Kanxing; Zhao, Chen

2014-01-01

USH2A mutations have been implicated in the disease etiology of several inherited diseases, including Usher syndrome type 2 (USH2), nonsyndromic retinitis pigmentosa (RP), and nonsyndromic deafness. The complex genetic and phenotypic spectrums relevant to USH2A defects make it difficult to manage patients with such mutations. In the present study, we aim to determine the genetic etiology and to characterize the correlated clinical phenotypes for three Chinese pedigrees with nonsyndromic RP, one with RP sine pigmento (RPSP), and one with USH2. Family histories and clinical details for all included patients were reviewed. Ophthalmic examinations included best corrected visual acuities, visual field measurements, funduscopy, and electroretinography. Targeted next-generation sequencing (NGS) was applied using two sequence capture arrays to reveal the disease causative mutations for each family. Genotype-phenotype correlations were also annotated. Seven USH2A mutations, including four missense substitutions (p.P2762A, p.G3320C, p.R3719H, and p.G4763R), two splice site variants (c.8223+1G>A and c.8559-2T>C), and a nonsense mutation (p.Y3745*), were identified as disease causative in the five investigated families, of which three reported to have consanguineous marriage. Among all seven mutations, six were novel, and one was recurrent. Two homozygous missense mutations (p.P2762A and p.G3320C) were found in one individual family suggesting a potential double hit effect. Significant phenotypic divergences were revealed among the five families. Three families of the five families were affected with early, moderated, or late onset RP, one with RPSP, and the other one with USH2. Our study expands the genotypic and phenotypic variability relevant to USH2A mutations, which would help with a clear insight into the complex genetic and phenotypic spectrums relevant to USH2A defects, and is complementary for a better management of patients with such mutations. We have also

Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype.

PubMed

Knowles, Michael R; Ostrowski, Lawrence E; Leigh, Margaret W; Sears, Patrick R; Davis, Stephanie D; Wolf, Whitney E; Hazucha, Milan J; Carson, Johnny L; Olivier, Kenneth N; Sagel, Scott D; Rosenfeld, Margaret; Ferkol, Thomas W; Dell, Sharon D; Milla, Carlos E; Randell, Scott H; Yin, Weining; Sannuti, Aruna; Metjian, Hilda M; Noone, Peadar G; Noone, Peter J; Olson, Christina A; Patrone, Michael V; Dang, Hong; Lee, Hye-Seung; Hurd, Toby W; Gee, Heon Yung; Otto, Edgar A; Halbritter, Jan; Kohl, Stefan; Kircher, Martin; Krischer, Jeffrey; Bamshad, Michael J; Nickerson, Deborah A; Hildebrandt, Friedhelm; Shendure, Jay; Zariwala, Maimoona A

2014-03-15

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder of motile cilia, but the genetic cause is not defined for all patients with PCD. To identify disease-causing mutations in novel genes, we performed exome sequencing, follow-up characterization, mutation scanning, and genotype-phenotype studies in patients with PCD. Whole-exome sequencing was performed using NimbleGen capture and Illumina HiSeq sequencing. Sanger-based sequencing was used for mutation scanning, validation, and segregation analysis. We performed exome sequencing on an affected sib-pair with normal ultrastructure in more than 85% of cilia. A homozygous splice-site mutation was detected in RSPH1 in both siblings; parents were carriers. Screening RSPH1 in 413 unrelated probands, including 325 with PCD and 88 with idiopathic bronchiectasis, revealed biallelic loss-of-function mutations in nine additional probands. Five affected siblings of probands in RSPH1 families harbored the familial mutations. The 16 individuals with RSPH1 mutations had some features of PCD; however, nasal nitric oxide levels were higher than in patients with PCD with other gene mutations (98.3 vs. 20.7 nl/min; P < 0.0003). Additionally, individuals with RSPH1 mutations had a lower prevalence (8 of 16) of neonatal respiratory distress, and later onset of daily wet cough than typical for PCD, and better lung function (FEV1), compared with 75 age- and sex-matched PCD cases (73.0 vs. 61.8, FEV1 % predicted; P = 0.043). Cilia from individuals with RSPH1 mutations had normal beat frequency (6.1 ± Hz at 25°C), but an abnormal, circular beat pattern. The milder clinical disease and higher nasal nitric oxide in individuals with biallelic mutations in RSPH1 provides evidence of a unique genotype-phenotype relationship in PCD, and suggests that mutations in RSPH1 may be associated with residual ciliary function.

Mutation Spectrum in the Large GTPase Dynamin 2, and Genotype–Phenotype Correlation in Autosomal Dominant Centronuclear Myopathy

PubMed Central

Böhm, Johann; Biancalana, Valérie; DeChene, Elizabeth T.; Bitoun, Marc; Pierson, Christopher R.; Schaefer, Elise; Karasoy, Hatice; Dempsey, Melissa A.; Klein, Fabrice; Dondaine, Nicolas; Kretz, Christine; Haumesser, Nicolas; Poirson, Claire; Toussaint, Anne; Greenleaf, Rebecca S.; Barger, Melissa A.; Mahoney, Lane J.; Kang, Peter B.; Zanoteli, Edmar; Vissing, John; Witting, Nanna; Echaniz-Laguna, Andoni; Wallgren-Pettersson, Carina; Dowling, James; Merlini, Luciano; Oldfors, Anders; Ousager, Lilian Bomme; Melki, Judith; Krause, Amanda; Jern, Christina; Oliveira, Acary S. B.; Petit, Florence; Jacquette, Aurélia; Chaussenot, Annabelle; Mowat, David; Leheup, Bruno; Cristofano, Michele; Aldea, Juan José Poza; Michel, Fabrice; Furby, Alain; Llona, Jose E. Barcena; Van Coster, Rudy; Bertini, Enrico; Urtizberea, Jon Andoni; Drouin-Garraud, Valérie; Béroud, Christophe; Prudhon, Bernard; Bedford, Melanie; Mathews, Katherine; Erby, Lori A. H.; Smith, Stephen A.; Roggenbuck, Jennifer; Crowe, Carol A.; Spitale, Allison Brennan; Johal, Sheila C.; Amato, Anthony A.; Demmer, Laurie A.; Jonas, Jessica; Darras, Basil T.; Bird, Thomas D.; Laurino, Mercy; Welt, Selman I.; Trotter, Cynthia; Guicheney, Pascale; Das, Soma; Mandel, Jean-Louis; Beggs, Alan H.; Laporte, Jocelyn

2012-01-01

Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype–phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot–Marie–Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT. PMID:22396310

Third trimester fetal heart rate predicts phenotype and mutation burden in the type 1 long QT syndrome.

PubMed

Winbo, Annika; Fosdal, Inger; Lindh, Maria; Diamant, Ulla-Britt; Persson, Johan; Wettrell, Göran; Rydberg, Annika

2015-08-01

Early diagnosis and risk stratification is of clinical importance in the long QT syndrome (LQTS), however, little genotype-specific data are available regarding fetal LQTS. We investigate third trimester fetal heart rate, routinely recorded within public maternal health care, as a possible marker for LQT1 genotype and phenotype. This retrospective study includes 184 fetuses from 2 LQT1 founder populations segregating p.Y111C and p.R518X (74 noncarriers and 110 KCNQ1 mutation carriers, whereof 13 double mutation carriers). Pedigree-based measured genotype analysis revealed significant associations between fetal heart rate, genotype, and phenotype; mean third trimester prelabor fetal heart rates obtained from obstetric records (gestational week 29-41) were lower per added mutation (no mutation, 143±5 beats per minute; single mutation, 134±8 beats per minute; double mutations, 111±6 beats per minute; P<0.0001), and lower in symptomatic versus asymptomatic mutation carriers (122±10 versus 137±9 beats per minute; P<0.0001). Strong correlations between fetal heart rate and neonatal heart rate (r=0.700; P<0.001), and postnatal QTc (r=-0.762; P<0.001) were found. In a multivariable model, fetal genotype explained the majority of variance in fetal heart rate (-10 beats per minute per added mutation; P<1.0×10(-23)). Arrhythmia symptoms and intrauterine β-blocker exposure each predicted -7 beats per minute, P<0.0001. In this study including 184 fetuses from 2 LQT1 founder populations, third trimester fetal heart rate discriminated between fetal genotypes and correlated with severity of postnatal cardiac phenotype. This finding strengthens the role of fetal heart rate in the early detection and risk stratification of LQTS, particularly for fetuses with double mutations, at high risk of early life-threatening arrhythmias. © 2015 American Heart Association, Inc.

Identification of mutations, genotype-phenotype correlation and prenatal diagnosis of maple syrup urine disease in Indian patients.

PubMed

Gupta, Deepti; Bijarnia-Mahay, Sunita; Saxena, Renu; Kohli, Sudha; Dua-Puri, Ratna; Verma, Jyotsna; Thomas, E; Shigematsu, Yosuke; Yamaguchi, Seiji; Deb, Roumi; Verma, Ishwar Chander

2015-09-01

Maple syrup urine disease (MSUD) is caused by mutations in genes BCKDHA, BCKDHB, DBT encoding E1α, E1β, and E2 subunits of enzyme complex, branched-chain alpha-ketoacid dehydrogenase (BCKDH). BCKDH participates in catabolism of branched-chain amino acids (BCAAs) - leucine, isoleucine and valine in the energy production pathway. Deficiency or defect in the enzyme complex causes accumulation of BCAAs and keto-acids leading to toxicity. Twenty-four patients with MSUD were enrolled in the study for molecular characterization and genotype-phenotype correlation. Molecular studies were carried out by sequencing of the 3 genes by Sanger method. Bioinformatics tools were employed to classify novel variations into pathogenic or benign. The predicted effects of novel changes on protein structure were elucidated by 3D modeling. Mutations were detected in 22 of 24 patients (11, 7 and 4 in BCKDHB, BCKDHA and DBT genes, respectively). Twenty mutations including 11 novel mutations were identified. Protein modeling in novel mutations showed alteration of structure and function of these subunits. Mutations, c.1065 delT (BCKDHB gene) and c.939G > C (DBT gene) were noted to be recurrent, identified in 6 of 22 alleles and 5 of 8 alleles, respectively. Two-third patients were of neonatal classical phenotype (16 of 24). BCKDHB gene mutations were present in 10 of these 16 patients. Prenatal diagnoses were performed in 4 families. Consanguinity was noted in 37.5% families. Although no obvious genotype-phenotype correlation could be found in our study, most cases with mutation in BCKDHB gene presented in neonatal period. Large number of novel mutations underlines the heterogeneity and distinctness of gene pool from India. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

A case of mild phenotype Alport syndrome caused by COL4A3 mutations.

PubMed

Kamijo, Masafumi; Kitamura, Mineaki; Muta, Kumiko; Uramatsu, Tadashi; Obata, Yoko; Nozu, Kandai; Kaito, Hiroshi; Iijima, Kazumoto; Mukae, Hiroshi; Nishino, Tomoya

2017-11-01

In a case of 41-year-old man with mild nephropathy, Alport syndrome (AS) was diagnosed from the renal biopsy. However, the α5 chain of type IV collagen expressed in the glomerular basement membrane, which was the atypical staining pattern of AS. Genetic testing suggested autosomal recessive AS from heterozygous mutations at two positions in the type IV collagen α3 chain. These two gene mutations represented a new pattern of mutation and was suggested the association with an atypical α5 chain expression and mild phenotype.

[NOD2 gene mutation in Moroccan patients with Crohn's disease: prevalence, genotypic study and correlation of NOD2 gene mutation with the phenotype of Crohn's disease].

PubMed

Tamzaourte, Mouna; Errabih, Ikram; Krami, Hayat; Maha, Fadlouallah; Maria, Lahmiri; Benzzoubeir, Nadia; Ouazzani, Laaziza; Sefiani, Ahmed; Ouazzani, Houria

2017-01-01

The aim of this study was to determine the prevalence of NOD2/CARD15 gene mutations in a group of Moroccan patients with Crohn's disease and to study its correlation with genotype-phenotypic expression. We conducted a cross-sectional case-control study over a period of 16 months. 101 patients with Crohn's disease were enrolled between January 2012 and April 2013 as well as a control group of 107 patients. We performed a genetic analysis to identify 3 NOD2 gene variants: p.Arg702Trp, p.Gly908Arg and p.Leu1007fsins. Then we conducted a study of the correlation between genotype and phenotypic expression. The genetic analysis of patients with Crohn's disease highlighted the presence of NOD2 mutation in 14 patients (13.77%) versus 7 patients (6.53%) in the control group. The study of the frequency of different alleles showed p.Gly908Arg mutation in 6.43%, p.Leu1007fsins in 0.99% and p.Arg702Trp in 0.49% versus 2.80%, 0% and 0.46% in the control group respectively. The study of the correlation between genotype and phenotypic expression showed that CARD15 mutation is associated with ileocecal Crohn's disease, with fistulizing and stenosing behavior in Crohn's disease as well as with severe evolution and frequent recourse to surgery and immunosuppressants. The prevalence of NOD2/ CARD15 mutation in our case series is low. This mutation is correlated with severe Crohn's disease.

Genome duplication and mutations in ACE2 cause multicellular, fast-sedimenting phenotypes in evolved Saccharomyces cerevisiae

PubMed Central

Oud, Bart; Guadalupe-Medina, Victor; Nijkamp, Jurgen F.; de Ridder, Dick; Pronk, Jack T.; van Maris, Antonius J. A.; Daran, Jean-Marc

2013-01-01

Laboratory evolution of the yeast Saccharomyces cerevisiae in bioreactor batch cultures yielded variants that grow as multicellular, fast-sedimenting clusters. Knowledge of the molecular basis of this phenomenon may contribute to the understanding of natural evolution of multicellularity and to manipulating cell sedimentation in laboratory and industrial applications of S. cerevisiae. Multicellular, fast-sedimenting lineages obtained from a haploid S. cerevisiae strain in two independent evolution experiments were analyzed by whole genome resequencing. The two evolved cell lines showed different frameshift mutations in a stretch of eight adenosines in ACE2, which encodes a transcriptional regulator involved in cell cycle control and mother-daughter cell separation. Introduction of the two ace2 mutant alleles into the haploid parental strain led to slow-sedimenting cell clusters that consisted of just a few cells, thus representing only a partial reconstruction of the evolved phenotype. In addition to single-nucleotide mutations, a whole-genome duplication event had occurred in both evolved multicellular strains. Construction of a diploid reference strain with two mutant ace2 alleles led to complete reconstruction of the multicellular-fast sedimenting phenotype. This study shows that whole-genome duplication and a frameshift mutation in ACE2 are sufficient to generate a fast-sedimenting, multicellular phenotype in S. cerevisiae. The nature of the ace2 mutations and their occurrence in two independent evolution experiments encompassing fewer than 500 generations of selective growth suggest that switching between unicellular and multicellular phenotypes may be relevant for competitiveness of S. cerevisiae in natural environments. PMID:24145419

Historical changes in population structure during rice breeding programs in the northern limits of rice cultivation.

PubMed

Shinada, Hiroshi; Yamamoto, Toshio; Yamamoto, Eiji; Hori, Kiyosumi; Yonemaru, Junichi; Matsuba, Shuichi; Fujino, Kenji

2014-04-01

The rice local population was clearly differentiated into six groups over the 100-year history of rice breeding programs in the northern limit of rice cultivation over the world. Genetic improvements in plant breeding programs in local regions have led to the development of new cultivars with specific agronomic traits under environmental conditions and generated the unique genetic structures of local populations. Understanding historical changes in genome structures and phenotypic characteristics within local populations may be useful for identifying profitable genes and/or genetic resources and the creation of new gene combinations in plant breeding programs. In the present study, historical changes were elucidated in genome structures and phenotypic characteristics during 100-year rice breeding programs in Hokkaido, the northern limit of rice cultivation in the world. We selected 63 rice cultivars to represent the historical diversity of this local population from landraces to the current breeding lines. The results of the phylogenetic analysis demonstrated that these cultivars clearly differentiated into six groups over the history of rice breeding programs. Significant differences among these groups were detected in five of the seven traits, indicating that the differentiation of the Hokkaido rice population into these groups was correlated with these phenotypic changes. These results demonstrated that breeding practices in Hokkaido have created new genetic structures for adaptability to specific environmental conditions and breeding objectives. They also provide a new strategy for rice breeding programs in which such unique genes in local populations in the world can explore the genetic potentials of the local populations.

Mutations in KIAA0586 Cause Lethal Ciliopathies Ranging from a Hydrolethalus Phenotype to Short-Rib Polydactyly Syndrome

PubMed Central

Alby, Caroline; Piquand, Kevin; Huber, Céline; Megarbané, André; Ichkou, Amale; Legendre, Marine; Pelluard, Fanny; Encha-Ravazi, Ferechté; Abi-Tayeh, Georges; Bessières, Bettina; El Chehadeh-Djebbar, Salima; Laurent, Nicole; Faivre, Laurence; Sztriha, László; Zombor, Melinda; Szabó, Hajnalka; Failler, Marion; Garfa-Traore, Meriem; Bole, Christine; Nitschké, Patrick; Nizon, Mathilde; Elkhartoufi, Nadia; Clerget-Darpoux, Françoise; Munnich, Arnold; Lyonnet, Stanislas; Vekemans, Michel; Saunier, Sophie; Cormier-Daire, Valérie; Attié-Bitach, Tania; Thomas, Sophie

2015-01-01

KIAA0586, the human ortholog of chicken TALPID3, is a centrosomal protein that is essential for primary ciliogenesis. Its disruption in animal models causes defects attributed to abnormal hedgehog signaling; these defects include polydactyly and abnormal dorsoventral patterning of the neural tube. Here, we report homozygous mutations of KIAA0586 in four families affected by lethal ciliopathies ranging from a hydrolethalus phenotype to short-rib polydactyly. We show defective ciliogenesis, as well as abnormal response to SHH-signaling activation in cells derived from affected individuals, consistent with a role of KIAA0586 in primary cilia biogenesis. Whereas centriolar maturation seemed unaffected in mutant cells, we observed an abnormal extended pattern of CEP290, a centriolar satellite protein previously associated with ciliopathies. Our data show the crucial role of KIAA0586 in human primary ciliogenesis and subsequent abnormal hedgehog signaling through abnormal GLI3 processing. Our results thus establish that KIAA0586 mutations cause lethal ciliopathies. PMID:26166481

Rice epigenomics and epigenetics: challenges and opportunities.

PubMed

Chen, Xiangsong; Zhou, Dao-Xiu

2013-05-01

During recent years rice genome-wide epigenomic information such as DNA methylation and histone modifications, which are important for genome activity has been accumulated. The function of a number of rice epigenetic regulators has been studied, many of which are found to be involved in a diverse range of developmental and stress-responsive pathways. Analysis of epigenetic variations among different rice varieties indicates that epigenetic modification may lead to inheritable phenotypic variation. Characterizing phenotypic consequences of rice epigenomic variations and the underlining chromatin mechanism and identifying epialleles related to important agronomic traits may provide novel strategies to enhance agronomically favorable traits and grain productivity in rice. Copyright © 2013 Elsevier Ltd. All rights reserved.

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

PubMed

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

2016-08-15

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

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

PubMed Central

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

2010-01-01

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

Novel mutations and their genotype-phenotype correlations in patients with Noonan syndrome, using next-generation sequencing.

PubMed

Tafazoli, Alireza; Eshraghi, Peyman; Pantaleoni, Francesca; Vakili, Rahim; Moghaddassian, Morteza; Ghahraman, Martha; Muto, Valentina; Paolacci, Stefano; Golyan, Fatemeh Fardi; Abbaszadegan, Mohammad Reza

2018-03-01

Noonan Syndrome (NS) is an autosomal dominant disorder with many variable and heterogeneous conditions. The genetic basis for 20-30% of cases is still unknown. This study evaluates Iranian Noonan patients both clinically and genetically for the first time. Mutational analysis of PTPN11 gene was performed in 15 Iranian patients, using PCR and Sanger sequencing at phase one. Then, as phase two, Next Generation Sequencing (NGS) in the form of targeted resequencing was utilized for analysis of exons from other related genes. Homology modelling for the novel founded mutations was performed as well. The genotype, phenotype correlation was done according to the molecular findings and clinical features. Previously reported mutation (p.N308D) in some patients and a novel mutation (p.D155N) in one of the patients were identified in phase one. After applying NGS methods, known and new variants were found in four patients in other genes, including: CBL (p. V904I), KRAS (p. L53W), SOS1 (p. I1302V), and SOS1 (p. R552G). Structural studies of two deduced novel mutations in related genes revealed deficiencies in the mutated proteins. Following genotype, phenotype correlation, a new pattern of the presence of intellectual disability in two patients was registered. NS shows strong variable expressivity along the high genetic heterogeneity especially in distinct populations and ethnic groups. Also possibly unknown other causative genes may be exist. Obviously, more comprehensive and new technologies like NGS methods are the best choice for detection of molecular defects in patients for genotype, phenotype correlation and disease management. Copyright © 2017 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.

Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog.

PubMed

Solomon, Benjamin D; Bear, Kelly A; Wyllie, Adrian; Keaton, Amelia A; Dubourg, Christele; David, Veronique; Mercier, Sandra; Odent, Sylvie; Hehr, Ute; Paulussen, Aimee; Clegg, Nancy J; Delgado, Mauricio R; Bale, Sherri J; Lacbawan, Felicitas; Ardinger, Holly H; Aylsworth, Arthur S; Bhengu, Ntombenhle Louisa; Braddock, Stephen; Brookhyser, Karen; Burton, Barbara; Gaspar, Harald; Grix, Art; Horovitz, Dafne; Kanetzke, Erin; Kayserili, Hulya; Lev, Dorit; Nikkel, Sarah M; Norton, Mary; Roberts, Richard; Saal, Howard; Schaefer, G B; Schneider, Adele; Smith, Erika K; Sowry, Ellen; Spence, M Anne; Shalev, Stavit A; Steiner, Carlos E; Thompson, Elizabeth M; Winder, Thomas L; Balog, Joan Z; Hadley, Donald W; Zhou, Nan; Pineda-Alvarez, Daniel E; Roessler, Erich; Muenke, Maximilian

2012-07-01

Holoprosencephaly (HPE), the most common malformation of the human forebrain, may result from mutations in over 12 genes. Sonic Hedgehog (SHH) was the first such gene discovered; mutations in SHH remain the most common cause of non-chromosomal HPE. The severity spectrum is wide, ranging from incompatibility with extrauterine life to isolated midline facial differences. To characterise genetic and clinical findings in individuals with SHH mutations. Through the National Institutes of Health and collaborating centres, DNA from approximately 2000 individuals with HPE spectrum disorders were analysed for SHH variations. Clinical details were examined and combined with published cases. This study describes 396 individuals, representing 157 unrelated kindreds, with SHH mutations; 141 (36%) have not been previously reported. SHH mutations more commonly resulted in non-HPE (64%) than frank HPE (36%), and non-HPE was significantly more common in patients with SHH than in those with mutations in the other common HPE related genes (p<0.0001 compared to ZIC2 or SIX3). Individuals with truncating mutations were significantly more likely to have frank HPE than those with non-truncating mutations (49% vs 35%, respectively; p=0.012). While mutations were significantly more common in the N-terminus than in the C-terminus (including accounting for the relative size of the coding regions, p=0.00010), no specific genotype-phenotype correlations could be established regarding mutation location. SHH mutations overall result in milder disease than mutations in other common HPE related genes. HPE is more frequent in individuals with truncating mutations, but clinical predictions at the individual level remain elusive.

A chondrodysplasia family produced by mutations in the diastrophic dysplasia sulfate transporter gene: Genotype/phenotype correlations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Superti-Furga, A.; Steinmann, B.; Gitzelmann, R.

1996-05-03

Achondrogenesis type 1B (ACG-1B), atelosteogenesis type 2 (AO-2), and diastrophic dysplasia (DTD) are recessively inherited chondrodysplasia of decreasing severity caused by mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene on chromosome 5. In these conditions, sulfate transport across the cell membrane is impaired which results in insufficient sulfation of cartilage proteoglycans and thus in an abnormally low sulfate content of cartilage. The severity of the phenotype correlates well with the predicted effect of the underlying DTDST mutations: homozygosity or compound heterozygosity for stop codons or transmembrane domain substitutions mostly result in achondrogenesis type 1B, while other structural or regulatorymore » mutations usually result in one of the less severe phenotypes. The chondrodysplasia arising at the DTDST locus constitute a bone dysplasia family with recessive inheritance. 28 refs., 2 tabs.« less

The clinical phenotype of Lynch syndrome due to germline PMS2 mutations

PubMed Central

Senter, Leigha; Clendenning, Mark; Sotamaa, Kaisa; Hampel, Heather; Green, Jane; Potter, John D.; Lindblom, Annika; Lagerstedt, Kristina; Thibodeau, Stephen N.; Lindor, Noralane M.; Young, Joanne; Winship, Ingrid; Dowty, James G.; White, Darren M.; Hopper, John L.; Baglietto, Laura; Jenkins, Mark A.; de la Chapelle, Albert

2009-01-01

Background and Aims Although the clinical phenotype of Lynch syndrome (also known as Hereditary Nonpolyposis Colorectal Cancer) has been well described, little is known about disease in PMS2 mutation carriers. Now that mutation detection methods can discern mutations in PMS2 from mutations in its pseudogenes, more mutation carriers have been identified. Information about the clinical significance of PMS2 mutations is crucial for appropriate counseling. Here, we report the clinical characteristics of a large series of PMS2 mutation carriers. Methods We performed PMS2 mutation analysis using long range PCR and MLPA for 99 probands diagnosed with Lynch syndrome-associated tumors showing isolated loss of PMS2 by immunohistochemistry. Penetrance was calculated using a modified segregation analysis adjusting for ascertainment. Results Germline PMS2 mutations were detected in 62% of probands (n = 55 monoallelic; 6 biallelic). Among families with monoallelic PMS2 mutations, 65.5% met revised Bethesda guidelines. Compared with the general population, in mutation carriers, the incidence of colorectal cancer was 5.2 fold higher and the incidence of endometrial cancer was 7.5 fold higher. In North America, this translates to a cumulative cancer risk to age 70 of 15–20% for colorectal cancer, 15% for endometrial cancer, and 25–32% for any Lynch syndrome-associated cancer. No elevated risk for non-Lynch syndrome-associated cancers was observed. Conclusions PMS2 mutations contribute significantly to Lynch syndrome but the penetrance for monoallelic mutation carriers appears to be lower than that for the other mismatch repair genes. Modified counseling and cancer surveillance guidelines for PMS2 mutation carriers are proposed. PMID:18602922

Malaysian weedy rice shows its true stripes: wild Oryza and elite rice cultivars shape agricultural weed evolution in Southeast Asia.

PubMed

Song, Beng-Kah; Chuah, Tse-Seng; Tam, Sheh May; Olsen, Kenneth M

2014-10-01

Weedy rice is a close relative of domesticated rice (Oryza sativa) that competes aggressively with the crop and limits rice productivity worldwide. Most genetic studies of weedy rice have focused on populations in regions where no reproductively compatible wild Oryza species occur (North America, Europe and northern Asia). Here, we examined the population genetics of weedy rice in Malaysia, where wild rice (O. rufipogon) can be found growing in close proximity to cultivated and weedy rice. Using 375 accessions and a combined analysis of 24 neutral SSR loci and two rice domestication genes (sh4, controlling seed shattering, and Bh4, controlling hull colour), we addressed the following questions: (i) What is the relationship of Malaysian weedy rice to domesticated and wild rice, and to weedy rice strains in the USA? (ii) To what extent does the presence of O. rufipogon influence the genetic and phenotypic diversity of Malaysian weeds? (iii) What do the distributions of sh4 and Bh4 alleles and associated phenotypes reveal about the origin and contemporary evolution of Malaysian weedy rice? Our results reveal the following: independent evolutionary origins for Malaysian weeds and US strains, despite their very close phenotypic resemblance; wild-to-weed gene flow in Malaysian weed populations, including apparent adaptive introgression of seed-shattering alleles; and a prominent role for modern Malaysian cultivars in the origin and recent proliferation of Malaysian weeds. These findings suggest that the genetic complexity and adaptability of weedy crop relatives can be profoundly influenced by proximity to reproductively compatible wild and domesticated populations. © 2014 John Wiley & Sons Ltd.

A hot-spot mutation in CDC42 (p.Tyr64Cys) and novel phenotypes in the third patient with Takenouchi-Kosaki syndrome.

PubMed

Motokawa, Midori; Watanabe, Satoshi; Nakatomi, Akiko; Kondoh, Tatsuro; Matsumoto, Tadashi; Morifuji, Kanako; Sawada, Hirotake; Nishimura, Toyoki; Nunoi, Hiroyuki; Yoshiura, Koh-Ichiro; Moriuchi, Hiroyuki; Dateki, Sumito

2018-03-01

Takenouchi-Kosaki syndrome (TKS) is a congenital malformation syndrome characterized by severe developmental delay, macrothrombocytopenia, camptodactyly, sensorineural hearing loss, and dysmorphic facial features. Recently, a heterozygous de novo mutation (p.Tyr64Cys) in the CDC42 gene, which encodes a key small GTP-binding protein of the Rho-subfamily, was identified in two unrelated patients with TKS. We herein report a third patient with TKS who had the same heterozygous CDC42 mutation. The phenotype of the patient was very similar to those of the two previously reported patients with TKS; however, she also demonstrated novel clinical manifestations, such as congenital hypothyroidism and immunological disturbance. Thus, despite the heterozygous mutation of CDC42 (p.Tyr64Cys) likely being a hot-spot mutation for TKS, its phenotype may be variable. Further studies and the accumulation of patients with CDC42 mutations are needed to clarify the phenotype in patients with TKS and the pathophysiological roles of the CDC42 mutation.

Loss of function at RAE2, a previously unidentified EPFL, is required for awnlessness in cultivated Asian rice.

PubMed

Bessho-Uehara, Kanako; Wang, Diane R; Furuta, Tomoyuki; Minami, Anzu; Nagai, Keisuke; Gamuyao, Rico; Asano, Kenji; Angeles-Shim, Rosalyn B; Shimizu, Yoshihiro; Ayano, Madoka; Komeda, Norio; Doi, Kazuyuki; Miura, Kotaro; Toda, Yosuke; Kinoshita, Toshinori; Okuda, Satohiro; Higashiyama, Tetsuya; Nomoto, Mika; Tada, Yasuomi; Shinohara, Hidefumi; Matsubayashi, Yoshikatsu; Greenberg, Anthony; Wu, Jianzhong; Yasui, Hideshi; Yoshimura, Atsushi; Mori, Hitoshi; McCouch, Susan R; Ashikari, Motoyuki

2016-08-09

Domestication of crops based on artificial selection has contributed numerous beneficial traits for agriculture. Wild characteristics such as red pericarp and seed shattering were lost in both Asian (Oryza sativa) and African (Oryza glaberrima) cultivated rice species as a result of human selection on common genes. Awnedness, in contrast, is a trait that has been lost in both cultivated species due to selection on different sets of genes. In a previous report, we revealed that at least three loci regulate awn development in rice; however, the molecular mechanism underlying awnlessness remains unknown. Here we isolate and characterize a previously unidentified EPIDERMAL PATTERNING FACTOR-LIKE (EPFL) family member named REGULATOR OF AWN ELONGATION 2 (RAE2) and identify one of its requisite processing enzymes, SUBTILISIN-LIKE PROTEASE 1 (SLP1). The RAE2 precursor is specifically cleaved by SLP1 in the rice spikelet, where the mature RAE2 peptide subsequently induces awn elongation. Analysis of RAE2 sequence diversity identified a highly variable GC-rich region harboring multiple independent mutations underlying protein-length variation that disrupt the function of the RAE2 protein and condition the awnless phenotype in Asian rice. Cultivated African rice, on the other hand, retained the functional RAE2 allele despite its awnless phenotype. Our findings illuminate the molecular function of RAE2 in awn development and shed light on the independent domestication histories of Asian and African cultivated rice.

Kinetics and the mass transfer mechanism of hydrogen sulfide removal by biochar derived from rice hull.

PubMed

Shang, Guofeng; Liu, Liang; Chen, Ping; Shen, Guoqing; Li, Qiwu

2016-05-01

The biochar derived from rice hull was evaluated for its abilities to remove hydrogen sulfide (H2S) from gas phase. The surface area and pH of the biochar were compared. The biochar derived from rice hull was evaluated for its abilities to remove hydrogen sulfide (H2S) from gas phase. The surface area and pH of the biochar were compared. The different pyrolysis temperature has great influence on the adsorption of H2S. At the different pyrolysis temperature, the H2S removal efficiency of rice hull-derived biochar was different. The adsorption capacities of biochar were 2.09 mg·g(-1), 2.65 mg·g(-1), 16.30 mg·g(-1), 20.80 mg·g(-1), and 382.70 mg·g(-1), which their pyrolysis temperatures were 100 °C, 200 °C, 300 °C, 400 °C and 500 °C respectively. Based on the Yoon-Nelson model, it analyzed the mass transfer mechanism of hydrogen sulfide adsorption by biochar. The paper focuses on the biochar derived from rice hull-removed hydrogen sulfide (H2S) from gas phase. The surface area and pH of the biochar were compared. The different pyrolysis temperatures have great influence on the adsorption of H2S. At the different pyrolysis temperatures, the H2S removal efficiency of rice hull-derived biohar was different. The adsorption capacities of biochar were 2.09, 2.65, 16.30, 20.80, and 382.70 mg·g(-1), and their pyrolysis temperatures were 100, 200, 300, 400, and 500 °C, respectively. Based on the Yoon-Nelson model, the mass transfer mechanism of hydrogen sulfide adsorption by biochar was analyzed.

Frequency of MELAS main mutation in a phenotype-targeted young ischemic stroke patient population.

PubMed

Tatlisumak, Turgut; Putaala, Jukka; Innilä, Markus; Enzinger, Christian; Metso, Tiina M; Curtze, Sami; von Sarnowski, Bettina; Amaral-Silva, Alexandre; Jungehulsing, Gerhard Jan; Tanislav, Christian; Thijs, Vincent; Rolfs, Arndt; Norrving, Bo; Fazekas, Franz; Suomalainen, Anu; Kolodny, Edwin H

2016-02-01

Mitochondrial diseases, predominantly mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), may occasionally underlie or coincide with ischemic stroke (IS) in young and middle-aged individuals. We searched for undiagnosed patients with MELAS in a target subpopulation of unselected young IS patients enrolled in the Stroke in Young Fabry Patients study (sifap1). Among the 3291 IS patients aged 18-55 years recruited to the sifap1 study at 47 centers across 14 European countries, we identified potential MELAS patients with the following phenotypic features: (a) diagnosed cardiomyopathy or (b) presence of two of the three following findings: migraine, short stature (≤165 cm for males; ≤155 cm for females), and diabetes. Identified patients' blood samples underwent analysis of the common MELAS mutation, m.3243A>G in the MTTL1 gene of mitochondrial DNA. Clinical and cerebral MRI features of the mutation carriers were reviewed. We analyzed blood samples of 238 patients (177 with cardiomyopathy) leading to identification of four previously unrecognized MELAS main mutation carrier-patients. Their clinical and MRI characteristics were within the expectation for common IS patients except for severe hearing loss in one patient and hyperintensity of the pulvinar thalami on T1-weighted MRI in another one. Genetic testing for the m.3243A>G MELAS mutation in young patients with IS based on phenotypes suggestive of mitochondrial disease identifies previously unrecognized carriers of MELAS main mutation, but does not prove MELAS as the putative cause.

HSAN1 mutations in serine palmitoyltransferase reveal a close structure-function-phenotype relationship.

PubMed

Bode, Heiko; Bourquin, Florence; Suriyanarayanan, Saranya; Wei, Yu; Alecu, Irina; Othman, Alaa; Von Eckardstein, Arnold; Hornemann, Thorsten

2016-03-01

Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is a rare autosomal dominant inherited peripheral neuropathy caused by mutations in the SPTLC1 and SPTLC2 subunits of serine palmitoyltransferase (SPT). The mutations induce a permanent shift in the substrate preference from L-serine to L-alanine, which results in the pathological formation of atypical and neurotoxic 1-deoxy-sphingolipids (1-deoxySL). Here we compared the enzymatic properties of 11 SPTLC1 and six SPTLC2 mutants using a uniform isotope labelling approach. In total, eight SPT mutants (STPLC1p.C133W, p.C133Y, p.S331F, p.S331Y and SPTLC2p.A182P, p.G382V, p.S384F, p.I504F) were associated with increased 1-deoxySL synthesis. Despite earlier reports, canonical activity with l-serine was not reduced in any of the investigated SPT mutants. Three variants (SPTLC1p.S331F/Y and SPTLC2p.I505Y) showed an increased canonical activity and increased formation of C20 sphingoid bases. These three mutations are associated with an exceptionally severe HSAN1 phenotype, and increased C20 sphingosine levels were also confirmed in plasma of patients. A principal component analysis of the analysed sphingoid bases clustered the mutations into three separate entities. Each cluster was related to a distinct clinical outcome (no, mild and severe HSAN1 phenotype). A homology model based on the protein structure of the prokaryotic SPT recapitulated the same grouping on a structural level. Mutations associated with the mild form clustered around the active site, whereas mutations associated with the severe form were located on the surface of the protein. In conclusion, we showed that HSAN1 mutations in SPT have distinct biochemical properties, which allowed for the prediction of the clinical symptoms on the basis of the plasma sphingoid base profile. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Two Siblings With a CDKL5 Mutation: Genotype and Phenotype Evaluation.

PubMed

Hagebeuk, Eveline E O; Marcelis, Carlo L; Alders, Mariëlle; Kaspers, Ageeth; de Weerd, Al W

2015-10-01

This is the second report of a family with a recurrence of a CDKL5 mutation (c. 283-3_290del) in 2 sisters. Both parents tested negative for the mutation in all tissues, but germline mosaicism is likely. Clinically CDKL5 patients resemble those with Rett syndrome, caused by a MECP2 mutation, who experience a regression, after an initial normal development. Even though both siblings showed a typical CDKL5 phenotype, their presentation is different. From birth, the oldest daughter had a severe developmental delay, feeding problems, and hypotonia and experienced daily refractory seizures. The youngest daughter appeared to be normal until age 3 months. At that age seizures started, deterioration and regression became evident, and an epileptic encephalopathy developed. This report of familial recurrence, with suspected germline mosaicism in a healthy parent, has important consequences for genetic counseling. Although it is not possible to predict an exact recurrence risk, it is likely to be increased. © The Author(s) 2015.

The Association of Multiple Interacting Genes with Specific Phenotypes in Rice Using Gene Coexpression Networks1[C][W][OA

PubMed Central

Ficklin, Stephen P.; Luo, Feng; Feltus, F. Alex

2010-01-01

Discovering gene sets underlying the expression of a given phenotype is of great importance, as many phenotypes are the result of complex gene-gene interactions. Gene coexpression networks, built using a set of microarray samples as input, can help elucidate tightly coexpressed gene sets (modules) that are mixed with genes of known and unknown function. Functional enrichment analysis of modules further subdivides the coexpressed gene set into cofunctional gene clusters that may coexist in the module with other functionally related gene clusters. In this study, 45 coexpressed gene modules and 76 cofunctional gene clusters were discovered for rice (Oryza sativa) using a global, knowledge-independent paradigm and the combination of two network construction methodologies. Some clusters were enriched for previously characterized mutant phenotypes, providing evidence for specific gene sets (and their annotated molecular functions) that underlie specific phenotypes. PMID:20668062

Identification of a novel mutation in RIPK4 in a kindred with phenotypic features of Bartsocas-Papas and CHAND syndromes.

PubMed

Gollasch, Benjamin; Basmanav, Fitnat Buket; Nanda, Arti; Fritz, Günter; Mahmoudi, Hassnaa; Thiele, Holger; Wehner, Maria; Wolf, Sabrina; Altmüller, Janine; Nürnberg, Peter; Frank, Jorge; Betz, Regina C

2015-11-01

Three children from an expanded consanguineous Kuwaiti kindred presented with ankyloblepharon, sparse and curly hair, and hypoplastic nails, suggestive of CHAND syndrome (OMIM 214350) that belongs to the heterogeneous spectrum of ectodermal dysplasias. After exclusion of pathogenic mutations in TP63 we performed homozygosity mapping, followed by exome sequencing of one affected individual. We initially identified three homozygous mutations in the linked region, located in PWP2, MX2 and RIPK4. Recently, mutations in RIPK4 have been reported in Bartsocas-Papas syndrome (OMIM 263650) that shows overlapping clinical symptoms with the phenotype observed in the affected individuals studied here. Subsequent analysis of affected and non-affected family members showed that mutation c.850G>A (p.Glu284Lys) in RIPK4 was in complete segregation with the disease phenotype, in accordance with an autosomal recessive inheritance pattern, thus supporting pathogenicity of this variant. Interestingly, however, our patients did not have cleft lip/palate, a common feature encountered in Bartsocas-Papas syndrome. Whereas in Bartsocas-Papas syndromes missense mutations are usually located within the serin/threonin kinase of RIPK4, the mutation detected in our family resides just outside of the kinase domain, which could explain the milder phenotype. Our data raise the question if CHAND syndrome indeed is a distinct entity. Alternatively, CHAND and Bartsocas-Papas syndrome might be allelic disorders or RIPK4 mutations could confer varying degrees of phenotypic severity, depending on their localization within or outside functionally important domains. Our findings indicate that making an accurate diagnosis based only on the prevailing clinical symptoms is challenging. © 2015 Wiley Periodicals, Inc.

Phenotypic Variability in Autosomal Dominant Familial Alzheimer Disease due to the S170F Mutation of Presenilin-1.

PubMed

Tiedt, Hannes O; Benjamin, Beate; Niedeggen, Michael; Lueschow, Andreas

2018-02-22

In rare cases, patients with Alzheimer disease (AD) present at an early age and with a family history suggestive of an autosomal dominant mode of inheritance. Mutations of the presenilin-1 (PSEN1) gene are the most common causes of dementia in these patients. Early-onset and particularly familial AD patients frequently present with variable non-amnestic cognitive symptoms such as visual, language or behavioural changes as well as non-cognitive, e.g. motor, symptoms. To investigate the phenotypic variability in carriers of the PSEN1 S170F mutation. We report a family with 4 patients carrying the S170F mutation of whom 2 underwent detailed clinical examinations. We discuss our current findings in the context of previously reported S170F cases. The clinical phenotype was consistent regarding initial memory impairment and early onset in the late twenties found in all S170F patients. There were frequent non-amnestic cognitive changes and, at early stages of the disease, indications of a more pronounced disturbance of visuospatial abilities as compared to face and object recognition. Non-cognitive symptoms most often included myoclonus and cerebellar ataxia. A review of the available case reports indicates some phenotypic variability associated with the S170F mutation including different constellations of symptoms such as parkinsonism and delusions. The variable clinical findings associated with the S170F mutation highlight the relevance of atypical phenotypes in the context of research and under a clinical perspective. CSF sampling and detection of Aβ species may be essential to indicate AD pathology in unclear cases presenting with cognitive and motor symptoms at a younger age. © 2018 S. Karger AG, Basel.

Two novel mutations of fibrillin-1 gene correlate with different phenotypes of Marfan syndrome in Chinese families.

PubMed

Zhao, Feng; Pan, Xinyuan; Zhao, Kanxing; Zhao, Chen

2013-01-01

To identify the causative mutations in two Chinese families with autosomal dominant Marfan syndrome and to describe the associated phenotypes. Complete physical, ophthalmic, and cardiovascular examinations were given to the patients and unaffected individuals in the two families. Exclusive linkage mapping was performed for transforming growth factor beta receptor II (TGFBR2) and fibrillin-1 (FBN1) loci in both families. The entire coding region and flanking splice sites of the FBN1 gene were screened for mutations in the two families with Sanger sequencing. The potential mutations of FBN1 were tested in 100 normal controls. Lens dislocation was observed in two out of ten patients in the MF1 family and all patients in the MF2 family. However, the MF1 family displayed more severe cardiovascular and skeletal system involvement compared with the MF2 family. The transforming growth factor beta receptor II locus was excluded in both families by linkage analysis. A maximum multipoint lod score score of 2.83 was obtained for marker D15S992 (located in the FBN1 gene) in the MF1 family and 1.51 for the same marker in the MF2 family. Two novel mutations of FBN1, p.C271* and p.C637Y, were identified in the MF1 and MF2 families, respectively. Genotype-phenotype correlations in this study indicate that nonsense mutations of FBN1 may correlate with relatively severe systemic phenotypes when compared with cysteine substitutions, the most common type of FBN1 mutations. Genetic diagnosis for patients with Marfan syndrome would help with genetic counseling, clinical intervention, and prognosis.

Two novel mutations of fibrillin-1 gene correlate with different phenotypes of Marfan syndrome in Chinese families

PubMed Central

Zhao, Feng; Pan, Xinyuan; Zhao, Kanxing

2013-01-01

Purpose To identify the causative mutations in two Chinese families with autosomal dominant Marfan syndrome and to describe the associated phenotypes. Methods Complete physical, ophthalmic, and cardiovascular examinations were given to the patients and unaffected individuals in the two families. Exclusive linkage mapping was performed for transforming growth factor beta receptor II (TGFBR2) and fibrillin-1 (FBN1) loci in both families. The entire coding region and flanking splice sites of the FBN1 gene were screened for mutations in the two families with Sanger sequencing. The potential mutations of FBN1 were tested in 100 normal controls. Results Lens dislocation was observed in two out of ten patients in the MF1 family and all patients in the MF2 family. However, the MF1 family displayed more severe cardiovascular and skeletal system involvement compared with the MF2 family. The transforming growth factor beta receptor II locus was excluded in both families by linkage analysis. A maximum multipoint lod score score of 2.83 was obtained for marker D15S992 (located in the FBN1 gene) in the MF1 family and 1.51 for the same marker in the MF2 family. Two novel mutations of FBN1, p.C271* and p.C637Y, were identified in the MF1 and MF2 families, respectively. Conclusions Genotype-phenotype correlations in this study indicate that nonsense mutations of FBN1 may correlate with relatively severe systemic phenotypes when compared with cysteine substitutions, the most common type of FBN1 mutations. Genetic diagnosis for patients with Marfan syndrome would help with genetic counseling, clinical intervention, and prognosis. PMID:23592911

How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum.

PubMed

Banka, Siddharth; Veeramachaneni, Ratna; Reardon, William; Howard, Emma; Bunstone, Sancha; Ragge, Nicola; Parker, Michael J; Crow, Yanick J; Kerr, Bronwyn; Kingston, Helen; Metcalfe, Kay; Chandler, Kate; Magee, Alex; Stewart, Fiona; McConnell, Vivienne P M; Donnelly, Deirdre E; Berland, Siren; Houge, Gunnar; Morton, Jenny E; Oley, Christine; Revencu, Nicole; Park, Soo-Mi; Davies, Sally J; Fry, Andrew E; Lynch, Sally Ann; Gill, Harinder; Schweiger, Susann; Lam, Wayne W K; Tolmie, John; Mohammed, Shehla N; Hobson, Emma; Smith, Audrey; Blyth, Moira; Bennett, Christopher; Vasudevan, Pradeep C; García-Miñaúr, Sixto; Henderson, Alex; Goodship, Judith; Wright, Michael J; Fisher, Richard; Gibbons, Richard; Price, Susan M; C de Silva, Deepthi; Temple, I Karen; Collins, Amanda L; Lachlan, Katherine; Elmslie, Frances; McEntagart, Meriel; Castle, Bruce; Clayton-Smith, Jill; Black, Graeme C; Donnai, Dian

2012-04-01

MLL2 mutations are detected in 55 to 80% of patients with Kabuki syndrome (KS). In 20 to 45% patients with KS, the genetic basis remains unknown, suggesting possible genetic heterogeneity. Here, we present the largest yet reported cohort of 116 patients with KS. We identified MLL2 variants in 74 patients, of which 47 are novel and a majority are truncating. We show that pathogenic missense mutations were commonly located in exon 48. We undertook a systematic facial KS morphology study of patients with KS at our regional dysmorphology meeting. Our data suggest that nearly all patients with typical KS facial features have pathogenic MLL2 mutations, although KS can be phenotypically variable. Furthermore, we show that MLL2 mutation-positive KS patients are more likely to have feeding problems, kidney anomalies, early breast bud development, joint dislocations and palatal malformations in comparison with MLL2 mutation-negative patients. Our work expands the mutation spectrum of MLL2 that may help in better understanding of this molecule, which is important in gene expression, epigenetic control of active chromatin states, embryonic development and cancer. Our analyses of the phenotype indicates that MLL2 mutation-positive and -negative patients differ systematically, and genetic heterogeneity of KS is not as extensive as previously suggested. Moreover, phenotypic variability of KS suggests that MLL2 testing should be considered even in atypical patients.

Gene-specific of endocannabinoid receptor 1 (cnr1a) by ethanol probably leads to the development of fetal alcohol spectrum disorder (FASD) phenotypes in Japanese rice fish (Oryzias latipes) embryogenesis

USDA-ARS?s Scientific Manuscript database

Developmental ethanol exposure is able to induce Fetal Alcohol Spectrum Disorder (FASD) phenotypes in Japanese rice fish (Oryzias latipes). This study investigated possible differential expression of cannabinoid receptor (cnr) mRNAs during Japanese rice fish embryogenesis and variability to ethanol-...

Identification of QTLs for resistant starch and total alkaloid content in brown and polished rice.

PubMed

Zeng, Y W; Sun, D; Du, J; Pu, X Y; Yang, S M; Yang, X M; Yang, T; Yang, J Z

2016-07-29

An F3 population consisting of 117 F2:3 families derived from a cross between two varieties of rice, Gongmi No. 3 and Diantun 502, with a large difference in their resistant starch and total alkaloid content, was used for quantitative trait locus (QTL) mapping. Two QTLs of resistant starch for rice (qRS7-1, qRS7-2) were identified in a linkage group on chromosome 7, which could explain phenotypic variance from 7.6 to 17.3%, due to additive effects for resistant starch from Gongmi No. 3 or over-dominance effects for qRS7-2 of the marker interval (RM3404-RM478) on chromosome 7 from Gongmi No. 3, accounting for 13.8-17.3% of the phenotypic variance. Two QTLs of total alkaloids for brown rice (qALb7-1, qALb7-2) were identified in the same linkage group, which could explain phenotypic variance from 7.7 and 19.3%, respectively, due to dominance or over-dominance effects for total alkaloids on chromosome 7 from Diantun 502. To our knowledge, these are the first QTLs to be identified, which are related to resistant starch and total alkaloid content in rice. These results are beneficial for understanding the genetic basis of, as well as for developing markers linked with, resistant starch and total alkaloids of functional components for marker-assisted selection breeding in rice.

Phenotypic Heterogeneity in a DFNA20/26 family segregating a novel ACTG1 mutation.

PubMed

Yuan, Yongyi; Gao, Xue; Huang, Bangqing; Lu, Jingqiao; Wang, Guojian; Lin, Xi; Qu, Yan; Dai, Pu

2016-02-01

Genetic factors play an important role in hearing loss, contributing to approximately 60% of cases of congenital hearing loss. Autosomal dominant deafness accounts for approximately 20% of cases of hereditary hearing loss. Diseases with autosomal dominant inheritance often show pleiotropy, different degrees of penetrance, and variable expressivity. A three-generation Chinese family with autosomal dominant nonsyndromic hearing impairment (ADNSHI) was enrolled in this study. Audiometric data and blood samples were collected from the family. In total, 129 known human deafness genes were sequenced using next-generation sequencing (NGS) to identify the responsible gene mutation in the family. Whole Exome Sequencing (WES) was performed to exclude any other variant that cosegregated with the phenotype. The age of onset of the affected family members was the second decade of life. The condition began with high-frequency hearing impairment in all family members excluding III:2. The novel ACTG1 c.638A > G (p.K213R) mutation was found in all affected family members and was not found in the unaffected family members. A heterozygous c.638A > G mutation in ACTG1 and homozygous c.109G > A (p.V37I) mutation in GJB2 were found in III:2, who was born with hearing loss. The WES result concurred with that of targeted sequencing of known deafness genes. The novel mutation p.K213R in ACTG1 was found to be co-segregated with hearing loss and the genetic cause of ADNSHI in this family. A homozygous mutation associated with recessive inheritance only rarely co-acts with a dominant mutation to result in hearing loss in a dominant family. In such cases, the mutations in the two genes, as in ACTG1 and GJB2 in the present study, may result in a more severe phenotype. Targeted sequencing of known deafness genes is one of the best choices to identify the genetic cause in hereditary hearing loss families.

Two recessive mutations in FGF5 are associated with the long-hair phenotype in donkeys.

PubMed

Legrand, Romain; Tiret, Laurent; Abitbol, Marie

2014-09-25

Seven donkey breeds are recognized by the French studbook. Individuals from the Pyrenean, Provence, Berry Black, Normand, Cotentin and Bourbonnais breeds are characterized by a short coat, while those from the Poitou breed (Baudet du Poitou) are characterized by a long-hair phenotype. We hypothesized that loss-of-function mutations in the FGF5 (fibroblast growth factor 5) gene, which are associated with a long-hair phenotype in several mammalian species, may account for the special coat feature of Poitou donkeys. To the best of our knowledge, mutations in FGF5 have never been described in Equidae. We sequenced the FGF5 gene from 35 long-haired Poitou donkeys, as well as from a panel of 67 short-haired donkeys from the six other French breeds and 131 short-haired ponies and horses. We identified a recessive c.433_434delAT frameshift deletion in FGF5, present in Poitou and three other donkey breeds and a recessive nonsense c.245G > A substitution, present in Poitou and four other donkey breeds. The frameshift deletion was associated with the long-hair phenotype in Poitou donkeys when present in two copies (n = 31) or combined with the nonsense mutation (n = 4). The frameshift deletion led to a stop codon at position 159 whereas the nonsense mutation led to a stop codon at position 82 in the FGF5 protein. In silico, the two truncated FGF5 proteins were predicted to lack the critical β strands involved in the interaction between FGF5 and its receptor, a mandatory step to inhibit hair growth. Our results highlight the allelic heterogeneity of the long-hair phenotype in donkeys and enlarge the panel of recessive FGF5 loss-of-function alleles described in mammals. Thanks to the DNA test developed in this study, breeders of non-Poitou breeds will have the opportunity to identify long-hair carriers in their breeding stocks.

Novel mutations of RPGR in Chinese retinitis pigmentosa patients and the genotype-phenotype correlation.

PubMed

Yang, Liping; Yin, Xiaobei; Feng, Lina; You, Debo; Wu, Lemeng; Chen, Ningning; Li, Aijun; Li, Genlin; Ma, Zhizhong

2014-01-01

X-linked Retinitis Pigmentosa (XLRP) accounts for 10-20% of all RP cases, and represents the most severe subtype of this disease. Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene are the most common causes of XLRP, accounting for over 70-75% of all XLRP cases. In this work, we analyzed all the exons of RPGR gene with Sanger sequencing in seven Chinese XLRP families, two of these with a provisional diagnosis of adRP but without male-to-male transmission. Three novel deletions (c.2233_34delAG; c.2236_37delGA and c.2403_04delAG) and two known nonsense mutations (c.851C→G and c.2260G→T) were identified in five families. Two novel deletions (c.2233_34delAG and c.2236_37delGA) resulted in the same frame shift (p.E746RfsX22), created similar phenotype in Family 3 and 4. The novel deletion (c.2403_04delAG; p.E802GfsX31) resulted in both XLRP and x-linked cone-rod dystrophy within the male patients of family 5, which suggested the presence of either genetic or environmental modifiers, or both, play a substantial role in disease expression. Genotype-phenotype correlation analysis suggested that (1) both patients and female carriers with mutation in Exon 8 (Family 1) manifest more severe disease than did those with ORF15 mutations (Family 2&3&4); (2) mutation close to downstream of ORF15 (Family 5) demonstrate the early preferential loss of cone function with moderate loss of rod function.

Estimation of loci involved in non-shattering of seeds in early rice domestication.

PubMed

Ishikawa, Ryo; Nishimura, Akinori; Htun, Than Myint; Nishioka, Ryo; Oka, Yumi; Tsujimura, Yuki; Inoue, Chizuru; Ishii, Takashige

2017-04-01

Rice (Oryza sativa L.) is widely cultivated around the world and is known to be domesticated from its wild form, O. rufipogon. A loss of seed shattering is one of the most obvious phenotypic changes selected for during rice domestication. Previously, three seed-shattering loci, qSH1, sh4, and qSH3 were reported to be involved in non-shattering of seeds of Japonica-type cultivated rice, O. sativa cv. Nipponbare. In this study, we focused on non-shattering characteristics of O. sativa Indica cv. IR36 having functional allele at qSH1. We produced backcross recombinant inbred lines having chromosomal segments from IR36 in the genetic background of wild rice, O. rufipogon W630. Histological and quantitative trait loci analyses of abscission layer formation were conducted. In the analysis of quantitative trait loci, a strong peak was observed close to sh4. We, nevertheless, found that some lines showed complete abscission layer formation despite carrying the IR36 allele at sh4, implying that non-shattering of seeds of IR36 could be regulated by the combination of mutations at sh4 and other seed-shattering loci. We also genotyped qSH3, a recently identified seed-shattering locus. Lines that have the IR36 alleles at sh4 and qSH3 showed inhibition of abscission layer formation but the degree of seed shattering was different from that of IR36. On the basis of these results, we estimated that non-shattering of seeds in early rice domestication involved mutations in at least three loci, and these genetic materials produced in this study may help to identify novel seed-shattering loci.

The impact of herbicide-resistant rice technology on phenotypic diversity and population structure of United States weedy rice.

PubMed

Burgos, Nilda Roma; Singh, Vijay; Tseng, Te Ming; Black, Howard; Young, Nelson D; Huang, Zhongyun; Hyma, Katie E; Gealy, David R; Caicedo, Ana L

2014-11-01

The use of herbicide-resistant (HR) Clearfield rice (Oryza sativa) to control weedy rice has increased in the past 12 years to constitute about 60% of rice acreage in Arkansas, where most U.S. rice is grown. To assess the impact of HR cultivated rice on the herbicide resistance and population structure of weedy rice, weedy samples were collected from commercial fields with a history of Clearfield rice. Panicles from each weedy type were harvested and tested for resistance to imazethapyr. The majority of plants sampled had at least 20% resistant offspring. These resistant weeds were 97 to 199 cm tall and initiated flowering from 78 to 128 d, generally later than recorded for accessions collected prior to the widespread use of Clearfield rice (i.e. historical accessions). Whereas the majority (70%) of historical accessions had straw-colored hulls, only 30% of contemporary HR weedy rice had straw-colored hulls. Analysis of genotyping-by-sequencing data showed that HR weeds were not genetically structured according to hull color, whereas historical weedy rice was separated into straw-hull and black-hull populations. A significant portion of the local rice crop genome was introgressed into HR weedy rice, which was rare in historical weedy accessions. Admixture analyses showed that HR weeds tend to possess crop haplotypes in the portion of chromosome 2 containing the ACETOLACTATE SYNTHASE gene, which confers herbicide resistance to Clearfield rice. Thus, U.S. HR weedy rice is a distinct population relative to historical weedy rice and shows modifications in morphology and phenology that are relevant to weed management. © 2014 American Society of Plant Biologists. All Rights Reserved.

Mutations in KIAA0586 Cause Lethal Ciliopathies Ranging from a Hydrolethalus Phenotype to Short-Rib Polydactyly Syndrome.

PubMed

Alby, Caroline; Piquand, Kevin; Huber, Céline; Megarbané, André; Ichkou, Amale; Legendre, Marine; Pelluard, Fanny; Encha-Ravazi, Ferechté; Abi-Tayeh, Georges; Bessières, Bettina; El Chehadeh-Djebbar, Salima; Laurent, Nicole; Faivre, Laurence; Sztriha, László; Zombor, Melinda; Szabó, Hajnalka; Failler, Marion; Garfa-Traore, Meriem; Bole, Christine; Nitschké, Patrick; Nizon, Mathilde; Elkhartoufi, Nadia; Clerget-Darpoux, Françoise; Munnich, Arnold; Lyonnet, Stanislas; Vekemans, Michel; Saunier, Sophie; Cormier-Daire, Valérie; Attié-Bitach, Tania; Thomas, Sophie

2015-08-06

KIAA0586, the human ortholog of chicken TALPID3, is a centrosomal protein that is essential for primary ciliogenesis. Its disruption in animal models causes defects attributed to abnormal hedgehog signaling; these defects include polydactyly and abnormal dorsoventral patterning of the neural tube. Here, we report homozygous mutations of KIAA0586 in four families affected by lethal ciliopathies ranging from a hydrolethalus phenotype to short-rib polydactyly. We show defective ciliogenesis, as well as abnormal response to SHH-signaling activation in cells derived from affected individuals, consistent with a role of KIAA0586 in primary cilia biogenesis. Whereas centriolar maturation seemed unaffected in mutant cells, we observed an abnormal extended pattern of CEP290, a centriolar satellite protein previously associated with ciliopathies. Our data show the crucial role of KIAA0586 in human primary ciliogenesis and subsequent abnormal hedgehog signaling through abnormal GLI3 processing. Our results thus establish that KIAA0586 mutations cause lethal ciliopathies. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

SOX10 mutation causes Waardenburg syndrome associated with distinctive phenotypic features in an Iranian family: A clue for phenotype-directed genetic analysis.

PubMed

Jalilian, Nazanin; Tabatabaiefar, Mohammad Amin; Alimadadi, Hossein; Noori-Daloii, Mohammad Reza

2017-05-01

Waardenburg syndrome (WS) is a neurocristopathy characterized by hearing impairment and pigmentary disturbances in hair, eyes, and skin. WS is clinically heterogeneous and can be subdivided into four major types (WS1-WS4) where WS4 or Shah-Waardenburg is diagnosed when WS2 is accompanied by Hirschsprung disease (HD). Mutations of SOX10, EDN3/EDNRB have been identified in association with WS4. This study was aimed to determine the pathogenic variant in an Iranian pedigree affected with WS4. A two-generation pedigree with three affected members and considerable phenotypic heterogeneity was recruited. The proband was a 15-year-old boy, with severe to profound sensorineural hearing impairment, heterochromia iridis, hypoplastic blue eyes and Hirschprung disease. The other two also presented characteristics of WS2 and complained of chronic constipation with normal anorectal reflex. Sequencing of all exons and exon-intron boundaries of SOX10, EDN3/EDNRB revealed a heterozygous variant c.422T > C in exon 3 of SOX10 confirmed by a series of evidence to be pathogenic. It resulted in p.L141P at the protein level. Leucin 141 is located in Nuclear Export signal, HMG box of the protein. This study is the first report of a WS4 family in the Iranian population. The mutation is associated with distinctive phenotypic profile (association of anosmia and chronic constipation with SOX10 mutations) and could further improve diagnosis and counseling of WS in the Iranian population and can contribute to phenotype-directed genetic analysis. Copyright © 2017 Elsevier B.V. All rights reserved.

Retinal phenotypic characterization of patients with ABCA4 retinopathydue to the homozygous p.Ala1773Val mutation

PubMed Central

López-Rubio, Salvador; Chacon-Camacho, Oscar F.; Matsui, Rodrigo; Guadarrama-Vallejo, Dalia; Astiazarán, Mirena C.

2018-01-01

Purpose To describe the retinal clinical features of a group of Mexican patients with Stargardt disease carrying the uncommon p.Ala1773Val founder mutation in ABCA4. Methods Ten patients carrying the p.Ala1773Val mutation, nine of them homozygously, were included. Visual function studies included best-corrected visual acuity, electroretinography, Goldmann kinetic visual fields, and full-field electroretinography (ERG). In addition, imaging studies, such as optical coherence tomography (OCT), short-wave autofluorescence imaging, and quantitative analyses of hypofluorescence, were performed in each patient. Results Best-corrected visual acuities ranged from 20/200 to 4/200. The median age of the patients at diagnosis was 23.3 years. The majority of the patients had photophobia and nyctalopia, and were classified as Fishman stage 4 (widespread choriocapillaris atrophy, resorption of flecks, and greatly reduced ERG amplitudes). An atypical retinal pigmentation pattern was observed in the patients, and the majority showed cone-rod dystrophy on full-field ERG. In vivo retinal microstructure assessment with OCT demonstrated central retinal thinning, variable loss of photoreceptors, and three different patterns of structural retinal degeneration. Two dissimilar patterns of abnormal autofluorescence were observed. No apparent age-related differences in the pattern of retinal degeneration were observed. Conclusions The results indicate that this particular mutation in ABCA4 is associated with a severe retinal phenotype and thus, could be classified as null. Careful phenotyping of patients carrying specific mutations in ABCA4 is essential to enhance our understanding of disease expression linked to particular mutations and the resulting genotype–phenotype correlations. PMID:29422768

Conditional Loss of Arx From the Developing Dorsal Telencephalon Results in Behavioral Phenotypes Resembling Mild Human ARX Mutations.

PubMed

Simonet, Jacqueline C; Sunnen, C Nicole; Wu, Jue; Golden, Jeffrey A; Marsh, Eric D

2015-09-01

Mutations in the Aristaless-Related Homeobox (ARX) gene cause structural anomalies of the brain, epilepsy, and neurocognitive deficits in children. During forebrain development, Arx is expressed in both pallial and subpallial progenitor cells. We previously demonstrated that elimination of Arx from subpallial-derived cortical interneurons generates an epilepsy phenotype with features overlapping those seen in patients with ARX mutations. In this report, we have selectively removed Arx from pallial progenitor cells that give rise to the cerebral cortical projection neurons. While no discernable seizure activity was recorded, these mice exhibited a peculiar constellation of behaviors. They are less anxious, less social, and more active when compared with their wild-type littermates. The overall cortical thickness was reduced, and the corpus callosum and anterior commissure were hypoplastic, consistent with a perturbation in cortical connectivity. Taken together, these data suggest that some of the structural and behavioral anomalies, common in patients with ARX mutations, are specifically due to alterations in pallial progenitor function. Furthermore, our data demonstrate that some of the neurobehavioral features found in patients with ARX mutations may not be due to on-going seizures, as is often postulated, given that epilepsy was eliminated as a confounding variable in these behavior analyses. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Tracing remobilization of nutrients and toxic elements after application of rice straw or derived ash / biochar in paddy soils

NASA Astrophysics Data System (ADS)

Schaller, Jörg; Wang, Jiajia; Planer-Friedrich, Britta

2017-04-01

More than 600 million tons of rice straw are produced each year as byproduct of rice grain production. As an increasing application, besides e.g. composting or fodder for animals, the straw remains on the field for decomposition and nutrient supply. A central concern during rice cultivation is accumulation of arsenic, but it is currently unclear how the application of rice straw or derived ash or biochar to paddy soils will influence arsenic uptake by the next generation of rice plants. Consequently, we assessed the element mobilization via soil microcosm incubations with straw or derived ash or biochar or without those amendments under flooding (40 days) and subsequent drainage (14 days). We focused on elements potentially influencing the uptake of arsenic by the next generation of rice plants (e.g. silicon, phosphorus, iron), or which are nutrients but toxic themselves at higher levels (sulfur, sulfide, iron, iron(II), manganese, copper, and zinc). We found significant differences in the release of arsenic, iron(II), sulfide, total sulfur, DOC, manganese, copper, and zinc . For example highest pore water Mn and As concentrations were found for soil amended with straw, whereas the straw amendment reduced S mobilization, possibly due to sulfate reduction by straw decomposing microbes. For P, we found highest pore water concentrations for straw, followed by biochar, ash and control. In summary, application of rice straw or derived ash or biochar strongly affect the element availability in paddy soil.

Evolution of cooperation in a multidimensional phenotype space.

PubMed

Kroumi, Dhaker; Lessard, Sabin

2015-06-01

The emergence of cooperation in populations of selfish individuals is a fascinating topic that has inspired much theoretical work. An important model to study cooperation is the phenotypic model, where individuals are characterized by phenotypic properties that are visible to others. The phenotype of an individual can be represented for instance by a vector x = (x1,…,xn), where x1,…,xn are integers. The population can be well mixed in the sense that everyone is equally likely to interact with everyone else, but the behavioral strategies of the individuals can depend on their distance in the phenotype space. A cooperator can choose to help other individuals exhibiting the same phenotype and defects otherwise. Cooperation is said to be favored by selection if it is more abundant than defection in the stationary state. This means that the average frequency of cooperators in the stationary state strictly exceeds 1/2. Antal et al. (2009c) found conditions that ensure that cooperation is more abundant than defection in a one-dimensional (i.e. n = 1) and an infinite-dimensional (i.e. n = ∞) phenotype space in the case of the Prisoner's Dilemma under weak selection. However, reality lies between these two limit cases. In this paper, we derive the corresponding condition in the case of a phenotype space of any finite dimension. This is done by applying a perturbation method to study a mutation-selection equilibrium under weak selection. This condition is obtained in the limit of a large population size by using the ancestral process. The best scenario for cooperation to be more likely to evolve is found to be a high population-scaled phenotype mutation rate, a low population-scaled strategy mutation rate and a high phenotype space dimension. The biological intuition is that a high population-scaled phenotype mutation rate reduces the quantity of interactions between cooperators and defectors, while a high population-scaled strategy mutation rate introduces newly

Deletion in a quantitative trait gene qPE9-1 associated with panicle erectness improves plant architecture during rice domestication.

PubMed

Zhou, Yong; Zhu, Jinyan; Li, Zhengyi; Yi, Chuandeng; Liu, Jun; Zhang, Honggen; Tang, Shuzhu; Gu, Minghong; Liang, Guohua

2009-09-01

Rice plant architecture is an important agronomic trait and a major determinant in high productivity. Panicle erectness is the preferred plant architecture in japonica rice, but the molecular mechanism underlying domestication of the erect panicle remains elusive. Here we report the map-based cloning of a major quantitative trait locus, qPE9-1, which plays an integral role in regulation of rice plant architecture including panicle erectness. The R6547 qPE9-1 gene encodes a 426-amino-acid protein, homologous to the keratin-associated protein 5-4 family. The gene is composed of three Von Willebrand factor type C domains, one transmembrane domain, and one 4-disulfide-core domain. Phenotypic comparisons of a set of near-isogenic lines and transgenic lines reveal that the functional allele (qPE9-1) results in drooping panicles, and the loss-of-function mutation (qpe9-1) leads to more erect panicles. In addition, the qPE9-1 locus regulates panicle and grain length, grain weight, and consequently grain yield. We propose that the panicle erectness trait resulted from a natural random loss-of-function mutation for the qPE9-1 gene and has subsequently been the target of artificial selection during japonica rice breeding.

Rice functional genomics research in China.

PubMed

Han, Bin; Xue, Yongbiao; Li, Jiayang; Deng, Xing-Wang; Zhang, Qifa

2007-06-29

Rice functional genomics is a scientific approach that seeks to identify and define the function of rice genes, and uncover when and how genes work together to produce phenotypic traits. Rapid progress in rice genome sequencing has facilitated research in rice functional genomics in China. The Ministry of Science and Technology of China has funded two major rice functional genomics research programmes for building up the infrastructures of the functional genomics study such as developing rice functional genomics tools and resources. The programmes were also aimed at cloning and functional analyses of a number of genes controlling important agronomic traits from rice. National and international collaborations on rice functional genomics study are accelerating rice gene discovery and application.

The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations.

PubMed

Senter, Leigha; Clendenning, Mark; Sotamaa, Kaisa; Hampel, Heather; Green, Jane; Potter, John D; Lindblom, Annika; Lagerstedt, Kristina; Thibodeau, Stephen N; Lindor, Noralane M; Young, Joanne; Winship, Ingrid; Dowty, James G; White, Darren M; Hopper, John L; Baglietto, Laura; Jenkins, Mark A; de la Chapelle, Albert

2008-08-01

Although the clinical phenotype of Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer) has been well described, little is known about disease in PMS2 mutation carriers. Now that mutation detection methods can discern mutations in PMS2 from mutations in its pseudogenes, more mutation carriers have been identified. Information about the clinical significance of PMS2 mutations is crucial for appropriate counseling. Here, we report the clinical characteristics of a large series of PMS2 mutation carriers. We performed PMS2 mutation analysis using long-range polymerase chain reaction and multiplex ligation-dependent probe amplification for 99 probands diagnosed with Lynch syndrome-associated tumors showing isolated loss of PMS2 by immunohistochemistry. Penetrance was calculated using a modified segregation analysis adjusting for ascertainment. Germ-line PMS2 mutations were detected in 62% of probands (n = 55 monoallelic; 6 biallelic). Among families with monoallelic PMS2 mutations, 65.5% met revised Bethesda guidelines. Compared with the general population, in mutation carriers, the incidence of colorectal cancer was 5.2-fold higher, and the incidence of endometrial cancer was 7.5-fold higher. In North America, this translates to a cumulative cancer risk to age 70 years of 15%-20% for colorectal cancer, 15% for endometrial cancer, and 25%-32% for any Lynch syndrome-associated cancer. No elevated risk for non-Lynch syndrome-associated cancers was observed. PMS2 mutations contribute significantly to Lynch syndrome, but the penetrance for monoallelic mutation carriers appears to be lower than that for the other mismatch repair genes. Modified counseling and cancer surveillance guidelines for PMS2 mutation carriers are proposed.

Association of a homozygous nonsense mutation in the ABCA4 (ABCR) gene with cone-rod dystrophy phenotype in an Italian family.

PubMed

Simonelli, Francesca; Testa, Francesco; Zernant, Jana; Nesti, Anna; Rossi, Settimio; Rinaldi, Ernesto; Allikmets, Rando

2004-01-01

Genetic variation in the ABCA4 (ABCR) gene has been associated with several distinct retinal phenotypes, including Stargardt disease/fundus flavimaculatus (STGD/FFM), cone-rod dystrophy (CRD), retinitis pigmentosa (RP) and age-related macular degeneration. The current model of genotype/phenotype association suggests that patients harboring deleterious mutations in both ABCR alleles would develop RP-like retinal pathology. Here we describe ABCA4-associated phenotypes, including a proband with a homozygous nonsense mutation in a family from Southern Italy. The proband had been originally diagnosed with STGD. Ophthalmologic examination included kinetic perimetry, electrophysiological studies and fluorescein angiography. DNA of the affected individual and family members was analyzed for variants in all 50 exons of the ABCA4 gene by screening on the ABCR400 microarray. A homozygous nonsense mutation 2971G>T (G991X) was detected in a patient initially diagnosed with STGD based on funduscopic evidence, including bull's eye depigmentation of the fovea and flecks at the posterior pole extending to the mid-peripheral retina. Since this novel nucleotide substitution results in a truncated, nonfunctional, ABCA4 protein, the patient was examined in-depth for the severity of the disease phenotype. Indeed, subsequent electrophysiological studies determined severely reduced cone amplitude as compared to the rod amplitude, suggesting the diagnosis of CRD. ABCR400 microarray is an efficient tool for determining causal genetic variation, including new mutations. A homozygous protein-truncating mutation in ABCA4 can cause a phenotype ranging from STGD to CRD as diagnosed at an early stage of the disease. Only a combination of comprehensive genotype/phenotype correlation studies will determine the proper diagnosis and prognosis of ABCA4-associated pathology. Copyright 2004 S. Karger AG, Basel

Introgression of resistance-conferring ALS mutations in herbicide-resistant weedy rice

USDA-ARS?s Scientific Manuscript database

Weedy red rice (Oryza sativa) competes aggressively with rice, reducing yields and grain quality. Clearfield™ rice, a nontransgenic, herbicide-resistant (HR) rice introduced in 2002 to control weedy rice, has resulted in some ALS-resistant weedy rice apparently due to gene flow. Studies were conduct...

Broadening the phenotype of DFNB28: Mutations in TRIOBP are associated with moderate, stable hereditary hearing impairment.

PubMed

Wesdorp, Mieke; van de Kamp, Jiddeke M; Hensen, Erik F; Schraders, Margit; Oostrik, Jaap; Yntema, Helger G; Feenstra, Ilse; Admiraal, Ronald J C; Kunst, Henricus P M; Tekin, Mustafa; Kanaan, Moien; Kremer, Hannie; Pennings, Ronald J E

2017-04-01

DFNB28 is characterized by prelingual, severe to profound sensorineural hearing impairment (HI). It is associated with mutations in exon 6 and 7 of TRIOBP and has not been reported in the European population. Here, we describe two isolated cases of Dutch origin with congenital, moderate HI and compound heterozygous mutations in TRIOBP. Three of the mutations are novel, one nonsense mutation (c.5014G>T (p.Gly1672*)) and two frameshift mutations (c.2653del (p.Arg885Alafs*120) and c.3460_3461del (p.Leu1154Alafs*29)). The fourth mutation is the known c.3232dup (p.Arg1078Profs*6) mutation. Longitudinal audiometric analyses in one of the subjects revealed that HI was stable over a period of 15 years. Vestibular function was normal. Predicted effects of the mutations do not explain the relatively mild phenotype in the presented subjects, whereas location of the mutation might well contribute to the milder HI in one of the subjects. It is known that isoform classes TRIOBP-4 and TRIOBP-5 are important for stereocilia stability and rigidity. To our knowledge, p.Gly1672* is the first pathogenic variant identified in DFNB28 that does not affect isoform class TRIOBP-4. This suggests that a single TRIOBP copy to encode wildtype TRIOBP-4 is insufficient for normal hearing, and that at least one TRIOBP copy to encode TRIOBP-5 is indispensable for normal inner ear function. Furthermore, this study demonstrates that DFNB28 can be milder than reported so far and that mutations in TRIOBP are thus associated with a heterogeneous phenotype. Copyright © 2017 Elsevier B.V. All rights reserved.

IDH1 mutation diminishes aggressive phenotype in glioma stem cells.

PubMed

Yao, Qi; Cai, Gang; Yu, Qi; Shen, Jianhong; Gu, Zhikai; Chen, Jian; Shi, Wei; Shi, Jinlong

2018-01-01

The R132H mutation in isocitrate dehydrogenase 1 (IDH1-R132H) is associated with better prognosis in glioma patients. Glioma stem cells (GSCs) in glioma are believed to be responsible for glioma growth and maintenance. However, the relation between the R132H mutation and GSCs is not fully understood. In the present study, GSC markers were detected in patients with IDH1-R132H or wild-type IDH1 (IDH1-wt) by tissue microarray immunohistochemistry (TMA-IHC). The relationship between the expression patterns of GSC markers and the clinicopathological characteristics in glioma were analyzed. To confirm this mutation's role in GSCs, the IDH1-R132H in GSCs isolated from glioblastoma patients with IDH1 mutations was overexpressed by using lentiviral constructs in vitro, and then the proliferation, differentiation, apoptosis, migration and invasion of the transfected GSCs were explored. At the molecular level, we detected Wnt/β-catenin signaling expression to verify its role in regulating the cellular properties of GSCs. The results showed that the positive rate of GSCs in patients with IDH1-R132H was significantly less than that in patients with IDH1-wt. The positive rate of GSCs was correlated with IDH1 mutation, TNM stage and poor overall survive. After transfection in vitro, IDH1-R132H overexpression led to reduced GSCs proliferation, migration and invasion, inducing apoptosis and improving GSC differentiation, accompanied by a significant reduction in activity of β-catenin. Several mediators, effectors and targets of the Wnt/β-catenin signaling were downregulated. The data demonstrate that IDH1 mutation reduces the malignant progression of glioma by causing a less aggressive phenotype of GSCs which are involved in the Wnt/β‑catenin signaling.

Mosaicism for dominant collagen 6 mutations as a cause for intrafamilial phenotypic variability.

PubMed

Donkervoort, Sandra; Hu, Ying; Stojkovic, Tanya; Voermans, Nicol C; Foley, A Reghan; Leach, Meganne E; Dastgir, Jahannaz; Bolduc, Véronique; Cullup, Thomas; de Becdelièvre, Alix; Yang, Lin; Su, Hai; Meilleur, Katherine; Schindler, Alice B; Kamsteeg, Erik-Jan; Richard, Pascale; Butterfield, Russell J; Winder, Thomas L; Crawford, Thomas O; Weiss, Robert B; Muntoni, Francesco; Allamand, Valérie; Bönnemann, Carsten G

2015-01-01

Collagen 6-related dystrophies and myopathies (COL6-RD) are a group of disorders that form a wide phenotypic spectrum, ranging from severe Ullrich congenital muscular dystrophy, intermediate phenotypes, to the milder Bethlem myopathy. Both inter- and intrafamilial variable expressivity are commonly observed. We present clinical, immunohistochemical, and genetic data on four COL6-RD families with marked intergenerational phenotypic heterogeneity. This variable expression seemingly masquerades as anticipation is due to parental mosaicism for a dominant mutation, with subsequent full inheritance and penetrance of the mutation in the heterozygous offspring. We also present an additional fifth simplex patient identified as a mosaic carrier. Parental mosaicism was confirmed in the four families through quantitative analysis of the ratio of mutant versus wild-type allele (COL6A1, COL6A2, and COL6A3) in genomic DNA from various tissues, including blood, dermal fibroblasts, and saliva. Consistent with somatic mosaicism, parental samples had lower ratios of mutant versus wild-type allele compared with the fully heterozygote offspring. However, there was notable variability of the mutant allele levels between tissues tested, ranging from 16% (saliva) to 43% (fibroblasts) in one mosaic father. This is the first report demonstrating mosaicism as a cause of intrafamilial/intergenerational variability of COL6-RD, and suggests that sporadic and parental mosaicism may be more common than previously suspected. © 2014 WILEY PERIODICALS, INC.

Process specific differential metabolomes for industrial gochujang types (pepper paste) manufactured using white rice, brown rice, and wheat.

PubMed

Jang, Yu Kyung; Shin, Gi Ru; Jung, Eun Sung; Lee, Sunmin; Lee, Sarah; Singh, Digar; Jang, Eun Seok; Shin, Dong Joo; Kim, Hye-Jin; Shin, Hye Won; Moon, Byoung Seok; Lee, Choong Hwan

2017-11-01

The metabolic perplexes for gochujang (GCJ) fermentative bioprocess, a traditional Korean pepper paste, has largely remain equivocal for preparative conditions and raw material (RM) additives exacerbating its commercial standardization. Herein, we outlined a differential non-targeted metabolite profiling for three GCJ (white rice-WR; brown rice-BR; wheat-WT) under varying processing steps (P1 - fermentation; P2 - meju addition; P3 - ripening; and P4 - red pepper addition). We correlated the process specific metabolomes with corresponding physicochemical factors, enzymatic phenotypes, and bioactivities for GCJ-types. The P1 was characterized by a uniform increase in the levels of RM-derived lysoPCs. In contrast, P2 was observed with proportionally higher levels of meju-released isoflavones and soyasaponins in WR-GCJ, followed by BR and WT-GCJ. The P3 involved a cumulative increase in primary metabolites in all GCJ samples except lower organic acid contents in WT-GCJ. The pepper derived flavonoids and alkaloids were selectively increased while P4 in all GCJ-types. Copyright © 2017 Elsevier Ltd. All rights reserved.

New mutation of the MPZ gene in a family with the Dejerine-Sottas disease phenotype.

PubMed

Floroskufi, Paraskewi; Panas, Marios; Karadima, Georgia; Vassilopoulos, Demetris

2007-05-01

Charcot-Marie-Tooth disease type 1B is associated with mutations in the myelin protein zero gene. In the present study a new myelin protein zero gene mutation (c.89T>C,Ile30Thr) was detected in a family with the Dejerine-Sottas disease phenotype. The results support the hypothesis that severe, early-onset neuropathy may be related to either an alteration of a conserved amino acid or a disruption of the tertiary structure of myelin protein zero.

A novel mutation in HESX1 causes combined pituitary hormone deficiency without septo optic dysplasia phenotypes.

PubMed

Takagi, Masaki; Takahashi, Mai; Ohtsu, Yoshiaki; Sato, Takeshi; Narumi, Satoshi; Arakawa, Hirokazu; Hasegawa, Tomonobu

2016-04-25

Heterozygous and/or homozygous HESX1 mutations have been reported to cause isolated growth hormone deficiency (IGHD) or combined pituitary hormone deficiency (CPHD), in association with septo optic dysplasia (SOD). We report a novel heterozygous HESX1 mutation in a CPHD patient without SOD phenotypes. The propositus was a one-year-old Japanese girl. Shortly after birth, she was found to be hypoglycemic. She was diagnosed with central adrenal insufficiency based on low cortisol and ACTH at a time of severe hypoglycemia. Further endocrine studies indicated that the patient also had central hypothyroidism and growth hormone deficiency. Using a next-generation sequencing strategy, we identified a novel heterozygous HESX1 mutation, c.326G>A (p.Arg109Gln). Western blotting and subcellular localization revealed no significant difference between wild type and mutant HESX1. Electrophoretic mobility shift assays showed that the mutant HESX1 abrogated DNA-binding ability. Mutant HESX1 was unable to repress PROP1-mediated activation. In conclusion, this study identified Arg109 as a critical residue in the HESX1 protein and extends our understanding of the phenotypic features, molecular mechanism, and developmental course associated with mutations in HESX1. When multiple genes need to be analyzed for mutations simultaneously, targeted sequence analysis of interesting genomic regions is an attractive approach.

Mutations in the human UBR1 gene and the associated phenotypic spectrum.

PubMed

Sukalo, Maja; Fiedler, Ariane; Guzmán, Celina; Spranger, Stephanie; Addor, Marie-Claude; McHeik, Jiad N; Oltra Benavent, Manuel; Cobben, Jan M; Gillis, Lynette A; Shealy, Amy G; Deshpande, Charu; Bozorgmehr, Bita; Everman, David B; Stattin, Eva-Lena; Liebelt, Jan; Keller, Klaus-Michael; Bertola, Débora Romeo; van Karnebeek, Clara D M; Bergmann, Carsten; Liu, Zhifeng; Düker, Gesche; Rezaei, Nima; Alkuraya, Fowzan S; Oğur, Gönül; Alrajoudi, Abdullah; Venegas-Vega, Carlos A; Verbeek, Nienke E; Richmond, Erick J; Kirbiyik, Ozgür; Ranganath, Prajnya; Singh, Ankur; Godbole, Koumudi; Ali, Fouad A M; Alves, Crésio; Mayerle, Julia; Lerch, Markus M; Witt, Heiko; Zenker, Martin

2014-05-01

Johanson-Blizzard syndrome (JBS) is a rare, autosomal recessive disorder characterized by exocrine pancreatic insufficiency, typical facial features, dental anomalies, hypothyroidism, sensorineural hearing loss, scalp defects, urogenital and anorectal anomalies, short stature, and cognitive impairment of variable degree. This syndrome is caused by a defect of the E3 ubiquitin ligase UBR1, which is part of the proteolytic N-end rule pathway. Herein, we review previously reported (n = 29) and a total of 31 novel UBR1 mutations in relation to the associated phenotype in patients from 50 unrelated families. Mutation types include nonsense, frameshift, splice site, missense, and small in-frame deletions consistent with the hypothesis that loss of UBR1 protein function is the molecular basis of JBS. There is an association of missense mutations and small in-frame deletions with milder physical abnormalities and a normal intellectual capacity, thus suggesting that at least some of these may represent hypomorphic UBR1 alleles. The review of clinical data of a large number of molecularly confirmed JBS cases allows us to define minimal clinical criteria for the diagnosis of JBS. For all previously reported and novel UBR1 mutations together with their clinical data, a mutation database has been established at LOVD. © 2014 WILEY PERIODICALS, INC.

The National Niemann-Pick Type C1 Disease Database: correlation of lipid profiles, mutations, and biochemical phenotypes

PubMed Central

Garver, William S.; Jelinek, David; Meaney, F. John; Flynn, James; Pettit, Kathleen M.; Shepherd, Glen; Heidenreich, Randall A.; Vockley, Cate M. Walsh; Castro, Graciela; Francis, Gordon A.

2010-01-01

Niemann-Pick type C1 disease (NPC1) is an autosomal recessive lysosomal storage disorder characterized by neonatal jaundice, hepatosplenomegaly, and progressive neurodegeneration. The present study provides the lipid profiles, mutations, and corresponding associations with the biochemical phenotype obtained from NPC1 patients who participated in the National NPC1 Disease Database. Lipid profiles were obtained from 34 patients (39%) in the survey and demonstrated significantly reduced plasma LDL cholesterol (LDL-C) and increased plasma triglycerides in the majority of patients. Reduced plasma HDL cholesterol (HDL-C) was the most consistent lipoprotein abnormality found in male and female NPC1 patients across age groups and occurred independent of changes in plasma triglycerides. A subset of 19 patients for whom the biochemical severity of known NPC1 mutations could be correlated with their lipid profile showed a strong inverse correlation between plasma HDL-C and severity of the biochemical phenotype. Gene mutations were available for 52 patients (59%) in the survey, including 52 different mutations and five novel mutations (Y628C, P887L, I923V, A1151T, and 3741_3744delACTC). Together, these findings provide novel information regarding the plasma lipoprotein changes and mutations in NPC1 disease, and suggest plasma HDL-C represents a potential biomarker of NPC1 disease severity. PMID:19744920

CAV3 mutations causing exercise intolerance, myalgia and rhabdomyolysis: Expanding the phenotypic spectrum of caveolinopathies.

PubMed

Scalco, Renata Siciliani; Gardiner, Alice R; Pitceathly, Robert D S; Hilton-Jones, David; Schapira, Anthony H; Turner, Chris; Parton, Matt; Desikan, Mahalekshmi; Barresi, Rita; Marsh, Julie; Manzur, Adnan Y; Childs, Anne-Marie; Feng, Lucy; Murphy, Elaine; Lamont, Phillipa J; Ravenscroft, Gianina; Wallefeld, William; Davis, Mark R; Laing, Nigel G; Holton, Janice L; Fialho, Doreen; Bushby, Kate; Hanna, Michael G; Phadke, Rahul; Jungbluth, Heinz; Houlden, Henry; Quinlivan, Ros

2016-08-01

Rhabdomyolysis is often due to a combination of environmental trigger(s) and genetic predisposition; however, the underlying genetic cause remains elusive in many cases. Mutations in CAV3 lead to various neuromuscular phenotypes with partial overlap, including limb girdle muscular dystrophy type 1C (LGMD1C), rippling muscle disease, distal myopathy and isolated hyperCKemia. Here we present a series of eight patients from seven families presenting with exercise intolerance and rhabdomyolysis caused by mutations in CAV3 diagnosed by next generation sequencing (NGS) (n = 6). Symptoms included myalgia (n = 7), exercise intolerance (n = 7) and episodes of rhabdomyolysis (n = 2). Percussion-induced rapid muscle contractions (PIRCs) were seen in five out of six patients examined. A previously reported heterozygous mutation in CAV3 (p.T78M) and three novel variants (p.V14I, p.F41S, p.F54V) were identified. Caveolin-3 immunolabeling in muscle was normal in 3/4 patients; however, immunoblotting showed more than 50% reduction of caveolin-3 in five patients compared with controls. This case series demonstrates that exercise intolerance, myalgia and rhabdomyolysis may be caused by CAV3 mutations and broadens the phenotypic spectrum of caveolinopathies. In our series, immunoblotting was a more sensitive method to detect reduced caveolin-3 levels than immunohistochemistry in skeletal muscle. Patients presenting with muscle pain, exercise intolerance and rhabdomyolysis should be routinely tested for PIRCs as this may be an important clinical clue for caveolinopathies, even in the absence of other "typical" features. The use of NGS may expand current knowledge concerning inherited diseases, and unexpected/atypical phenotypes may be attributed to well-known human disease genes. Copyright © 2016 Elsevier B.V. All rights reserved.

Wnt signaling pathway involvement in genotypic and phenotypic variations in Waardenburg syndrome type 2 with MITF mutations.

PubMed

Wang, Xue-Ping; Liu, Ya-Lan; Mei, Ling-Yun; He, Chu-Feng; Niu, Zhi-Jie; Sun, Jie; Zhao, Yu-Lin; Feng, Yong; Zhang, Hua

2018-05-01

Mutation in the gene encoding microphthalmia-associated transcription factor (MITF) lead to Waardenburg syndrome 2 (WS2), an autosomal dominantly inherited syndrome with auditory-pigmentary abnormalities, which is clinically and genetically heterogeneous. Haploinsufficiency may be the underlying mechanism for WS2. However, the mechanisms explaining the genotypic and phenotypic variations in WS2 caused by MITF mutations are unclear. A previous study revealed that MITF interacts with LEF-1, an important factor in the Wnt signaling pathway, to regulate its own transcription through LEF-1-binding sites on the MITF promoter. In this study, four different WS2-associated MITF mutations (p.R217I, p.R217G, p.R255X, p.R217del) that are associated with highly variable clinical features were chosen. According to the results, LEF-1 can activate the expression of MITF on its own, but MITF proteins inhibited the activation. This inhibition weakens when the dosage of MITF is reduced. Except for p.R217I, p.R255X, p.R217G, and p.R217del lose the ability to activate TYR completely and do not inhibit the LEF-1-mediated activation of the MITF-M promoter, and the haploinsufficiency created by mutant MITF can be overcome; correspondingly, the mutants' associated phenotypes are less severe than that of p.R217I. The dominant negative of p.R217del made it have a second-most severe phenotype. This study's data imply that MITF has a negative feedback loop of regulation to stabilize MITF gene dosage that involves the Wnt signaling pathway and that the interaction of MITF mutants with this pathway drives the genotypic and phenotypic differences observed in Waardenburg syndrome type 2 associated with MITF mutations.

A Genetic Screen Identifies a Requirement for Cysteine-Rich-Receptor-Like Kinases in Rice NH1 (OsNPR1)-Mediated Immunity.

PubMed

Chern, Mawsheng; Xu, Qiufang; Bart, Rebecca S; Bai, Wei; Ruan, Deling; Sze-To, Wing Hoi; Canlas, Patrick E; Jain, Rashmi; Chen, Xuewei; Ronald, Pamela C

2016-05-01

Systemic acquired resistance, mediated by the Arabidopsis NPR1 gene and the rice NH1 gene, confers broad-spectrum immunity to diverse pathogens. NPR1 and NH1 interact with TGA transcription factors to activate downstream defense genes. Despite the importance of this defense response, the signaling components downstream of NPR1/NH1 and TGA proteins are poorly defined. Here we report the identification of a rice mutant, snim1, which suppresses NH1-mediated immunity and demonstrate that two genes encoding previously uncharacterized cysteine-rich-receptor-like kinases (CRK6 and CRK10), complement the snim1 mutant phenotype. Silencing of CRK6 and CRK10 genes individually in the parental genetic background recreates the snim1 phenotype. We identified a rice mutant in the Kitaake genetic background with a frameshift mutation in crk10; this mutant also displays a compromised immune response highlighting the important role of crk10. We also show that elevated levels of NH1 expression lead to enhanced CRK10 expression and that the rice TGA2.1 protein binds to the CRK10 promoter. These experiments demonstrate a requirement for CRKs in NH1-mediated immunity and establish a molecular link between NH1 and induction of CRK10 expression.

A genetic screen identifies a requirement for cysteine-rich–receptor-like kinases in rice NH1 (OsNPR1)-mediated immunity

DOE PAGES

Chern, Mawsheng; Xu, Qiufang; Bart, Rebecca S.; ...

2016-05-13

Systemic acquired resistance, mediated by the Arabidopsis NPR1 gene and the rice NH1 gene, confers broad-spectrum immunity to diverse pathogens. NPR1 and NH1 interact with TGA transcription factors to activate downstream defense genes. Despite the importance of this defense response, the signaling components downstream of NPR1/NH1 and TGA proteins are poorly defined. Here we report the identification of a rice mutant, snim1, which suppresses NH1-mediated immunity and demonstrate that two genes encoding previously uncharacterized cysteine-rich-receptor-like kinases ( CRK6 and CRK10), complement the snim1 mutant phenotype. Silencing of CRK6 and CRK10 genes individually in the parental genetic background recreates the snim1more » phenotype. We identified a rice mutant in the Kitaake genetic background with a frameshift mutation in crk10; this mutant also displays a compromised immune response highlighting the important role of crk10. We also show that elevated levels of NH1 expression lead to enhanced CRK10 expression and that the rice TGA2.1 protein binds to the CRK10 promoter. Furthermore, these experiments demonstrate a requirement for CRKs in NH1-mediated immunity and establish a molecular link between NH1 and induction of CRK10 expression.« less

Investigating genotype-phenotype relationships in Rett syndrome using an international data set.

PubMed

Bebbington, A; Anderson, A; Ravine, D; Fyfe, S; Pineda, M; de Klerk, N; Ben-Zeev, B; Yatawara, N; Percy, A; Kaufmann, W E; Leonard, H

2008-03-11

Rett syndrome is an uncommon neurodevelopmental disorder with an incidence of 1:9,000 live female births. The principal genetic cause was first reported in 1999 when the association with mutations in the methyl-CpG-binding protein 2 (or MECP2) gene was identified. This study uses data from a large international database, InterRett, to examine genotype-phenotype relationships and compares these with previous findings in a population-based cohort. The data set for these analyses was derived from a subset of InterRett cases with subject information collected from the family, the clinician, or both. Individual phenotypic characteristics and clinical severity using three scales were compared among those with eight known recurrent pathogenic MECP2 mutations as well as those with C-terminal deletions (n = 272). Overall, p.R270X and p.R255X were the most severe and p.R133C and p.R294X were the mildest mutations. Significant differences by mutation were seen for individual phenotypic characteristics such as hand use, ambulation, and language. This multicenter investigation into the phenotypic correlates of MECP2 mutations in Rett syndrome has provided a greater depth of understanding than hitherto available about the specific phenotypic characteristics associated with commonly occurring mutations. Although the modifying influence of X inactivation on clinical severity could not be included in the analysis, the findings confirm clear genotype-phenotype relationships in Rett syndrome and show the benefits of collaboration crucial to effective research in rare disorders.

Rice brans, rice bran oils, and rice hulls: composition, food and industrial uses, and bioactivities in humans, animals, and cells.

PubMed

Friedman, Mendel

2013-11-13

Rice plants produce bioactive rice brans and hulls that have been reported to have numerous health-promoting effects in cells, animals, and humans. The main objective of this review is to consolidate and integrate the widely scattered information on the composition and the antioxidative, anti-inflammatory, and immunostimulating effects of rice brans from different rice cultivars, rice bran oils derived from rice brans, rice hulls, liquid rice hull smoke derived from rice hulls, and some of their bioactive compounds. As part of this effort, this paper also presents brief summaries on the preparation of health-promoting foods including bread, corn flakes, frankfurters, ice cream, noodles, pasta, tortillas, and zero-trans-fat shortening as well as industrial products such bioethanol and biodiesel fuels. Also covered are antibiotic, antiallergic, anticarcinogenic, antidiabetic, cardiovascular, allelochemical, and other beneficial effects and the mechanisms of the bioactivities. The results show that food-compatible and safe formulations with desirable nutritional and biological properties can be used to develop new multifunctional foods as well as bioethanol and biodiesel fuel. The overlapping aspects are expected to contribute to a better understanding of the potential impact of the described health-promoting potential of the rice-derived brans, oils, and hulls in food and medicine. Such an understanding will enhance nutrition and health and benefit the agricultural and industrial economies.

COLLAPSED ABNORMAL POLLEN1 Gene Encoding the Arabinokinase-Like Protein Is Involved in Pollen Development in Rice1[C][W][OA

PubMed Central

Ueda, Kenji; Yoshimura, Fumiaki; Miyao, Akio; Hirochika, Hirohiko; Nonomura, Ken-Ichi; Wabiko, Hiroetsu

2013-01-01

We isolated a pollen-defective mutant, collapsed abnormal pollen1 (cap1), from Tos17 insertional mutant lines of rice (Oryza sativa). The cap1 heterozygous plant produced equal numbers of normal and collapsed abnormal grains. The abnormal pollen grains lacked almost all cytoplasmic materials, nuclei, and intine cell walls and did not germinate. Genetic analysis of crosses revealed that the cap1 mutation did not affect female reproduction or vegetative growth. CAP1 encodes a protein consisting of 996 amino acids that showed high similarity to Arabidopsis (Arabidopsis thaliana) l-arabinokinase, which catalyzes the conversion of l-arabinose to l-arabinose 1-phosphate. A wild-type genomic DNA segment containing CAP1 restored mutants to normal pollen grains. During rice pollen development, CAP1 was preferentially expressed in anthers at the bicellular pollen stage, and the effects of the cap1 mutation were mainly detected at this stage. Based on the metabolic pathway of l-arabinose, cap1 pollen phenotype may have been caused by toxic accumulation of l-arabinose or by inhibition of cell wall metabolism due to the lack of UDP-l-arabinose derived from l-arabinose 1-phosphate. The expression pattern of CAP1 was very similar to that of another Arabidopsis homolog that showed 71% amino acid identity with CAP1. Our results suggested that CAP1 and related genes are critical for pollen development in both monocotyledonous and dicotyledonous plants. PMID:23629836

Changing phenotypic expression in a patient with a mitochondrial encephalopathy due to 13042G>A de novo mutation--a 5 year follow up.

PubMed

Schinwelski, M; Kierdaszuk, B; Dulski, J; Tońska, K; Kodroń, A; Sitek, E J; Bartnik, E; Kamińska, A; Kwieciński, H; Sławek, J

2015-08-01

Mutations in NADH dehydrogenase (ND) subunits of complex I lead to mitochondrial encephalomyopathies associated with various phenotypes. This report aims to present the patient's clinical symptomatology in the context of a very rare 13042G>A de novo mutation and with an emphasis on changing phenotypic expression and pronounced, long-standing response to levetiracetam.

Mutation of the RDR1 gene caused genome-wide changes in gene expression, regional variation in small RNA clusters and localized alteration in DNA methylation in rice.

PubMed

Wang, Ningning; Zhang, Di; Wang, Zhenhui; Xun, Hongwei; Ma, Jian; Wang, Hui; Huang, Wei; Liu, Ying; Lin, Xiuyun; Li, Ning; Ou, Xiufang; Zhang, Chunyu; Wang, Ming-Bo; Liu, Bao

2014-06-30

Endogenous small (sm) RNAs (primarily si- and miRNAs) are important trans/cis-acting regulators involved in diverse cellular functions. In plants, the RNA-dependent RNA polymerases (RDRs) are essential for smRNA biogenesis. It has been established that RDR2 is involved in the 24 nt siRNA-dependent RNA-directed DNA methylation (RdDM) pathway. Recent studies have suggested that RDR1 is involved in a second RdDM pathway that relies mostly on 21 nt smRNAs and functions to silence a subset of genomic loci that are usually refractory to the normal RdDM pathway in Arabidopsis. Whether and to what extent the homologs of RDR1 may have similar functions in other plants remained unknown. We characterized a loss-of-function mutant (Osrdr1) of the OsRDR1 gene in rice (Oryza sativa L.) derived from a retrotransposon Tos17 insertion. Microarray analysis identified 1,175 differentially expressed genes (5.2% of all expressed genes in the shoot-tip tissue of rice) between Osrdr1 and WT, of which 896 and 279 genes were up- and down-regulated, respectively, in Osrdr1. smRNA sequencing revealed regional alterations in smRNA clusters across the rice genome. Some of the regions with altered smRNA clusters were associated with changes in DNA methylation. In addition, altered expression of several miRNAs was detected in Osrdr1, and at least some of which were associated with altered expression of predicted miRNA target genes. Despite these changes, no phenotypic difference was identified in Osrdr1 relative to WT under normal condition; however, ephemeral phenotypic fluctuations occurred under some abiotic stress conditions. Our results showed that OsRDR1 plays a role in regulating a substantial number of endogenous genes with diverse functions in rice through smRNA-mediated pathways involving DNA methylation, and which participates in abiotic stress response.

Thomsen or Becker myotonia? A novel autosomal recessive nonsense mutation in the CLCN1 gene associated with a mild phenotype.

PubMed

Gurgel-Giannetti, Juliana; Senkevics, Adriano S; Zilbersztajn-Gotlieb, Dinorah; Yamamoto, Lydia U; Muniz, Viviane P; Pavanello, Rita C M; Oliveira, Acary B; Zatz, Mayana; Vainzof, Mariz

2012-02-01

We describe a large Brazilian consanguineous kindred with 3 clinically affected patients with a Thomsen myotonia phenotype. They carry a novel homozygous nonsense mutation in the CLCN1 gene (K248X). None of the 6 heterozygote carriers show any sign of myotonia on clinical evaluation or electromyography. These findings confirm the autosomal recessive inheritance of the novel mutation in this family, as well as the occurrence of phenotypic variability in the autosomal recessive forms of myotonia. Copyright © 2011 Wiley Periodicals, Inc.

NF1 truncating mutations associated to aggressive clinical phenotype with elephantiasis neuromatosa and solid malignancies.

PubMed

Ponti, Giovanni; Martorana, Davide; Pellacani, Giovanni; Ruini, Cristel; Loschi, Pietro; Baccarani, Alessio; De Santis, Giorgio; Pollio, Annamaria; Neri, Tauro Maria; Mandel, Victor Desmond; Maiorana, Antonio; Maccio, Livia; Maccaferri, Monia; Tomasi, Aldo

2014-06-01

Von Recklinghausen disease is a syndrome characterized by a wide phenotypic variability giving rise to both, cutaneous and visceral benign and malignant neoplasms. The first include cutaneous neurofibromas, subcutaneous and plexiform neurofibromas. The latter can undergo malignant transformation and/or determine elephantiasis neuromatosa. Visceral tumors may include malignant peripheral nerve sheet tumors, gastrointestinal stromal tumors, cerebral gliomas and abdominal neurofibromas. In the present study, the authors discuss the clinical and biomolecular characterization of a cohort of 20 families with a diagnosis of type 1 neurofibromatosis. Clinically, the cohort includes three probands with elephantiasis neuromatosa and a peculiarly high incidence of breast and gastrointestinal cancer. Among the 14 NF1 mutations documented, 10 encoding for a truncated protein have been associated to particularly aggressive clinical phenotypes including elephantiasis neuromatosa, malignant peripheral nerve sheet tumors, breast cancer, gastrointestinal stromal tumors. This effect on protein synthesis, rather than the type of NF1 mutation, is the key to the explanation of the genotype-phenotype correlations in the context of neurofibromatosis type 1. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Mapping disease-related missense mutations in the immunoglobulin-like fold domain of lamin A/C reveals novel genotype-phenotype associations for laminopathies.

PubMed

Scharner, Juergen; Lu, Hui-Chun; Fraternali, Franca; Ellis, Juliet A; Zammit, Peter S

2014-06-01

Mutations in A-type nuclear lamins cause laminopathies. However, genotype-phenotype correlations using the 340 missense mutations within the LMNA gene are unclear: partially due to the limited availability of three-dimensional structure. The immunoglobulin (Ig)-like fold domain has been solved, and using bioinformatics tools (including Polyphen-2, Fold X, Parameter OPtimized Surfaces, and PocketPicker) we characterized 56 missense mutations for position, surface exposure, change in charge and effect on Ig-like fold stability. We find that 21 of the 27 mutations associated with a skeletal muscle phenotype are distributed throughout the Ig-like fold, are nonsurface exposed and predicted to disrupt overall stability of the Ig-like fold domain. Intriguingly, the remaining 6 mutations clustered, had higher surface exposure, and did not affect stability. The majority of 9 lipodystrophy or 10 premature aging syndrome mutations also did not disrupt Ig-like fold domain stability and were surface exposed and clustered in distinct regions that overlap predicted binding pockets. Although buried, the 10 cardiac mutations had no other consistent properties. Finally, most lipodystrophy and premature aging mutations resulted in a -1 net charge change, whereas skeletal muscle mutations caused no consistent net charge changes. Since premature aging, lipodystrophy and the subset of 6 skeletal muscle mutations cluster tightly in distinct, charged regions, they likely affect lamin A/C -protein/DNA/RNA interactions: providing a consistent genotype-phenotype relationship for mutations in this domain. Thus, this subgroup of skeletal muscle laminopathies that we term the 'Skeletal muscle cluster', may have a distinct pathological mechanism. These novel associations refine the ability to predict clinical features caused by certain LMNA missense mutations. © 2013 Wiley Periodicals, Inc.

A recurrent mutation causing Melnick-Needles syndrome in females confers a severe, lethal phenotype in males.

PubMed

Spencer, Careni; Lombaard, Hendrik; Wise, Amy; Krause, Amanda; Robertson, Stephen P

2018-04-01

Melnick-Needles syndrome (MNS; MIM 309350) is an X-linked skeletal dysplasia caused by mutations in FLNA. Females with the condition present with characteristic facial features, short stature, skeletal anomalies, including poorly modeled and sclerotic bones, and structural abnormalities such as cardiac and urological defects. Previously males were thought to present with either a mild phenotype compatible with life or a severe lethal presentation depending on the maternal phenotype. The discovery of a limited number of mutations in FLNA as the cause of the condition has clarified the molecular basis of the disorder, but only a very small number of severely affected males have been reported with MNS. Furthermore, no mildly affected males have been described with a molecular confirmation of the condition. In this report, we describe the clinical and molecular findings of a mildly affected mother with MNS and her severely affected son. They shared a well-documented disease-causing variant in FLNA, p.(Ala1188Thr), one of two highly recurrent mutations leading to the disorder. This is only the fourth report of a male with perinatal lethal MNS and a molecular confirmation; it is the first description of this specific mutation in a male. © 2018 Wiley Periodicals, Inc.

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

PubMed

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

2016-08-01

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

Accelerating public sector rice breeding with high-density KASP markers derived from whole genome sequencing of indica rice.

PubMed

Steele, Katherine A; Quinton-Tulloch, Mark J; Amgai, Resham B; Dhakal, Rajeev; Khatiwada, Shambhu P; Vyas, Darshna; Heine, Martin; Witcombe, John R

2018-01-01

Few public sector rice breeders have the capacity to use NGS-derived markers in their breeding programmes despite rapidly expanding repositories of rice genome sequence data. They rely on > 18,000 mapped microsatellites (SSRs) for marker-assisted selection (MAS) using gel analysis. Lack of knowledge about target SNP and InDel variant loci has hampered the uptake by many breeders of Kompetitive allele-specific PCR (KASP), a proprietary technology of LGC genomics that can distinguish alleles at variant loci. KASP is a cost-effective single-step genotyping technology, cheaper than SSRs and more flexible than genotyping by sequencing (GBS) or array-based genotyping when used in selection programmes. Before this study, there were 2015 rice KASP marker loci in the public domain, mainly identified by array-based screening, leaving large proportions of the rice genome with no KASP coverage. Here we have addressed the urgent need for a wide choice of appropriate rice KASP assays and demonstrated that NGS can detect many more KASP to give full genome coverage. Through re-sequencing of nine indica rice breeding lines or released varieties, this study has identified 2.5 million variant sites. Stringent filtering of variants generated 1.3 million potential KASP assay designs, including 92,500 potential functional markers. This strategy delivers a 650-fold increase in potential selectable KASP markers at a density of 3.1 per 1 kb in the indica crosses analysed and 377,178 polymorphic KASP design sites on average per cross. This knowledge is available to breeders and has been utilised to improve the efficiency of public sector breeding in Nepal, enabling identification of polymorphic KASP at any region or quantitative trait loci in relevant crosses. Validation of 39 new KASP was carried out by genotyping progeny from a range of crosses to show that they detected segregating alleles. The new KASP have replaced SSRs to aid trait selection during marker-assisted backcrossing in

Automated deep-phenotyping of the vertebrate brain

PubMed Central

Allalou, Amin; Wu, Yuelong; Ghannad-Rezaie, Mostafa; Eimon, Peter M; Yanik, Mehmet Fatih

2017-01-01

Here, we describe an automated platform suitable for large-scale deep-phenotyping of zebrafish mutant lines, which uses optical projection tomography to rapidly image brain-specific gene expression patterns in 3D at cellular resolution. Registration algorithms and correlation analysis are then used to compare 3D expression patterns, to automatically detect all statistically significant alterations in mutants, and to map them onto a brain atlas. Automated deep-phenotyping of a mutation in the master transcriptional regulator fezf2 not only detects all known phenotypes but also uncovers important novel neural deficits that were overlooked in previous studies. In the telencephalon, we show for the first time that fezf2 mutant zebrafish have significant patterning deficits, particularly in glutamatergic populations. Our findings reveal unexpected parallels between fezf2 function in zebrafish and mice, where mutations cause deficits in glutamatergic neurons of the telencephalon-derived neocortex. DOI: http://dx.doi.org/10.7554/eLife.23379.001 PMID:28406399

Genotype-phenotype analysis of a rare type of osteogenesis imperfecta in four Chinese families with WNT1 mutations.

PubMed

Liu, Yi; Song, Lijie; Ma, Doudou; Lv, Fang; Xu, Xiaojie; Wang, Jianyi; Xia, Weibo; Jiang, Yan; Wang, Ou; Song, Yuwen; Xing, Xiaoping; Asan; Li, Mei

2016-10-01

Osteogenesis imperfecta (OI) is a rare inherited disease characterized by increased bone fragility and vulnerability to fractures. Recently, WNT1 is identified as a new candidate gene for OI, here we detect pathogenic mutations in WNT1 and analyze the genotype-phenotype association in four Chinese families with OI. We designed a targeted next generation sequencing panel with known fourteen OI-related genes. We applied the approach to detect pathogenic mutations in OI patients and confirmed the mutations with Sanger sequencing and cosegregation analysis. Clinical fractures, bone mineral density (BMD) and the other clinical manifestations were evaluated. We also observed the effects of bisphosphonates in OI patients with WNT1 mutations. Four compound heterozygous mutations (c.110T>C; c.505 G>T; c. 385G>A; c.506 G>A) in WNT1 were detected in three unrelated families. These four mutations had not been reported yet. A recurrent homozygous mutation (c.506dupG) was identified in the other two families. These patients had moderate to severe OI, white to blue sclera, absence of dentinogenesis imperfecta and no brain malformation. We did not observe clear genotype-phenotype correlation in WNT1 mutated OI patients. Though bisphosphonates increased BMD in WNT1 related OI patients, height did not increase and fracture continued. We reported four novel heterozygous variants and confirmed a previous reported WNT1 mutation in four Chinese families with a clinical diagnosis of OI. Our study expanded OI spectrum and confirmed moderate to severe bone fragility induced by WNT1 defects. Copyright © 2016 Elsevier B.V. All rights reserved.

Patient-derived iPSCs show premature neural differentiation and neuron-type specific phenotypes relevant to neurodevelopment

PubMed Central

Yeh, Erika; Dao, Dang Q.; Wu, Zhi Y.; Kandalam, Santoshi M.; Camacho, Federico M.; Tom, Curtis; Zhang, Wandong; Krencik, Robert; Rauen, Katherine A.; Ullian, Erik M.; Weiss, Lauren A.

2017-01-01

Ras/MAPK pathway signaling is a major participant in neurodevelopment, and evidence suggests that BRAF, a key Ras signal mediator, influences human behavior. We studied the role of the mutation BRAFQ257R, the most common cause of cardiofaciocutaneous syndrome (CFC), in an induced pluripotent stem cell (iPSC)-derived model of human neurodevelopment. In iPSC-derived neuronal cultures from CFC subjects, we observed decreased p-AKT and p-ERK1/2 compared to controls, as well as a depleted neural progenitor pool and rapid neuronal maturation. Pharmacological PI3K/AKT pathway manipulation recapitulated cellular phenotypes in control cells and attenuated them in CFC cells. CFC cultures displayed altered cellular subtype ratios and increased intrinsic excitability. Moreover, in CFC cells, Ras/MAPK pathway activation and morphological abnormalities exhibited cell subtype-specific differences. Our results highlight the importance of exploring specific cellular subtypes and of using iPSC models to reveal relevant human-specific neurodevelopmental events. PMID:29158583

Estimating rice yield related traits and quantitative trait loci analysis under different nitrogen treatments using a simple tower-based field phenotyping system with modified single-lens reflex cameras

NASA Astrophysics Data System (ADS)

Naito, Hiroki; Ogawa, Satoshi; Valencia, Milton Orlando; Mohri, Hiroki; Urano, Yutaka; Hosoi, Fumiki; Shimizu, Yo; Chavez, Alba Lucia; Ishitani, Manabu; Selvaraj, Michael Gomez; Omasa, Kenji

2017-03-01

Application of field based high-throughput phenotyping (FB-HTP) methods for monitoring plant performance in real field conditions has a high potential to accelerate the breeding process. In this paper, we discuss the use of a simple tower based remote sensing platform using modified single-lens reflex cameras for phenotyping yield traits in rice under different nitrogen (N) treatments over three years. This tower based phenotyping platform has the advantages of simplicity, ease and stability in terms of introduction, maintenance and continual operation under field conditions. Out of six phenological stages of rice analyzed, the flowering stage was the most useful in the estimation of yield performance under field conditions. We found a high correlation between several vegetation indices (simple ratio (SR), normalized difference vegetation index (NDVI), transformed vegetation index (TVI), corrected transformed vegetation index (CTVI), soil-adjusted vegetation index (SAVI) and modified soil-adjusted vegetation index (MSAVI)) and multiple yield traits (panicle number, grain weight and shoot biomass) across a three trials. Among all of the indices studied, SR exhibited the best performance in regards to the estimation of grain weight (R2 = 0.80). Under our tower-based field phenotyping system (TBFPS), we identified quantitative trait loci (QTL) for yield related traits using a mapping population of chromosome segment substitution lines (CSSLs) and a single nucleotide polymorphism data set. Our findings suggest the TBFPS can be useful for the estimation of yield performance during early crop development. This can be a major opportunity for rice breeders whom desire high throughput phenotypic selection for yield performance traits.

A major QTL controlling deep rooting on rice chromosome 4.

PubMed

Uga, Yusaku; Yamamoto, Eiji; Kanno, Noriko; Kawai, Sawako; Mizubayashi, Tatsumi; Fukuoka, Shuichi

2013-10-24

Drought is the most serious abiotic stress that hinders rice production under rainfed conditions. Breeding for deep rooting is a promising strategy to improve the root system architecture in shallow-rooting rice cultivars to avoid drought stress. We analysed the quantitative trait loci (QTLs) for the ratio of deep rooting (RDR) in three F₂ mapping populations derived from crosses between each of three shallow-rooting varieties ('ARC5955', 'Pinulupot1', and 'Tupa729') and a deep-rooting variety, 'Kinandang Patong'. In total, we detected five RDR QTLs on chromosomes 2, 4, and 6. In all three populations, QTLs on chromosome 4 were found to be located at similar positions; they explained from 32.0% to 56.6% of the total RDR phenotypic variance. This suggests that one or more key genetic factors controlling the root growth angle in rice is located in this region of chromosome 4.

Phenotypic spectrum of autosomal recessive cone-rod dystrophies caused by mutations in the ABCA4 (ABCR) gene.

PubMed

Klevering, B Jeroen; Blankenagel, Anita; Maugeri, Alessandra; Cremers, Frans P M; Hoyng, Carel B; Rohrschneider, Klaus

2002-06-01

To describe the phenotype of 12 patients with autosomal recessive or isolated cone-rod types of progressive retinal degeneration (CRD) caused by mutations in the ABCA4 gene. The charts of patients who had originally received a diagnosis of isolated or autosomal recessive CRD were reviewed after molecular analysis revealed mutations in the ABCA4 gene. In two of the patients both the photopic and scotopic electroretinogram were nonrecordable. In the remainder, the photopic cone b-wave amplitudes appeared to be more seriously affected than the scotopic rod b-wave amplitudes. Although the clinical presentation was heterogeneous, all patients experienced visual loss early in life, impaired color vision, and a central scotoma. Fundoscopy revealed evidence of early-onset maculopathy, sometimes accompanied by involvement of the retinal periphery in the later stages of the disease. Mutations in the ABCA4 gene are the pathologic cause of the CRD-like dystrophy in these patients, and the resultant clinical pictures are complex and heterogeneous. Given this wide clinical spectrum of CRD-like phenotypes associated with ABCA4 mutations, detailed clinical subclassifications are difficult and may not be very useful.

CDH23 mutation and phenotype heterogeneity: a profile of 107 diverse families with Usher syndrome and nonsyndromic deafness.

PubMed

Astuto, L M; Bork, J M; Weston, M D; Askew, J W; Fields, R R; Orten, D J; Ohliger, S J; Riazuddin, S; Morell, R J; Khan, S; Riazuddin, S; Kremer, H; van Hauwe, P; Moller, C G; Cremers, C W R J; Ayuso, C; Heckenlively, J R; Rohrschneider, K; Spandau, U; Greenberg, J; Ramesar, R; Reardon, W; Bitoun, P; Millan, J; Legge, R; Friedman, T B; Kimberling, W J

2002-08-01

Usher syndrome type I is characterized by congenital hearing loss, retinitis pigmentosa (RP), and variable vestibular areflexia. Usher syndrome type ID, one of seven Usher syndrome type I genetic localizations, have been mapped to a chromosomal interval that overlaps with a nonsyndromic-deafness localization, DFNB12. Mutations in CDH23, a gene that encodes a putative cell-adhesion protein with multiple cadherin-like domains, are responsible for both Usher syndrome and DFNB12 nonsyndromic deafness. Specific CDH23 mutational defects have been identified that differentiate these two phenotypes. Only missense mutations of CDH23 have been observed in families with nonsyndromic deafness, whereas nonsense, frameshift, splice-site, and missense mutations have been identified in families with Usher syndrome. In the present study, a panel of 69 probands with Usher syndrome and 38 probands with recessive nonsyndromic deafness were screened for the presence of mutations in the entire coding region of CDH23, by heteroduplex, single-strand conformation polymorphism, and direct sequence analyses. A total of 36 different CDH23 mutations were detected in 45 families; 33 of these mutations were novel, including 18 missense, 3 nonsense, 5 splicing defects, 5 microdeletions, and 2 insertions. A total of seven mutations were common to more than one family. Numerous exonic and intronic polymorphisms also were detected. Results of ophthalmologic examinations of the patients with nonsyndromic deafness have found asymptomatic RP-like manifestations, indicating that missense mutations may have a subtle effect in the retina. Furthermore, patients with mutations in CDH23 display a wide range of hearing loss and RP phenotypes, differing in severity, age at onset, type, and the presence or absence of vestibular areflexia.

CDH23 Mutation and Phenotype Heterogeneity: A Profile of 107 Diverse Families with Usher Syndrome and Nonsyndromic Deafness

PubMed Central

Astuto, L. M.; Bork, J. M.; Weston, M. D.; Askew, J. W.; Fields, R. R.; Orten, D. J.; Ohliger, S. J.; Riazuddin, S.; Morell, R. J.; Khan, S.; Riazuddin, S.; Kremer, H.; van Hauwe, P.; Moller, C. G.; Cremers, C. W. R. J.; Ayuso, C.; Heckenlively, J. R.; Rohrschneider, K.; Spandau, U.; Greenberg, J.; Ramesar, R.; Reardon, W.; Bitoun, P.; Millan, J.; Legge, R.; Friedman, T. B.; Kimberling, W. J.

2002-01-01

Usher syndrome type I is characterized by congenital hearing loss, retinitis pigmentosa (RP), and variable vestibular areflexia. Usher syndrome type ID, one of seven Usher syndrome type I genetic localizations, have been mapped to a chromosomal interval that overlaps with a nonsyndromic-deafness localization, DFNB12. Mutations in CDH23, a gene that encodes a putative cell-adhesion protein with multiple cadherin-like domains, are responsible for both Usher syndrome and DFNB12 nonsyndromic deafness. Specific CDH23 mutational defects have been identified that differentiate these two phenotypes. Only missense mutations of CDH23 have been observed in families with nonsyndromic deafness, whereas nonsense, frameshift, splice-site, and missense mutations have been identified in families with Usher syndrome. In the present study, a panel of 69 probands with Usher syndrome and 38 probands with recessive nonsyndromic deafness were screened for the presence of mutations in the entire coding region of CDH23, by heteroduplex, single-strand conformation polymorphism, and direct sequence analyses. A total of 36 different CDH23 mutations were detected in 45 families; 33 of these mutations were novel, including 18 missense, 3 nonsense, 5 splicing defects, 5 microdeletions, and 2 insertions. A total of seven mutations were common to more than one family. Numerous exonic and intronic polymorphisms also were detected. Results of ophthalmologic examinations of the patients with nonsyndromic deafness have found asymptomatic RP–like manifestations, indicating that missense mutations may have a subtle effect in the retina. Furthermore, patients with mutations in CDH23 display a wide range of hearing loss and RP phenotypes, differing in severity, age at onset, type, and the presence or absence of vestibular areflexia. PMID:12075507

A pyramid breeding of eight grain-yield related quantitative trait loci based on marker-assistant and phenotype selection in rice (Oryza sativa L.).

PubMed

Zong, Guo; Wang, Ahong; Wang, Lu; Liang, Guohua; Gu, Minghong; Sang, Tao; Han, Bin

2012-07-20

1000-Grain weight and spikelet number per panicle are two important components for rice grain yield. In our previous study, eight quantitative trait loci (QTLs) conferring spikelet number per panicle and 1000-grain weight were mapped through sequencing-based genotyping of 150 rice recombinant inbred lines (RILs). In this study, we validated the effects of four QTLs from Nipponbare using chromosome segment substitution lines (CSSLs), and pyramided eight grain yield related QTLs. The new lines containing the eight QTLs with positive effects showed increased panicle and spikelet size as compared with the parent variety 93-11. We further proposed a novel pyramid breeding scheme based on marker-assistant and phenotype selection (MAPS). This scheme allowed pyramiding of as many as 24 QTLs at a single hybridization without massive cross work. This study provided insights into the molecular basis of rice grain yield for direct wealth for high-yielding rice breeding. Copyright © 2012. Published by Elsevier Ltd.

Mutation of a Rice Gene Encoding a Phenylalanine Biosynthetic Enzyme Results in Accumulation of Phenylalanine and Tryptophan[W

PubMed Central

Yamada, Tetsuya; Matsuda, Fumio; Kasai, Koji; Fukuoka, Shuichi; Kitamura, Keisuke; Tozawa, Yuzuru; Miyagawa, Hisashi; Wakasa, Kyo

2008-01-01

Two distinct biosynthetic pathways for Phe in plants have been proposed: conversion of prephenate to Phe via phenylpyruvate or arogenate. The reactions catalyzed by prephenate dehydratase (PDT) and arogenate dehydratase (ADT) contribute to these respective pathways. The Mtr1 mutant of rice (Oryza sativa) manifests accumulation of Phe, Trp, and several phenylpropanoids, suggesting a link between the synthesis of Phe and Trp. Here, we show that the Mtr1 mutant gene (mtr1-D) encodes a form of rice PDT with a point mutation in the putative allosteric regulatory region of the protein. Transformed callus lines expressing mtr1-D exhibited all the characteristics of Mtr1 callus tissue. Biochemical analysis revealed that rice PDT possesses both PDT and ADT activities, with a preference for arogenate as substrate, suggesting that it functions primarily as an ADT. The wild-type enzyme is feedback regulated by Phe, whereas the mutant enzyme showed a reduced feedback sensitivity, resulting in Phe accumulation. In addition, these observations indicate that rice PDT is critical for regulating the size of the Phe pool in plant cells. Feeding external Phe to wild-type callus tissue and seedlings resulted in Trp accumulation, demonstrating a connection between Phe accumulation and Trp pool size. PMID:18487352

Concordant but Varied Phenotypes among Duchenne Muscular Dystrophy Patient-Specific Myoblasts Derived using a Human iPSC-Based Model.

PubMed

Choi, In Young; Lim, HoTae; Estrellas, Kenneth; Mula, Jyothi; Cohen, Tatiana V; Zhang, Yuanfan; Donnelly, Christopher J; Richard, Jean-Philippe; Kim, Yong Jun; Kim, Hyesoo; Kazuki, Yasuhiro; Oshimura, Mitsuo; Li, Hongmei Lisa; Hotta, Akitsu; Rothstein, Jeffrey; Maragakis, Nicholas; Wagner, Kathryn R; Lee, Gabsang

2016-06-07

Duchenne muscular dystrophy (DMD) remains an intractable genetic disease. Althogh there are several animal models of DMD, there is no human cell model that carries patient-specific DYSTROPHIN mutations. Here, we present a human DMD model using human induced pluripotent stem cells (hiPSCs). Our model reveals concordant disease-related phenotypes with patient-dependent variation, which are partially reversed by genetic and pharmacological approaches. Our "chemical-compound-based" strategy successfully directs hiPSCs into expandable myoblasts, which exhibit a myogenic transcriptional program, forming striated contractile myofibers and participating in muscle regeneration in vivo. DMD-hiPSC-derived myoblasts show disease-related phenotypes with patient-to-patient variability, including aberrant expression of inflammation or immune-response genes and collagens, increased BMP/TGFβ signaling, and reduced fusion competence. Furthermore, by genetic correction and pharmacological "dual-SMAD" inhibition, the DMD-hiPSC-derived myoblasts and genetically corrected isogenic myoblasts form "rescued" multi-nucleated myotubes. In conclusion, our findings demonstrate the feasibility of establishing a human "DMD-in-a-dish" model using hiPSC-based disease modeling. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Phenotypic and molecular characterisation of efficient nitrogen-fixing Azotobacter strains from rice fields for crop improvement.

PubMed

Sahoo, Ranjan K; Ansari, Mohammad W; Dangar, Tushar K; Mohanty, Santanu; Tuteja, Narendra

2014-05-01

Biological nitrogen fixation (BNF) is highly effective in the field and potentially useful to reduce adverse effects chemical fertilisers. Here, Azotobacter species were selected via phenotypic, biochemical and molecular characterisations from different rice fields. Acetylene reduction assay of Azotobacter spp. showed that Azotobacter vinelandii (Az3) fixed higher amount of nitrogen (121.09 nmol C2H4 mg(-1) bacteria h(-1)). Likewise, its plant growth functions, viz. siderophore, hydrogen cyanide, salicylic acid, IAA, GA3, zeatin, NH3, phosphorus solubilisation, ACC deaminase and iron tolerance, were also higher. The profile of gDNA, plasmid DNA and cellular protein profile depicted inter-generic and inter-specific diversity among the isolates of A. vinelandii. The PCR-amplified genes nifH, nifD and nifK of 0.87, 1.4 and 1.5 kb , respectively, were ascertained by Southern blot hybridisation in isolates of A. vinelandii. The 16S rRNA sequence from A. vinelandii (Az3) was novel, and its accession number (JQ796077) was received from NCBI data base. Biofertiliser formulation of novel A. vinelandii isolates along with commercial one was evaluated in rice (Oriza sativa L. var. Khandagiri) fields. The present finding revealed that treatment T4 (Az3) (A. vinelandii) are highly efficient to improved growth and yield of rice crop.

Characteristics of siRNAs derived from Southern rice black-streaked dwarf virus in infected rice and their potential role in host gene regulation.

PubMed

Xu, Donglin; Zhou, Guohui

2017-02-10

Virus-derived siRNAs (vsiRNAs)-mediated RNA silencing plays important roles in interaction between plant viruses and their hosts. Southern rice black-streaked dwarf virus (SRBSDV) is a newly emerged devastating rice reovirus with ten dsRNA genomic segments. The characteristics of SRBSDV-derived siRNAs and their biological implications in SRBSDV-rice interaction remain unexplored. VsiRNAs profiling from SRBSDV-infected rice samples was done via small RNA deep sequencing. The putative rice targets of abundantly expressed vsiRNAs were bioinformatically predicted and subjected to functional annotation. Differential expression analysis of rice targets and RNA silencing components between infected and healthy samples was done using RT-qPCR. The vsiRNA was barely detectable at 14 days post infection (dpi) but abundantly present along with elevated expression level of the viral genome at 28 dpi. From the 28-dpi sample, 70,878 reads of 18 ~ 30-nt vsiRNAs were recognized (which mostly were 21-nt and 22-nt), covering 75 ~ 91% of the length of the ten genomic segments respectively. 86% of the vsiRNAs had a <50% GC content and 79% of them were 5'-uridylated or adenylated. The production of vsiRNAs had no strand polarity but varied among segment origins. Each segment had a few hotspot regions where vsiRNAs of high abundance were produced. 151 most abundant vsiRNAs were predicted to target 844 rice genes, including several types of host resistance or pathogenesis related genes encoding F-box/LRR proteins, receptor-like protein kinases, universal stress proteins, tobamovirus multiplication proteins, and RNA silencing components OsDCL2a and OsAGO17 respectively, some of which showed down regulation in infected plants in RT-qPCR. GO and KEGG classification showed that a majority of the predicted targets were related to cell parts and cellular processes and involved in carbohydrate metabolism, translation, and signal transduction. The silencing component genes OsDCL2a, Os

Patterns of Novel Alleles and Genotype/Phenotype Correlations Resulting from the Analysis of 108 Previously Undetected Mutations in Patients Affected by Neurofibromatosis Type I

PubMed Central

Bonatti, Francesco; Adorni, Alessia; Matichecchia, Annalisa; Mozzoni, Paola; Uliana, Vera; Pisani, Francesco; Garavelli, Livia; Graziano, Claudio; Gnoli, Maria; Bigoni, Stefania; Boschi, Elena; Martorana, Davide; Percesepe, Antonio

2017-01-01

Neurofibromatosis type I, a genetic disorder due to mutations in the NF1 gene, is characterized by a high mutation rate (about 50% of the cases are de novo) but, with the exception of whole gene deletions associated with a more severe phenotype, no specific hotspots and few solid genotype/phenotype correlations. After retrospectively re-evaluating all NF1 gene variants found in the diagnostic activity, we studied 108 patients affected by neurofibromatosis type I who harbored mutations that had not been previously reported in the international databases, with the aim of analyzing their type and distribution along the gene and of correlating them with the phenotypic features of the affected patients. Out of the 108 previously unreported variants, 14 were inherited by one of the affected parents and 94 were de novo. Twenty-nine (26.9%) mutations were of uncertain significance, whereas 79 (73.2%) were predicted as pathogenic or probably pathogenic. No differential distribution in the exons or in the protein domains was observed and no statistically significant genotype/phenotype correlation was found, confirming previous evidences. PMID:28961165

Constitutive expression of transgenes encoding derivatives of the synthetic antimicrobial peptide BP100: impact on rice host plant fitness.

PubMed

Nadal, Anna; Montero, Maria; Company, Nuri; Badosa, Esther; Messeguer, Joaquima; Montesinos, Laura; Montesinos, Emilio; Pla, Maria

2012-09-04

The Biopeptide BP100 is a synthetic and strongly cationic α-helical undecapeptide with high, specific antibacterial activity against economically important plant-pathogenic bacteria, and very low toxicity. It was selected from a library of synthetic peptides, along with other peptides with activities against relevant bacterial and fungal species. Expression of the BP100 series of peptides in plants is of major interest to establish disease-resistant plants and facilitate molecular farming. Specific challenges were the small length, peptide degradation by plant proteases and toxicity to the host plant. Here we approached the expression of the BP100 peptide series in plants using BP100 as a proof-of-concept. Our design considered up to three tandemly arranged BP100 units and peptide accumulation in the endoplasmic reticulum (ER), analyzing five BP100 derivatives. The ER retention sequence did not reduce the antimicrobial activity of chemically synthesized BP100 derivatives, making this strategy possible. Transformation with sequences encoding BP100 derivatives (bp100der) was over ten-fold less efficient than that of the hygromycin phosphotransferase (hptII) transgene. The BP100 direct tandems did not show higher antimicrobial activity than BP100, and genetically modified (GM) plants constitutively expressing them were not viable. In contrast, inverted repeats of BP100, whether or not elongated with a portion of a natural antimicrobial peptide (AMP), had higher antimicrobial activity, and fertile GM rice lines constitutively expressing bp100der were produced. These GM lines had increased resistance to the pathogens Dickeya chrysanthemi and Fusarium verticillioides, and tolerance to oxidative stress, with agronomic performance comparable to untransformed lines. Constitutive expression of transgenes encoding short cationic α-helical synthetic peptides can have a strong negative impact on rice fitness. However, GM plants expressing, for example, BP100 based on inverted

Genetic control of inflorescence architecture during rice domestication

PubMed Central

Zhu, Zuofeng; Tan, Lubin; Fu, Yongcai; Liu, Fengxia; Cai, Hongwei; Xie, Daoxin; Wu, Feng; Wu, Jianzhong; Matsumoto, Takashi; Sun, Chuanqing

2013-01-01

Inflorescence architecture is a key agronomical factor determining grain yield, and thus has been a major target of cereal crop domestication. Transition from a spread panicle typical of ancestral wild rice (Oryza rufipogon Griff.) to the compact panicle of present cultivars (O. sativa L.) was a crucial event in rice domestication. Here we show that the spread panicle architecture of wild rice is controlled by a dominant gene, OsLG1, a previously reported SBP-domain transcription factor that controls rice ligule development. Association analysis indicates that a single-nucleotide polymorphism-6 in the OsLG1 regulatory region led to a compact panicle architecture in cultivars during rice domestication. We speculate that the cis-regulatory mutation can fine-tune the spatial expression of the target gene, and that selection of cis-regulatory mutations might be an efficient strategy for crop domestication. PMID:23884108

Characterization of the major fragance gene from an aromatic japonica rice and analysis of its diversity in Asian cultivated rice

PubMed Central

Bourgis, F.; Guyot, R.; Gherbi, H.; Tailliez, E.; Amabile, I.; Salse, J.; Lorieux, M.; Delseny, M.

2008-01-01

In Asian cultivated rice (Oryza sativa L.), aroma is one of the most valuable traits in grain quality and 2-ACP is the main volatile compound contributing to the characteristic popcorn-like odour of aromatic rices. Although the major locus for grain fragrance (frg gene) has been described recently in Basmati rice, this gene has not been characterised in true japonica varieties and molecular information available on the genetic diversity and evolutionary origin of this gene among the different varieties is still limited. Here we report on characterisation of the frg gene in the Azucena variety, one of the few aromatic japonica cultivars. We used a RIL population from a cross between Azucena and IR64, a non-aromatic indica, the reference genomic sequence of Nipponbare (japonica) and 93–11 (indica) as well as an Azucena BAC library, to identify the major fragance gene in Azucena. We thus identified a betaine aldehyde dehydrogenase gene, badh2, as the candidate locus responsible for aroma, which presented exactly the same mutation as that identified in Basmati and Jasmine-like rices. Comparative genomic analyses showed very high sequence conservation between Azucena and Nipponbare BADH2, and a MITE was identified in the promotor region of the BADH2 allele in 93–11. The badh2 mutation and MITE were surveyed in a representative rice collection, including traditional aromatic and non-aromatic rice varieties, and strongly suggested a monophylogenetic origin of this badh2 mutation in Asian cultivated rices. Altogether these new data are discussed here in the light of current hypotheses on the origin of rice genetic diversity. PMID:18491070

Novel mutations in the Wiskott-Aldrich syndrome protein gene and their effects on transcriptional, translational, and clinical phenotypes.

PubMed

Lemahieu, V; Gastier, J M; Francke, U

1999-01-01

Wiskott-Aldrich syndrome (WAS) is an X-linked recessive immunodeficiency characterized by thrombocytopenia, eczema, and recurrent infections, and caused by mutations in the WAS protein (WASP) gene. WASP contains several functional domains through which it interacts with proteins involved in intracellular signaling and regulation of the actin cytoskeleton. In this report, 17 WASP gene mutations were identified, 12 of which are novel. DNA of affected males and obligate carriers was PCR amplified and analyzed by SSCA, heteroduplex analysis, and direct sequencing. The effects of the mutations at the mRNA and protein level were ascertained by RT-PCR and Western blot analyses. All missense mutations were located in exons 1-4. Most of the nonsense, frameshift and splice site mutations were found in exons 6-11. Mutations that alter splice sites led to the synthesis of several types of mRNAs, a fraction of which represented the normally spliced product. The presence of normally spliced transcripts was correlated with a milder phenotype. When one such case was studied by Western blotting, reduced amounts of normal-size WASP were present. In other cases as well, a correlation was found between the amount of normal or mutant WASP present and the phenotypes of the affected individuals. No protein was detected in two individuals with severe WAS. Reduced levels of a normal-size WASP with a missense mutation were seen in two individuals with XLT. It is concluded that mutation analysis at the DNA level is not sufficient for predicting clinical course. Studies at the transcript and protein level are needed for a better assessment.

Tunable porous structure of carbon nanosheets derived from puffed rice for high energy density supercapacitors

NASA Astrophysics Data System (ADS)

Hou, Jianhua; Jiang, Kun; Tahir, Muhammad; Wu, Xiaoge; Idrees, Faryal; Shen, Ming; Cao, Chuanbao

2017-12-01

The development of green and clean synthetic techniques to overcome energy requirements have motivated the researchers for the utilization of sustainable biomass. Driven by this desire we choose rice as starting materials source. After the explosion effect, the precursor is converted into puffed rice with a honeycomb-like structures composed of thin sheets. These honeycomb-like macrostructures, effectively prevent the cross-linking tendency towards the adjacent nanosheets during activation process. Furthermore, tuneable micro/mesoporous structures with ultrahigh specific surface areas (SBET) are successfully designed by KOH activation. The highest SBET of 3326 m2 g-1 with optimized proportion of small-mesopores is achieved at 850 °C. The rice-derived porous N-doped carbon nanosheets (NCS-850) are used as the active electrode materials for supercapacitors. It exhibites high specific capacitance specifically of 218 F g-1 at 80 A g-1 in 6 M KOH and a high-energy density of 104 Wh kg-1 (53 Wh L-1) in the ionic liquid electrolytes. These are the highest values among the reported biomass-derived carbon materials for the best of our knowledge. The present work demonstrates that the combination of "puffing effect" and common chemical activation can turn natural products such as rice into functional products with prospective applications in high-performance energy storage devices.

Targeted Mutagenesis in Rice Using TALENs and the CRISPR/Cas9 System.

PubMed

Endo, Masaki; Nishizawa-Yokoi, Ayako; Toki, Seiichi

2016-01-01

Sequence-specific nucleases (SSNs), such as zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the clustered regularly interspersed short palindromic repeats (CRISPR)/CRISPR-associated protein 9 nuclease (Cas9) system, are powerful tools for understanding gene function and for developing novel traits in plants. In plant species for which transformation and regeneration systems using protoplasts are not yet established, direct delivery to nuclei of SSNs either in the form of RNA or protein is difficult. Thus, Agrobacterium-mediated transformation of SSN expression constructs in cultured cells is a practical means of delivering targeted mutagenesis in some plant species including rice. Because targeted mutagenesis occurs stochastically in transgenic cells and SSN-mediated targeted mutagenesis often leads to no selectable phenotype, identification of highly mutated cell lines is a critical step in obtaining regenerated plants with desired mutations.

Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations.

PubMed

Van Montfrans, Joris M; Hartman, Esther A R; Braun, Kees P J; Hennekam, Eric A M; Hak, Elisabeth A; Nederkoorn, Paul J; Westendorp, Willeke F; Bredius, Robbert G M; Kollen, Wouter J W; Schölvinck, Elisabeth H; Legger, G Elizabeth; Meyts, Isabelle; Liston, Adrian; Lichtenbelt, Klaske D; Giltay, Jacques C; Van Haaften, Gijs; De Vries Simons, Gaby M; Leavis, Helen; Sanders, Cornelis J G; Bierings, Marc B; Nierkens, Stefan; Van Gijn, Marielle E

2016-05-01

To determine the genotype-phenotype association in patients with adenosine deaminase-2 (ADA2) deficiency due to identical homozygous R169Q mutations inCECR1 METHODS: We present a case series of nine ADA2-deficient patients with an identical homozygous R169Q mutation. Clinical and diagnostic data were collected and available MRI studies were reviewed. We performed genealogy and haplotype analyses and measured serum ADA2 activity. ADA2 activity values were correlated to clinical symptoms. Age of presentation differed widely between the nine presented patients (range: 0 months to 8 years). The main clinical manifestations were (hepato)splenomegaly (8/9), skin involvement (8/9) and neurological involvement (8/9, of whom 6 encountered stroke). Considerable variation was seen in type, frequency and intensity of other symptoms, which included aplastic anaemia, acute myeloid leukaemia and cutaneous ulcers. Common laboratory abnormalities included cytopenias and hypogammaglobulinaemia. ADA2 enzyme activity in patients was significantly decreased compared with healthy controls. ADA2 activity levels tended to be lower in patients with stroke compared with patients without stroke. Genealogical studies did not identify a common ancestor; however, based on allele frequency, a North-West European founder effect can be noted. Three patients underwent haematopoietic cell transplantation, after which ADA2 activity was restored and clinical symptoms resolved. This case series revealed large phenotypic variability in patients with ADA2 deficiency though they were homozygous for the same R169Q mutation inCECR1 Disease modifiers, including epigenetic and environmental factors, thus seem important in determining the phenotype. Furthermore, haematopoietic cell transplantation appears promising for those patients with a severe clinical phenotype. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions

NSD1 Mutations Are the Major Cause of Sotos Syndrome and Occur in Some Cases of Weaver Syndrome but Are Rare in Other Overgrowth Phenotypes

PubMed Central

Douglas, Jenny; Hanks, Sandra; Temple, I. Karen; Davies, Sally; Murray, Alexandra; Upadhyaya, Meena; Tomkins, Susan; Hughes, Helen E.; Cole, Trevor R. P.; Rahman, Nazneen

2003-01-01

Sotos syndrome is a childhood overgrowth syndrome characterized by a distinctive facial appearance, height and head circumference >97th percentile, advanced bone age, and developmental delay. Weaver syndrome is characterized by the same criteria but has its own distinctive facial gestalt. Recently, a 2.2-Mb chromosome 5q35 microdeletion, encompassing NSD1, was reported as the major cause of Sotos syndrome, with intragenic NSD1 mutations identified in a minority of cases. We evaluated 75 patients with childhood overgrowth, for intragenic mutations and large deletions of NSD1. The series was phenotypically scored into four groups, prior to the molecular analyses: the phenotype in group 1 (n=37) was typical of Sotos syndrome; the phenotype in group 2 (n=13) was Sotos-like but with some atypical features; patients in group 3 (n=7) had Weaver syndrome, and patients in group 4 (n=18) had an overgrowth condition that was neither Sotos nor Weaver syndrome. We detected three deletions and 32 mutations (13 frameshift, 8 nonsense, 2 splice-site, and 9 missense) that are likely to impair NSD1 functions. The truncating mutations were spread throughout NSD1, but there was evidence of clustering of missense mutations in highly conserved functional domains between exons 13 and 23. There was a strong correlation between presence of an NSD1 alteration and clinical phenotype, in that 28 of 37 (76%) patients in group 1 had NSD1 mutations or deletions, whereas none of the patients in group 4 had abnormalities of NSD1. Three patients with Weaver syndrome had NSD1 mutations, all between amino acids 2142 and 2184. We conclude that intragenic mutations of NSD1 are the major cause of Sotos syndrome and account for some Weaver syndrome cases but rarely occur in other childhood overgrowth phenotypes. PMID:12464997

Colorectal cancer risk variants at 8q23.3 and 11q23.1 are associated with disease phenotype in APC mutation carriers.

PubMed

Ghorbanoghli, Z; Nieuwenhuis, M H; Houwing-Duistermaat, J J; Jagmohan-Changur, S; Hes, F J; Tops, C M; Wagner, A; Aalfs, C M; Verhoef, S; Gómez García, E B; Sijmons, R H; Menko, F H; Letteboer, T G; Hoogerbrugge, N; van Wezel, T; Vasen, H F A; Wijnen, J T

2016-10-01

Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome caused by germline mutations in the APC gene and characterized by the development of multiple colorectal adenomas and a high risk of developing colorectal cancer (CRC). The severity of polyposis is correlated with the site of the APC mutation. However, there is also phenotypic variability within families with the same underlying APC mutation, suggesting that additional factors influence the severity of polyposis. Genome-wide association studies identified several single nucleotide polymorphisms (SNPs) that are associated with CRC. We assessed whether these SNPs are associated with polyp multiplicity in proven APC mutation carriers. Sixteen CRC-associated SNPs were analysed in a cohort of 419 APC germline mutation carriers from 182 families. Clinical data were retrieved from the Dutch Polyposis Registry. Allele frequencies of the SNPs were compared for patients with <100 colorectal adenomas versus patients with ≥100 adenomas, using generalized estimating equations with the APC genotype as a covariate. We found a trend of association of two of the tested SNPs with the ≥100 adenoma phenotype: the C alleles of rs16892766 at 8q23.3 (OR 1.71, 95 % CI 1.05-2.76, p = 0.03, dominant model) and rs3802842 at 11q23.1 (OR 1.51, 95 % CI 1.03-2.22, p = 0.04, dominant model). We identified two risk variants that are associated with a more severe phenotype in APC mutation carriers. These risk variants may partly explain the phenotypic variability in families with the same APC gene defect. Further studies with a larger sample size are recommended to evaluate and confirm the phenotypic effect of these SNPs in FAP.

Adult siblings with homozygous G6PC3 mutations expand our understanding of the severe congenital neutropenia type 4 (SCN4) phenotype.

PubMed

Fernandez, Bridget A; Green, Jane S; Bursey, Ford; Barrett, Brendan; MacMillan, Andrée; McColl, Sarah; Fernandez, Sara; Rahman, Proton; Mahoney, Krista; Pereira, Sergio L; Scherer, Stephen W; Boycott, Kym M; Woods, Michael O

2012-11-21

Severe congenital neutropenia type 4 (SCN4) is an autosomal recessive disorder caused by mutations in the third subunit of the enzyme glucose-6-phosphatase (G6PC3). Its core features are congenital neutropenia and a prominent venous skin pattern, and affected individuals have variable birth defects. Oculocutaneous albinism type 4 (OCA4) is caused by autosomal recessive mutations in SLC45A2. We report a sister and brother from Newfoundland, Canada with complex phenotypes. The sister was previously reported by Cullinane et al., 2011. We performed homozygosity mapping, next generation sequencing and conventional Sanger sequencing to identify mutations that cause the phenotype in this family. We have also summarized clinical data from 49 previously reported SCN4 cases with overlapping phenotypes and interpret the medical histories of these siblings in the context of the literature. The siblings' phenotype is due in part to a homozygous mutation in G6PC3, [c.829C > T, p.Gln277X]. Their ages are 38 and 37 years respectively and they are the oldest SCN4 patients published to date. Both presented with congenital neutropenia and later developed Crohn disease. We suggest that the latter is a previously unrecognized SCN4 manifestation and that not all affected individuals have an intellectual disability. The sister also has a homozygous mutation in SLC45A2, which explains her severe oculocutaneous hypopigmentation. Her brother carried one SLC45A2 mutation and was diagnosed with "partial OCA" in childhood. This family highlights that apparently novel syndromes can in fact be caused by two known autosomal recessive disorders.

Rapid generation of genetic diversity by multiplex CRISPR/Cas9 genome editing in rice.

PubMed

Shen, Lan; Hua, Yufeng; Fu, Yaping; Li, Jian; Liu, Qing; Jiao, Xiaozhen; Xin, Gaowei; Wang, Junjie; Wang, Xingchun; Yan, Changjie; Wang, Kejian

2017-05-01

The clustered regularly interspaced short palindromic repeats (CRISPR)-associated endonuclease 9 (CRISPR/Cas9) system has emerged as a promising technology for specific genome editing in many species. Here we constructed one vector targeting eight agronomic genes in rice using the CRISPR/Cas9 multiplex genome editing system. By subsequent genetic transformation and DNA sequencing, we found that the eight target genes have high mutation efficiencies in the T 0 generation. Both heterozygous and homozygous mutations of all editing genes were obtained in T 0 plants. In addition, homozygous sextuple, septuple, and octuple mutants were identified. As the abundant genotypes in T 0 transgenic plants, various phenotypes related to the editing genes were observed. The findings demonstrate the potential of the CRISPR/Cas9 system for rapid introduction of genetic diversity during crop breeding.

Comparison of lesional skin c-KIT mutations with clinical phenotype in patients with mastocytosis.

PubMed

Chan, I J; Tharp, M D

2018-06-01

Activating c-KIT mutations cause abnormal mast cell growth and appear to play a role in mastocytosis. However, the correlation of c-KIT mutations with disease phenotypes is poorly characterized. To evaluate the correlation of c-KIT mutations with clinical presentations and laboratory findings. Total cellular RNA was isolated from the skin lesions of 43 adults and 7 children with mastocytosis, and PCR amplicons of cDNA were sequenced for c-KIT mutations. The most common activating mutation, KIT-D816V, was identified in 72% of adults and 57% of children. Additional activating mutations, namely, V560G and the internal tandem duplications (ITDs) 502-503dupAY, were detected in 12% of adults and 8% of children. V560G occurred more commonly in our patients than previously reported, and it appeared to be associated with more advanced disease. Otherwise, the presence or absence of activating mutations did not correlate with skin lesion morphology, disease extent or total serum tryptase levels. Four adults had expression only of wild-type KIT, while two others had expression of a truncated KIT lacking tyrosine kinase activity; yet these patients were clinically indistinguishable from those patients with activating c-KIT mutations. Activating c-KIT mutations exist in a significant portion of patients with mastocytosis, but not all patients showed expression of these mutations. Except for V560G, the presence or absence of activating c-KIT mutations did not predict the extent of disease. These observations suggest that although activating c-KIT mutations are associated with mast cell growth, other genes probably play a role in the cause of mastocytosis. © 2018 British Association of Dermatologists.

Novel phenotype associated with a mutation in the KCNA1(Kv1.1) gene

PubMed Central

D'Adamo, Maria C.; Gallenmüller, Constanze; Servettini, Ilenio; Hartl, Elisabeth; Tucker, Stephen J.; Arning, Larissa; Biskup, Saskia; Grottesi, Alessandro; Guglielmi, Luca; Imbrici, Paola; Bernasconi, Pia; Di Giovanni, Giuseppe; Franciolini, Fabio; Catacuzzeno, Luigi; Pessia, Mauro; Klopstock, Thomas

2015-01-01

Episodic ataxia type 1 (EA1) is an autosomal dominant K+ channelopathy which manifests with short attacks of cerebellar ataxia and dysarthria, and may also show interictal myokymia. Episodes can be triggered by emotional or physical stress, startle response, sudden postural change or fever. Here we describe a 31-year-old man displaying markedly atypical symptoms, including long-lasting attacks of jerking muscle contractions associated with hyperthermia, severe migraine, and a relatively short-sleep phenotype. A single nucleotide change in KCNA1 (c.555C>G) was identified that changes a highly conserved residue (p.C185W) in the first transmembrane segment of the voltage-gated K+ channel Kv1.1. The patient is heterozygous and the mutation was inherited from his asymptomatic mother. Next generation sequencing revealed no variations in the CACNA1A, CACNB4, KCNC3, KCNJ10, PRRT2 or SCN8A genes of either the patient or mother, except for a benign variant in SLC1A3. Functional analysis of the p.C185W mutation in KCNA1 demonstrated a deleterious dominant-negative phenotype where the remaining current displayed slower activation kinetics, subtle changes in voltage-dependence and faster recovery from slow inactivation. Structural modeling also predicts the C185W mutation to be functionally deleterious. This description of novel clinical features, associated with a Kv1.1 mutation highlights a possibly unrecognized relationship between K+ channel dysfunction, hyperthermia and migraine in EA1, and suggests that thorough assessments for these symptoms should be carefully considered for all patients affected by EA1. PMID:25642194

A major QTL controlling deep rooting on rice chromosome 4

PubMed Central

Uga, Yusaku; Yamamoto, Eiji; Kanno, Noriko; Kawai, Sawako; Mizubayashi, Tatsumi; Fukuoka, Shuichi

2013-01-01

Drought is the most serious abiotic stress that hinders rice production under rainfed conditions. Breeding for deep rooting is a promising strategy to improve the root system architecture in shallow-rooting rice cultivars to avoid drought stress. We analysed the quantitative trait loci (QTLs) for the ratio of deep rooting (RDR) in three F2 mapping populations derived from crosses between each of three shallow-rooting varieties (‘ARC5955', ‘Pinulupot1', and ‘Tupa729') and a deep-rooting variety, ‘Kinandang Patong'. In total, we detected five RDR QTLs on chromosomes 2, 4, and 6. In all three populations, QTLs on chromosome 4 were found to be located at similar positions; they explained from 32.0% to 56.6% of the total RDR phenotypic variance. This suggests that one or more key genetic factors controlling the root growth angle in rice is located in this region of chromosome 4. PMID:24154623

Mutation in a locus linked to penB-nmp causes suppression of the Mtr phenotype of Neisseria gonorrhoeae.

PubMed Central

Shinners, E N; Catlin, B W

1988-01-01

The chromosomal locus mtr, which encodes low-level resistance to multiple antibacterial agents in Neisseria gonorrhoeae, is subject to phenotypic suppression by env mutations that increase the permeability of the envelope. We have identified a new locus, mom (for modifier of Mtr), which is located on the chromosome very close to penB and nmp, loci known to be linked to each other and to spc. Phenotypic suppression of Mtr was recognized by reductions of resistance to benzylpenicillin and also to oxacillin and the hydrophobic agents novobiocin and erythromycin. The resistance to each of these antibiotics returned to the Mtr levels in mom+ transformants isolated by selection for increased resistance to either novobiocin or erythromycin; the accompanying change of the outer membrane protein I seroreactions confirmed the proximity of nmp and mom. Thus, some mutant gonococci display wild-type antibiotic susceptibilities but can express multiple resistance following a mom+ mutation that releases the suppressed Mtr phenotype. PMID:3142343

The UK MRC Mitochondrial Disease Patient Cohort Study: clinical phenotypes associated with the m.3243A>G mutation--implications for diagnosis and management.

PubMed

Nesbitt, Victoria; Pitceathly, Robert D S; Turnbull, Doug M; Taylor, Robert W; Sweeney, Mary G; Mudanohwo, Ese E; Rahman, Shamima; Hanna, Michael G; McFarland, Robert

2013-08-01

Population-based studies suggest the m.3243A>G mutation in MTTL1 is the most common disease-causing mtDNA mutation, with a carrier rate of 1 in 400 people. The m.3243A>G mutation is associated with several clinical syndromes including mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS), maternally inherited deafness and diabetes (MIDD) and progressive external ophthalmoplegia (PEO). Many patients affected by this mutation exhibit a clinical phenotype that does not fall within accepted criteria for the currently recognised classical mitochondrial syndromes. We have defined the phenotypic spectrum associated with the m.3243A>G mtDNA mutation in 129 patients, from 83 unrelated families, recruited to the Mitochondrial Disease Patient Cohort Study UK. 10% of patients exhibited a classical MELAS phenotype, 30% had MIDD, 6% MELAS/MIDD, 2% MELAS/chronic PEO (CPEO) and 5% MIDD/CPEO overlap syndromes. 6% had PEO and other features of mitochondrial disease not consistent with another recognised syndrome. Isolated sensorineural hearing loss occurred in 3%. 28% of patients demonstrated a panoply of clinical features, which were not consistent with any of the classical syndromes associated with the m.3243A>G mutation. 9% of individuals harbouring the mutation were clinically asymptomatic. Following this study we propose guidelines for screening and for the management of confirmed cases.

Hereditary Angioedema Due to C1 Inhibitor Deficiency in Serbia: Two Novel Mutations and Evidence of Genotype-Phenotype Association

PubMed Central

Andrejević, Slađana; Korošec, Peter; Šilar, Mira; Košnik, Mitja; Mijanović, Radovan; Bonači-Nikolić, Branka; Rijavec, Matija

2015-01-01

Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease characterized by recurrent life-threatening oedemas and/or abdominal pain and caused by mutations affecting the C1 inhibitor gene, SERPING1. We sought to investigate the spectrum of SERPING1 mutations in Serbia and the possible genotype-phenotype association. C1-INH-HAE was diagnosed on the basis of clinical and laboratory criteria in 40 patients from 27 families; four were asymptomatic. Mutational analysis of the SERPING1 gene was performed by sequencing and multiplex ligation-dependent probe amplification. Disease-causing mutations in SERPING1 were identified in all patients. In C1-INH-HAE type I, we identified 19 different mutations, including 6 missense mutations, 6 nonsense mutations, 2 small deletions, 1 small insertion, 2 splicing defects and 2 large deletions. Two of the mutations (c.300C>T and c.1184_1185insTA) are reported here for the first time. All C1-INH-HAE type II patients from three families harboured the same substitution (c.1396C>T). Based on the type of mutation identified in the SERPING1 gene, patients were divided into two groups: group 1 (nonsense, frameshift, large deletions/insertions, splicing defect, and mutations at Arg444) or group 2 (missense, excluding mutations at Arg444). Significant differences were found in the clinical severity score (P = 0.005), prevalence of laryngeal (P = 0.040) and facial (P = 0.013) oedema, and long-term prophylaxis (P = 0.023) between the groups with different types of mutations. Because our population consisted of related subjects, differences in the severity score between mutation groups were further confirmed using the generalized estimating equation (P = 0.038). Our study identified 20 different disease-causing mutations, including two novel mutations, in all C1-INH-HAE patients, highlighting the heterogeneity of mutations in the SERPING1 gene. Furthermore, it appears that mutations with a clear effect

Hereditary Angioedema Due to C1 Inhibitor Deficiency in Serbia: Two Novel Mutations and Evidence of Genotype-Phenotype Association.

PubMed

Andrejević, Slađana; Korošec, Peter; Šilar, Mira; Košnik, Mitja; Mijanović, Radovan; Bonači-Nikolić, Branka; Rijavec, Matija

2015-01-01

Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease characterized by recurrent life-threatening oedemas and/or abdominal pain and caused by mutations affecting the C1 inhibitor gene, SERPING1. We sought to investigate the spectrum of SERPING1 mutations in Serbia and the possible genotype-phenotype association. C1-INH-HAE was diagnosed on the basis of clinical and laboratory criteria in 40 patients from 27 families; four were asymptomatic. Mutational analysis of the SERPING1 gene was performed by sequencing and multiplex ligation-dependent probe amplification. Disease-causing mutations in SERPING1 were identified in all patients. In C1-INH-HAE type I, we identified 19 different mutations, including 6 missense mutations, 6 nonsense mutations, 2 small deletions, 1 small insertion, 2 splicing defects and 2 large deletions. Two of the mutations (c.300C>T and c.1184_1185insTA) are reported here for the first time. All C1-INH-HAE type II patients from three families harboured the same substitution (c.1396C>T). Based on the type of mutation identified in the SERPING1 gene, patients were divided into two groups: group 1 (nonsense, frameshift, large deletions/insertions, splicing defect, and mutations at Arg444) or group 2 (missense, excluding mutations at Arg444). Significant differences were found in the clinical severity score (P = 0.005), prevalence of laryngeal (P = 0.040) and facial (P = 0.013) oedema, and long-term prophylaxis (P = 0.023) between the groups with different types of mutations. Because our population consisted of related subjects, differences in the severity score between mutation groups were further confirmed using the generalized estimating equation (P = 0.038). Our study identified 20 different disease-causing mutations, including two novel mutations, in all C1-INH-HAE patients, highlighting the heterogeneity of mutations in the SERPING1 gene. Furthermore, it appears that mutations with a clear effect

Hypomorphic mutations of SEC23B gene account for mild phenotypes of congenital dyserythropoietic anemia type II

PubMed Central

Russo, Roberta; Langella, Concetta; Esposito, Maria Rosaria; Gambale, Antonella; Vitiello, Francesco; Vallefuoco, Fara; Ek, Torben; Yang, Elizabeth; Iolascon, Achille

2013-01-01

Congenital dyserythropoietic anemia type II, a recessive disorder of erythroid differentiation, is due to mutations in SEC23B, a component of the core trafficking machinery COPII. In no case homozygosity or compound heterozygosity for nonsense mutation(s) was found. This study represents the first description of molecular mechanisms underlying SEC23B hypomorphic genotypes by the analysis of five novel mutations. Our findings suggest that reduction of SEC23B gene expression is not associated with CDA II severe clinical presentation; conversely, the combination of a hypomorphic allele with one functionally altered results in more severe phenotypes. We propose a mechanism of compensation SEC23A-mediated which justifies these observations. PMID:23453696

A cytoplasmically transmissible hypovirulence phenotype associated with mitochondrial DNA mutations in the chestnut blight fungus Cryphonectria parasitica.

PubMed Central

Monteiro-Vitorello, C B; Bell, J A; Fulbright, D W; Bertrand, H

1995-01-01

Mutations causing mitochondrial defects were induced in a virulent strain of the chestnut blight fungus Cryphonectria parasitica (Murr.) Barr. Virulence on apples and chestnut trees was reduced in four of six extensively characterized mutants. Relative to the virulent progenitor, the attenuated mutants had reduced growth rates, abnormal colony morphologies, and few asexual spores, and they resembled virus-infected strains. The respiratory defects and attenuated virulence phenotypes (hypovirulence) were transmitted from two mutants to a virulent strain by hyphal contact. The infectious transmission of hypovirulence occurred independently of the transfer of nuclei, did not involve a virus, and dynamically reflects fungal diseases caused by mitochondrial mutations. In these mutants, mitochondrial mutations are further implicated in generation of the attenuated state by (i) uniparental (maternal) inheritance of the trait, (ii) presence of high levels of cyanide-insensitive mitochondrial alternative oxidase activity, (iii) cytochrome deficiencies, and (iv) structural abnormalities in the mtDNA. Hence, cytoplasmically transmissible hypovirulence phenotypes found in virus-free strains of C. parasitica from recovering trees may be caused by mutant forms of mtDNA. Images Fig. 2 Fig. 4 PMID:11607549

Suppression of the rice fatty-acid desaturase gene OsSSI2 enhances resistance to blast and leaf blight diseases in rice.

PubMed

Jiang, Chang-Jie; Shimono, Masaki; Maeda, Satoru; Inoue, Haruhiko; Mori, Masaki; Hasegawa, Morifumi; Sugano, Shoji; Takatsuji, Hiroshi

2009-07-01

Fatty acids and their derivatives play important signaling roles in plant defense responses. It has been shown that suppressing a gene for stearoyl acyl carrier protein fatty-acid desaturase (SACPD) enhances the resistance of Arabidopsis (SSI2) and soybean to multiple pathogens. In this study, we present functional analyses of a rice homolog of SSI2 (OsSSI2) in disease resistance of rice plants. A transposon insertion mutation (Osssi2-Tos17) and RNAi-mediated knockdown of OsSSI2 (OsSSI2-kd) reduced the oleic acid (18:1) level and increased that of stearic acid (18:0), indicating that OsSSI2 is responsible for fatty-acid desaturase activity. These plants displayed spontaneous lesion formation in leaf blades, retarded growth, slight increase in endogenous free salicylic acid (SA) levels, and SA/benzothiadiazole (BTH)-specific inducible genes, including WRKY45, a key regulator of SA/BTH-induced resistance, in rice. Moreover, the OsSSI2-kd plants showed markedly enhanced resistance to the blast fungus Magnaporthe grisea and leaf-blight bacteria Xanthomonas oryzae pv. oryzae. These results suggest that OsSSI2 is involved in the negative regulation of defense responses in rice, as are its Arabidopsis and soybean counterparts. Microarray analyses identified 406 genes that were differentially expressed (>or=2-fold) in OsSSI2-kd rice plants compared with wild-type rice and, of these, approximately 39% were BTH responsive. Taken together, our results suggest that induction of SA-responsive genes, including WRKY45, is likely responsible for enhanced disease resistance in OsSSI2-kd rice plants.

The structural effects of mutations can aid in differential phenotype prediction of beta-myosin heavy chain (Myosin-7) missense variants.

PubMed

Al-Numair, Nouf S; Lopes, Luis; Syrris, Petros; Monserrat, Lorenzo; Elliott, Perry; Martin, Andrew C R

2016-10-01

High-throughput sequencing platforms are increasingly used to screen patients with genetic disease for pathogenic mutations, but prediction of the effects of mutations remains challenging. Previously we developed SAAPdap (Single Amino Acid Polymorphism Data Analysis Pipeline) and SAAPpred (Single Amino Acid Polymorphism Predictor) that use a combination of rule-based structural measures to predict whether a missense genetic variant is pathogenic. Here we investigate whether the same methodology can be used to develop a differential phenotype predictor, which, once a mutation has been predicted as pathogenic, is able to distinguish between phenotypes-in this case the two major clinical phenotypes (hypertrophic cardiomyopathy, HCM and dilated cardiomyopathy, DCM) associated with mutations in the beta-myosin heavy chain (MYH7) gene product (Myosin-7). A random forest predictor trained on rule-based structural analyses together with structural clustering data gave a Matthews' correlation coefficient (MCC) of 0.53 (accuracy, 75%). A post hoc removal of machine learning models that performed particularly badly, increased the performance (MCC = 0.61, Acc = 79%). This proof of concept suggests that methods used for pathogenicity prediction can be extended for use in differential phenotype prediction. Analyses were implemented in Perl and C and used the Java-based Weka machine learning environment. Please contact the authors for availability. andrew@bioinf.org.uk or andrew.martin@ucl.ac.uk Supplementary data are available at Bioinformatics online. © The Authors 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Epidermolysis bullosa with congenital pyloric atresia: novel mutations in the beta 4 integrin gene (ITGB4) and genotype/phenotype correlations.

PubMed

Nakano, A; Pulkkinen, L; Murrell, D; Rico, J; Lucky, A W; Garzon, M; Stevens, C A; Robertson, S; Pfendner, E; Uitto, J

2001-05-01

Epidermolysis bullosa with pyloric atresia (EB-PA: OMIM 226730), also known as Carmi syndrome, is a rare autosomal recessive genodermatosis that manifests with neonatal mucocutaneous fragility associated with congenital pyloric atresia. The disease is frequently lethal within the first year, but nonlethal cases have been reported. Mutations in the genes encoding subunit polypeptides of the alpha 6 beta 4 integrin (ITGA6 and ITGB4) have been demonstrated in EB-PA patients. To extend the repertoire of mutations and to identify genotype-phenotype correlations, we examined seven new EB-PA families, four with lethal and three with nonlethal disease variants. DNA from patients was screened for mutations using heteroduplex analysis followed by nucleotide sequencing of PCR products spanning all beta 4 integrin-coding sequences. Mutation analysis disclosed 12 distinct mutations, 11 of them novel. Four mutations predicted a premature termination codon as a result of nonsense mutations or small out-of-frame insertions or deletions, whereas seven were missense mutations. This brings the total number of distinct ITGB4 mutations to 33. The mutation database indicates that premature termination codons are associated predominantly with the lethal EB-PA variants, whereas missense mutations are more prevalent in nonlethal forms. However, the consequences of the missense mutations are position dependent, and substitutions of highly conserved amino acids may have lethal consequences. In general, indirect immunofluorescence studies of affected skin revealed negative staining for beta 4 integrin in lethal cases and positive, but attenuated, staining in nonlethal cases and correlated with clinical phenotype. The data on specific mutations in EB-PA patients allows prenatal testing and preimplantation genetic diagnosis in families at risk.

Craniosynostosis and Noonan syndrome with KRAS mutations: Expanding the phenotype with a case report and review of the literature.

PubMed

Addissie, Yonit A; Kotecha, Udhaya; Hart, Rachel A; Martinez, Ariel F; Kruszka, Paul; Muenke, Maximilian

2015-11-01

Noonan syndrome (NS) is a multiple congenital anomaly syndrome caused by germline mutations in genes coding for components of the Ras-mitogen-activated protein kinase (RAS-MAPK) pathway. Features include short stature, characteristic facies, congenital heart anomalies, and developmental delay. While there is considerable clinical heterogeneity in NS, craniosynostosis is not a common feature of the condition. Here, we report on a 2 month-old girl with Noonan syndrome associated with a de novo mutation in KRAS (p.P34Q) and premature closure of the sagittal suture. We provide a review of the literature of germline KRAS mutations and find that approximately 10% of published cases have craniosynostosis. Our findings expand on the NS phenotype and suggest that germline mutations in the KRAS gene are causally involved in craniosynostosis, supporting the role of the RAS-MAPK pathway as a mediator of aberrant bone growth in cranial sutures. The inclusion of craniosynostosis as a possible phenotype in KRAS-associated Noonan Syndrome has implications in the differential diagnosis and surgical management of individuals with craniosynostosis. © 2015 Wiley Periodicals, Inc.

The rem Mutations in the ATP-Binding Groove of the Rad3/XPD Helicase Lead to Xeroderma pigmentosum-Cockayne Syndrome-Like Phenotypes

PubMed Central

Montelone, Beth A.; Aguilera, Andrés

2014-01-01

The eukaryotic TFIIH complex is involved in Nucleotide Excision Repair and transcription initiation. We analyzed three yeast mutations of the Rad3/XPD helicase of TFIIH known as rem (recombination and mutation phenotypes). We found that, in these mutants, incomplete NER reactions lead to replication fork breaking and the subsequent engagement of the homologous recombination machinery to restore them. Nevertheless, the penetrance varies among mutants, giving rise to a phenotype gradient. Interestingly, the mutations analyzed reside at the ATP-binding groove of Rad3 and in vivo experiments reveal a gain of DNA affinity upon damage of the mutant Rad3 proteins. Since mutations at the ATP-binding groove of XPD in humans are present in the Xeroderma pigmentosum-Cockayne Syndrome (XP-CS), we recreated rem mutations in human cells, and found that these are XP-CS-like. We propose that the balance between the loss of helicase activity and the gain of DNA affinity controls the capacity of TFIIH to open DNA during NER, and its persistence at both DNA lesions and promoters. This conditions NER efficiency and transcription resumption after damage, which in human cells would explain the XP-CS phenotype, opening new perspectives to understand the molecular basis of the role of XPD in human disease. PMID:25500814

The rem mutations in the ATP-binding groove of the Rad3/XPD helicase lead to Xeroderma pigmentosum-Cockayne syndrome-like phenotypes.

PubMed

Herrera-Moyano, Emilia; Moriel-Carretero, María; Montelone, Beth A; Aguilera, Andrés

2014-12-01

The eukaryotic TFIIH complex is involved in Nucleotide Excision Repair and transcription initiation. We analyzed three yeast mutations of the Rad3/XPD helicase of TFIIH known as rem (recombination and mutation phenotypes). We found that, in these mutants, incomplete NER reactions lead to replication fork breaking and the subsequent engagement of the homologous recombination machinery to restore them. Nevertheless, the penetrance varies among mutants, giving rise to a phenotype gradient. Interestingly, the mutations analyzed reside at the ATP-binding groove of Rad3 and in vivo experiments reveal a gain of DNA affinity upon damage of the mutant Rad3 proteins. Since mutations at the ATP-binding groove of XPD in humans are present in the Xeroderma pigmentosum-Cockayne Syndrome (XP-CS), we recreated rem mutations in human cells, and found that these are XP-CS-like. We propose that the balance between the loss of helicase activity and the gain of DNA affinity controls the capacity of TFIIH to open DNA during NER, and its persistence at both DNA lesions and promoters. This conditions NER efficiency and transcription resumption after damage, which in human cells would explain the XP-CS phenotype, opening new perspectives to understand the molecular basis of the role of XPD in human disease.

Zebrafish cdc6 hypomorphic mutation causes Meier-Gorlin syndrome-like phenotype.

PubMed

Yao, Likun; Chen, Jing; Wu, Xiaotong; Jia, Shunji; Meng, Anming

2017-11-01

Cell Division Cycle 6 (Cdc6) is a component of pre-replicative complex (preRC) forming on DNA replication origins in eukaryotes. Recessive mutations in ORC1, ORC4, ORC6, CDT1 or CDC6 of the preRC in human cause Meier-Gorlin syndrome (MGS) that is characterized by impaired post-natal growth, short stature and microcephaly. However, vertebrate models of MGS have not been reported. Through N-ethyl-N-nitrosourea mutagenesis and Cas9 knockout, we generate several cdc6 mutant lines in zebrafish. Loss-of-function mutations of cdc6, as manifested by cdc6tsu4305 and cdc6tsu7cd mutants, lead to embryonic lethality due to cell cycle arrest at the S phase and extensive apoptosis. Embryos homozygous for a cdc6 hypomorphic mutation, cdc6tsu21cd, develop normally during embryogenesis. Later on, compared with their wild-type (WT) siblings, cdc6tsu21cd mutant fish show growth retardation, and their body weight and length in adulthood are greatly reduced, which resemble human MGS. Surprisingly, cdc6tsu21cd mutant fish become males with a short life and fail to mate with WT females, suggesting defective reproduction. Overexpression of Cdc6 mutant forms, which mimic human CDC6(T323R) mutation found in a MGS patient, in zebrafish cdc6tsu4305 mutant embryos partially represses cell death phenotype, suggesting that the human CDC6(T323R) mutation is a hypomorph. cdc6tsu21cd mutant fish will be useful to detect more tissue defects and develop medical treatment strategies for MGS patients. © The Author 2017. Published by Oxford University Press.

Zebrafish cdc6 hypomorphic mutation causes Meier-Gorlin syndrome-like phenotype

PubMed Central

Yao, Likun; Chen, Jing; Wu, Xiaotong; Jia, Shunji; Meng, Anming

2017-01-01

Abstract Cell Division Cycle 6 (Cdc6) is a component of pre-replicative complex (preRC) forming on DNA replication origins in eukaryotes. Recessive mutations in ORC1, ORC4, ORC6, CDT1 or CDC6 of the preRC in human cause Meier-Gorlin syndrome (MGS) that is characterized by impaired post-natal growth, short stature and microcephaly. However, vertebrate models of MGS have not been reported. Through N-ethyl-N-nitrosourea mutagenesis and Cas9 knockout, we generate several cdc6 mutant lines in zebrafish. Loss-of-function mutations of cdc6, as manifested by cdc6tsu4305 and cdc6tsu7cd mutants, lead to embryonic lethality due to cell cycle arrest at the S phase and extensive apoptosis. Embryos homozygous for a cdc6 hypomorphic mutation, cdc6tsu21cd, develop normally during embryogenesis. Later on, compared with their wild-type (WT) siblings, cdc6tsu21cd mutant fish show growth retardation, and their body weight and length in adulthood are greatly reduced, which resemble human MGS. Surprisingly, cdc6tsu21cd mutant fish become males with a short life and fail to mate with WT females, suggesting defective reproduction. Overexpression of Cdc6 mutant forms, which mimic human CDC6(T323R) mutation found in a MGS patient, in zebrafish cdc6tsu4305 mutant embryos partially represses cell death phenotype, suggesting that the human CDC6(T323R) mutation is a hypomorph. cdc6tsu21cd mutant fish will be useful to detect more tissue defects and develop medical treatment strategies for MGS patients. PMID:28985365

Functional mapping of quantitative trait loci associated with rice tillering.

PubMed

Liu, G F; Li, M; Wen, J; Du, Y; Zhang, Y-M

2010-10-01

Several biologically significant parameters that are related to rice tillering are closely associated with rice grain yield. Although identification of the genes that control rice tillering and therefore influence crop yield would be valuable for rice production management and genetic improvement, these genes remain largely unidentified. In this study, we carried out functional mapping of quantitative trait loci (QTLs) for rice tillering in 129 doubled haploid lines, which were derived from a cross between IR64 and Azucena. We measured the average number of tillers in each plot at seven developmental stages and fit the growth trajectory of rice tillering with the Wang-Lan-Ding mathematical model. Four biologically meaningful parameters in this model--the potential maximum for tiller number (K), the optimum tiller time (t(0)), and the increased rate (r), or the reduced rate (c) at the time of deviation from t(0)--were our defined variables for multi-marker joint analysis under the framework of penalized maximum likelihood, as well as composite interval mapping. We detected a total of 27 QTLs that accounted for 2.49-8.54% of the total phenotypic variance. Nine common QTLs across multi-marker joint analysis and composite interval mapping showed high stability, while one QTL was environment-specific and three were epistatic. We also identified several genomic segments that are associated with multiple traits. Our results describe the genetic basis of rice tiller development, enable further marker-assisted selection in rice cultivar development, and provide useful information for rice production management.

The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome

PubMed Central

Makita, Naomasa; Behr, Elijah; Shimizu, Wataru; Horie, Minoru; Sunami, Akihiko; Crotti, Lia; Schulze-Bahr, Eric; Fukuhara, Shigetomo; Mochizuki, Naoki; Makiyama, Takeru; Itoh, Hideki; Christiansen, Michael; McKeown, Pascal; Miyamoto, Koji; Kamakura, Shiro; Tsutsui, Hiroyuki; Schwartz, Peter J.; George, Alfred L.; Roden, Dan M.

2008-01-01

Phenotypic overlap of type 3 long QT syndrome (LQT3) with Brugada syndrome (BrS) is observed in some carriers of mutations in the Na channel SCN5A. While this overlap is important for patient management, the clinical features, prevalence, and mechanisms underlying such overlap have not been fully elucidated. To investigate the basis for this overlap, we genotyped a cohort of 44 LQT3 families of multiple ethnicities from 7 referral centers and found a high prevalence of the E1784K mutation in SCN5A. Of 41 E1784K carriers, 93% had LQT3, 22% had BrS, and 39% had sinus node dysfunction. Heterologously expressed E1784K channels showed a 15.0-mV negative shift in the voltage dependence of Na channel inactivation and a 7.5-fold increase in flecainide affinity for resting-state channels, properties also seen with other LQT3 mutations associated with a mixed clinical phenotype. Furthermore, these properties were absent in Na channels harboring the T1304M mutation, which is associated with LQT3 without a mixed clinical phenotype. These results suggest that a negative shift of steady-state Na channel inactivation and enhanced tonic block by class IC drugs represent common biophysical mechanisms underlying the phenotypic overlap of LQT3 and BrS and further indicate that class IC drugs should be avoided in patients with Na channels displaying these behaviors. PMID:18451998

X-exome sequencing in Finnish families with Intellectual Disability - four novel mutations and two novel syndromic phenotypes

PubMed Central

2014-01-01

Background X-linked intellectual disability (XLID) is a group of genetically heterogeneous disorders characterized by substantial impairment in cognitive abilities, social and behavioral adaptive skills. Next generation sequencing technologies have become a powerful approach for identifying molecular gene mutations relevant for diagnosis. Methods & objectives Enrichment of X-chromosome specific exons and massively parallel sequencing was performed for identifying the causative mutations in 14 Finnish families, each of them having several males affected with intellectual disability of unknown cause. Results We found four novel mutations in known XLID genes. Two mutations; one previously reported missense mutation (c.1111C > T), and one novel frameshift mutation (c. 990_991insGCTGC) were identified in SLC16A2, a gene that has been linked to Allan-Herndon-Dudley syndrome (AHDS). One novel missense mutation (c.1888G > C) was found in GRIA3 and two novel splice donor site mutations (c.357 + 1G > C and c.985 + 1G > C) were identified in the DLG3 gene. One missense mutation (c.1321C > T) was identified in the candidate gene ZMYM3 in three affected males with a previously unrecognized syndrome characterized by unique facial features, aortic stenosis and hypospadia was detected. All of the identified mutations segregated in the corresponding families and were absent in > 100 Finnish controls and in the publicly available databases. In addition, a previously reported benign variant (c.877G > A) in SYP was identified in a large family with nine affected males in three generations, who have a syndromic phenotype. Conclusions All of the mutations found in this study are being reported for the first time in Finnish families with several affected male patients whose etiological diagnoses have remained unknown to us, in some families, for more than 30 years. This study illustrates the impact of X-exome sequencing to identify rare gene mutations

Adult hippocampus derived soluble factors induce a neuronal-like phenotype in mesenchymal stem cells.

PubMed

Rivera, Francisco J; Sierralta, Walter D; Minguell, Jose J; Aigner, Ludwig

2006-10-02

Bone marrow-derived mesenchymal stem cells (MSCs) are not restricted in their differentiation fate to cells of the mesenchymal lineage. They acquire a neural phenotype in vitro and in vivo after transplantation in the central nervous system. Here we investigated whether soluble factors derived from different brain regions are sufficient to induce a neuronal phenotype in MSCs. We incubated bone marrow-derived MSCs in conditioned medium (CM) derived from adult hippocampus (HCM), cortex (CoCM) or cerebellum (CeCM) and analyzed the cellular morphology and the expression of neuronal and glial markers. In contrast to muscle derived conditioned medium, which served as control, conditioned medium derived from the different brain regions induced a neuronal morphology and the expression of the neuronal markers GAP-43 and neurofilaments in MSCs. Hippocampus derived conditioned medium had the strongest activity. It was independent of NGF or BDNF; and it was restricted to the neuronal differentiation fate, since no induction of the astroglial marker GFAP was observed. The work indicates that soluble factors present in the brain are sufficient to induce a neuronal phenotype in MSCs.

SLC52A2 mutations cause SCABD2 phenotype: A second report.

PubMed

Babanejad, Mojgan; Adeli, Omid Ali; Nikzat, Nooshin; Beheshtian, Maryam; Azarafra, Hakimeh; Sadeghnia, Farnaz; Mohseni, Marzieh; Najmabadi, Hossein; Kahrizi, Kimia

2018-01-01

Autosomal recessive cerebellar ataxias (ARCAs) are a large group of neurodegenerative disorders that manifest mainly in children and young adults. Most ARCAs are heterogeneous with respect to age at onset, severity of disease progression, and frequency of extracerebellar and systemic signs. The phenotype of a consanguineous Iranian family was characterized using clinical testing and pedigree analysis. Whole-exome sequencing was used to identify the disease-causing gene in this family. Using whole exome sequencing (WES), a novel missense mutation in SLC52A2 gene is reported in a consanguineous Iranian family with progressive severe hearing loss, optic atrophy and ataxia. This is the second report of the genotype-phenotype correlation between this syndrome named spinocerebellar ataxia with blindness and deafness type 2 (SCABD2) and SLC52A2 gene. Copyright © 2017 Elsevier B.V. All rights reserved.

A cytochrome P450, OsDSS1, is involved in growth and drought stress responses in rice (Oryza sativa L.).

PubMed

Tamiru, Muluneh; Undan, Jerwin R; Takagi, Hiroki; Abe, Akira; Yoshida, Kakoto; Undan, Jesusa Q; Natsume, Satoshi; Uemura, Aiko; Saitoh, Hiromasa; Matsumura, Hideo; Urasaki, Naoya; Yokota, Takao; Terauchi, Ryohei

2015-05-01

Cytochrome P450s are among the largest protein coding gene families in plant genomes. However, majority of the genes remain uncharacterized. Here, we report the characterization of dss1, a rice mutant showing dwarfism and reduced grain size. The dss1 phenotype is caused by a non-synonymous point mutation we identified in DSS1, which is member of a P450 gene cluster located on rice chromosome 3 and corresponds to the previously reported CYP96B4/SD37 gene. Phenotypes of several dwarf mutants characterized in rice are associated with defects in the biosynthesis or perception of the phytohormones gibberellins (GAs) and brassinosteroids (BRs). However, both GA and BR failed to rescue the dss1 phenotype. Hormone profiling revealed the accumulation of abscisic acid (ABA) and ABA metabolites, as well as significant reductions in GA19 and GA53 levels, precursors of the bioactive GA1, in the mutant. The dss1 contents of cytokinin and auxins were not significantly different from wild-type plants. Consistent with the accumulation of ABA and metabolites, germination and early growth was delayed in dss1, which also exhibited an enhanced tolerance to drought. Additionally, expressions of members of the DSS1/CYP96B gene cluster were regulated by drought stress and exogenous ABA. RNA-seq-based transcriptome profiling revealed, among others, that cell wall-related genes and genes involved in lipid metabolism were up- and down-regulated in dss1, respectively. Taken together, these findings suggest that DSS1 mediates growth and stress responses in rice by fine-tuning GA-to-ABA balance, and might as well play a role in lipid metabolism.

Fisher's geometrical model emerges as a property of complex integrated phenotypic networks.

PubMed

Martin, Guillaume

2014-05-01

Models relating phenotype space to fitness (phenotype-fitness landscapes) have seen important developments recently. They can roughly be divided into mechanistic models (e.g., metabolic networks) and more heuristic models like Fisher's geometrical model. Each has its own drawbacks, but both yield testable predictions on how the context (genomic background or environment) affects the distribution of mutation effects on fitness and thus adaptation. Both have received some empirical validation. This article aims at bridging the gap between these approaches. A derivation of the Fisher model "from first principles" is proposed, where the basic assumptions emerge from a more general model, inspired by mechanistic networks. I start from a general phenotypic network relating unspecified phenotypic traits and fitness. A limited set of qualitative assumptions is then imposed, mostly corresponding to known features of phenotypic networks: a large set of traits is pleiotropically affected by mutations and determines a much smaller set of traits under optimizing selection. Otherwise, the model remains fairly general regarding the phenotypic processes involved or the distribution of mutation effects affecting the network. A statistical treatment and a local approximation close to a fitness optimum yield a landscape that is effectively the isotropic Fisher model or its extension with a single dominant phenotypic direction. The fit of the resulting alternative distributions is illustrated in an empirical data set. These results bear implications on the validity of Fisher's model's assumptions and on which features of mutation fitness effects may vary (or not) across genomic or environmental contexts.

Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1.

PubMed

Hamvas, Aaron; Deterding, Robin R; Wert, Susan E; White, Frances V; Dishop, Megan K; Alfano, Danielle N; Halbower, Ann C; Planer, Benjamin; Stephan, Mark J; Uchida, Derek A; Williames, Lee D; Rosenfeld, Jill A; Lebel, Robert Roger; Young, Lisa R; Cole, F Sessions; Nogee, Lawrence M

2013-09-01

Mutations in the gene encoding thyroid transcription factor, NKX2-1, result in neurologic abnormalities, hypothyroidism, and neonatal respiratory distress syndrome (RDS) that together are known as the brain-thyroid-lung syndrome. To characterize the spectrum of associated pulmonary phenotypes, we identified individuals with mutations in NKX2-1 whose primary manifestation was respiratory disease. Retrospective and prospective approaches identified infants and children with unexplained diffuse lung disease for NKX2-1 sequencing. Histopathologic results and electron micrographs were assessed, and immunohistochemical analysis for surfactant-associated proteins was performed in a subset of 10 children for whom lung tissue was available. We identified 16 individuals with heterozygous missense, nonsense, and frameshift mutations and five individuals with heterozygous, whole-gene deletions of NKX2-1. Neonatal RDS was the presenting pulmonary phenotype in 16 individuals (76%), interstitial lung disease in four (19%), and pulmonary fibrosis in one adult family member. Altogether, 12 individuals (57%) had the full triad of neurologic, thyroid, and respiratory manifestations, but five (24%) had only pulmonary symptoms at the time of presentation. Recurrent respiratory infections were a prominent feature in nine subjects. Lung histopathology demonstrated evidence of disrupted surfactant homeostasis in the majority of cases, and at least five cases had evidence of disrupted lung growth. Patients with mutations in NKX2-1 may present with pulmonary manifestations in the newborn period or during childhood when thyroid or neurologic abnormalities are not apparent. Surfactant dysfunction and, in more severe cases, disrupted lung development are likely mechanisms for the respiratory disease.

Heterogeneous Pulmonary Phenotypes Associated With Mutations in the Thyroid Transcription Factor Gene NKX2-1

PubMed Central

Deterding, Robin R.; Wert, Susan E.; White, Frances V.; Dishop, Megan K.; Alfano, Danielle N.; Halbower, Ann C.; Planer, Benjamin; Stephan, Mark J.; Uchida, Derek A.; Williames, Lee D.; Rosenfeld, Jill A.; Lebel, Robert Roger; Young, Lisa R.; Cole, F. Sessions; Nogee, Lawrence M.

2013-01-01

Background: Mutations in the gene encoding thyroid transcription factor, NKX2-1, result in neurologic abnormalities, hypothyroidism, and neonatal respiratory distress syndrome (RDS) that together are known as the brain-thyroid-lung syndrome. To characterize the spectrum of associated pulmonary phenotypes, we identified individuals with mutations in NKX2-1 whose primary manifestation was respiratory disease. Methods: Retrospective and prospective approaches identified infants and children with unexplained diffuse lung disease for NKX2-1 sequencing. Histopathologic results and electron micrographs were assessed, and immunohistochemical analysis for surfactant-associated proteins was performed in a subset of 10 children for whom lung tissue was available. Results: We identified 16 individuals with heterozygous missense, nonsense, and frameshift mutations and five individuals with heterozygous, whole-gene deletions of NKX2-1. Neonatal RDS was the presenting pulmonary phenotype in 16 individuals (76%), interstitial lung disease in four (19%), and pulmonary fibrosis in one adult family member. Altogether, 12 individuals (57%) had the full triad of neurologic, thyroid, and respiratory manifestations, but five (24%) had only pulmonary symptoms at the time of presentation. Recurrent respiratory infections were a prominent feature in nine subjects. Lung histopathology demonstrated evidence of disrupted surfactant homeostasis in the majority of cases, and at least five cases had evidence of disrupted lung growth. Conclusions: Patients with mutations in NKX2-1 may present with pulmonary manifestations in the newborn period or during childhood when thyroid or neurologic abnormalities are not apparent. Surfactant dysfunction and, in more severe cases, disrupted lung development are likely mechanisms for the respiratory disease. PMID:23430038

Parkinson Disease Phenotype in Ashkenazi Jews with and without LRRK2 G2019S mutations

PubMed Central

Alcalay, Roy N.; Mirelman, Anat; Saunders-Pullman, Rachel; Tang, Ming-X; Santana, Helen Mejia; Raymond, Deborah; Roos, Ernest; Orbe-Reilly, Martha; Gurevich, Tanya; Shira, Anat Bar; Weisz, Mali Gana; Yasinovsky, Kira; Zalis, Maayan; Thaler, Avner; Deik, Andres; Barrett, Matthew James; Cabassa, Jose; Groves, Mark; Hunt, Ann L.; Lubarr, Naomi; Luciano, Marta San; Miravite, Joan; Palmese, Christina; Sachdev, Rivka; Sarva, Harini; Severt, Lawrence; Shanker, Vicki; Swan, Matthew Carrington; Soto-Valencia, Jeannie; Johannes, Brooke; Ortega, Robert; Fahn, Stanley; Cote, Lucien; Waters, Cheryl; Mazzoni, Pietro; Ford, Blair; Louis, Elan; Levy, Oren; Rosado, Llency; Ruiz, Diana; Dorovski, Tsvyatko; Pauciulo, Michael; Nichols, William; Orr-Urtreger, Avi; Ozelius, Laurie; Clark, Lorraine; Giladi, Nir; Bressman, Susan; Marder, Karen S

2013-01-01

Background The phenotype of Parkinson disease (PD) patients with and without LRRK2 G2019S mutations is reported to be similar; however large uniformly evaluated series are lacking. Objective To characterize the clinical phenotype of Ashkenazi Jewish (AJ) PD carriers of the LRRK2 G2019S mutation. Methods We studied 553 AJ PD patients, including 65 patients who were previously reported, from three sites (two in New York and one in Tel-Aviv). GBA mutation carriers were excluded. Evaluations included the Montreal Cognitive Assessment (MoCA), the Unified Parkinson's Disease Rating Scale (UPDRS), the geriatric depression scale (GDS) and the non-motor symptoms (NMS) questionnaire. Regression models were constructed to test the association between clinical and demographic features and LRRK2 status (outcome) in 488 newly recruited participants. Results LRRK2 G2019S carriers (n=97) and non-carriers (n=391) were similar in age and age-at-onset of PD. Carriers had longer disease duration (8.6years versus 6.1years, p<0.001), were more likely to be women (51.5% versus 37.9%, p=0.015) and more often reported first symptoms in lower extremities (40.0% versus 19.2%, p<0.001). In logistic models adjusted for age, disease duration, gender, education, and site, carriers were more likely to have lower extremity onset (p<0.001), postural instability gait difficulty (PIGD, p=0.043) and persistent levodopa response for>5 years (p=0.042). Performance on UPDRS, MoCA, GDS and NMS did not differ by mutation status. Conclusion PD in AJ-LRRK2 G2019S mutation carriers is similar to idiopathic PD, but characterized by more frequent lower extremity involvement at onset and PIGD without the associated cognitive impairment. PMID:24243757

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

PubMed

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

1993-10-01

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

Mutation of RNA polymerase beta subunit (rpoB) promotes hVISA-to-VISA phenotypic conversion of strain Mu3.

PubMed

Matsuo, Miki; Hishinuma, Tomomi; Katayama, Yuki; Cui, Longzhu; Kapi, Maria; Hiramatsu, Keiichi

2011-09-01

The clinical vancomycin-intermediate Staphylococcus aureus (VISA) strain Mu50 carries two mutations in the vraSR and graRS two-component regulatory systems (TCRSs), namely, vraS(I5N) and graR(N197S) (hereinafter designated graR). The clinical heterogeneously vancomycin-intermediate S. aureus (hVISA) strain Mu3 shares with Mu50 the mutation in vraS that encodes the VraS two-component histidine kinase. Previously, we showed that introduction of the plasmid pgraR, carrying the mutated two-component response regulator graR, converted the hVISA strain Mu3 into VISA (vancomycin MIC = 4 mg/liter). Subsequently, however, we found that the introduction of a single copy of graR into the Mu3 chromosome by a gene replacement method did not confer on Mu3 the VISA phenotype. The gene-replaced strain Mu3graR thus obtained remained hVISA (MIC ≤ 2 mg/liter), although a small increase in vancomycin MIC was observed compared to that of the parent strain Mu3. Reevaluation of the Mu3 and Mu50 genomes revealed the presence of another mutation responsible for the expression of the VISA phenotype in Mu50. Here, we demonstrate that in addition to the two regulator mutations, a third mutation found in the Mu50 rpoB gene, encoding the RNA polymerase β subunit, was required for Mu3 to achieve the level of vancomycin resistance of Mu50. The selection of strain Mu3graR with rifampin gave rise to rpoB mutants with various levels of increased vancomycin resistance. Furthermore, 3 (33%) of 10 independently isolated VISA strains established from the heterogeneous subpopulations of Mu3graR were found to possess rpoB mutations with or without an accompanying rifampin-resistance phenotype. The data indicate that a sizable proportion of the resistant hVISA cell subpopulations is composed of spontaneous rpoB mutants with various degrees of increased vancomycin resistance.

The Impact of Herbicide-Resistant Rice Technology on Phenotypic Diversity and Population Structure of United States Weedy Rice1[W][OPEN

PubMed Central

Burgos, Nilda Roma; Singh, Vijay; Tseng, Te Ming; Black, Howard; Young, Nelson D.; Huang, Zhongyun; Hyma, Katie E.; Gealy, David R.; Caicedo, Ana L.

2014-01-01

The use of herbicide-resistant (HR) Clearfield rice (Oryza sativa) to control weedy rice has increased in the past 12 years to constitute about 60% of rice acreage in Arkansas, where most U.S. rice is grown. To assess the impact of HR cultivated rice on the herbicide resistance and population structure of weedy rice, weedy samples were collected from commercial fields with a history of Clearfield rice. Panicles from each weedy type were harvested and tested for resistance to imazethapyr. The majority of plants sampled had at least 20% resistant offspring. These resistant weeds were 97 to 199 cm tall and initiated flowering from 78 to 128 d, generally later than recorded for accessions collected prior to the widespread use of Clearfield rice (i.e. historical accessions). Whereas the majority (70%) of historical accessions had straw-colored hulls, only 30% of contemporary HR weedy rice had straw-colored hulls. Analysis of genotyping-by-sequencing data showed that HR weeds were not genetically structured according to hull color, whereas historical weedy rice was separated into straw-hull and black-hull populations. A significant portion of the local rice crop genome was introgressed into HR weedy rice, which was rare in historical weedy accessions. Admixture analyses showed that HR weeds tend to possess crop haplotypes in the portion of chromosome 2 containing the ACETOLACTATE SYNTHASE gene, which confers herbicide resistance to Clearfield rice. Thus, U.S. HR weedy rice is a distinct population relative to historical weedy rice and shows modifications in morphology and phenology that are relevant to weed management. PMID:25122473

Cardio‐facio‐cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype–phenotype relationships and overlap with Costello syndrome

PubMed Central

Nava, Caroline; Hanna, Nadine; Michot, Caroline; Pereira, Sabrina; Pouvreau, Nathalie; Niihori, Tetsuya; Aoki, Yoko; Matsubara, Yoichi; Arveiler, Benoit; Lacombe, Didier; Pasmant, Eric; Parfait, Béatrice; Baumann, Clarisse; Héron, Delphine; Sigaudy, Sabine; Toutain, Annick; Rio, Marlène; Goldenberg, Alice; Leheup, Bruno; Verloes, Alain; Cavé, Hélène

2007-01-01

Cardio‐facio‐cutaneous (CFC) syndrome, Noonan syndrome (NS), and Costello syndrome (CS) are clinically related developmental disorders that have been recently linked to mutations in the RAS/MEK/ERK signalling pathway. This study was a mutation analysis of the KRAS, BRAF, MEK1 and MEK2 genes in a total of 130 patients (40 patients with a clinical diagnosis of CFC, 20 patients without HRAS mutations from the French Costello family support group, and 70 patients with NS without PTPN11 or SOS1 mutations). BRAF mutations were found in 14/40 (35%) patients with CFC and 8/20 (40%) HRAS‐negative patients with CS. KRAS mutations were found in 1/40 (2.5%) patients with CFC, 2/20 (10%) HRAS‐negative patients with CS and 4/70 patients with NS (5.7%). MEK1 mutations were found in 4/40 patients with CFC (10%), 4/20 (20%) HRAS‐negative patients with CS and 3/70 (4.3%) patients with NS, and MEK2 mutations in 4/40 (10%) patients with CFC. Analysis of the major phenotypic features suggests significant clinical overlap between CS and CFC. The phenotype associated with MEK mutations seems less severe, and is compatible with normal mental development. Features considered distinctive for CS were also found to be associated with BRAF or MEK mutations. Because of its particular cancer risk, the term “Costello syndrome” should only be used for patients with proven HRAS mutation. These results confirm that KRAS is a minor contributor to NS and show that MEK is involved in some cases of NS, demonstrating a phenotypic continuum between the clinical entities. Although some associated features appear to be characteristic of a specific gene, no simple rule exists to distinguish NS from CFC easily. PMID:17704260

Prediction of phenotypes of missense mutations in human proteins from biological assemblies.

PubMed

Wei, Qiong; Xu, Qifang; Dunbrack, Roland L

2013-02-01

Single nucleotide polymorphisms (SNPs) are the most frequent variation in the human genome. Nonsynonymous SNPs that lead to missense mutations can be neutral or deleterious, and several computational methods have been presented that predict the phenotype of human missense mutations. These methods use sequence-based and structure-based features in various combinations, relying on different statistical distributions of these features for deleterious and neutral mutations. One structure-based feature that has not been studied significantly is the accessible surface area within biologically relevant oligomeric assemblies. These assemblies are different from the crystallographic asymmetric unit for more than half of X-ray crystal structures. We find that mutations in the core of proteins or in the interfaces in biological assemblies are significantly more likely to be disease-associated than those on the surface of the biological assemblies. For structures with more than one protein in the biological assembly (whether the same sequence or different), we find the accessible surface area from biological assemblies provides a statistically significant improvement in prediction over the accessible surface area of monomers from protein crystal structures (P = 6e-5). When adding this information to sequence-based features such as the difference between wildtype and mutant position-specific profile scores, the improvement from biological assemblies is statistically significant but much smaller (P = 0.018). Combining this information with sequence-based features in a support vector machine leads to 82% accuracy on a balanced dataset of 50% disease-associated mutations from SwissVar and 50% neutral mutations from human/primate sequence differences in orthologous proteins. Copyright © 2012 Wiley Periodicals, Inc.

Human SOD1 ALS Mutations in a Drosophila Knock-In Model Cause Severe Phenotypes and Reveal Dosage-Sensitive Gain- and Loss-of-Function Components.

PubMed

Şahin, Aslı; Held, Aaron; Bredvik, Kirsten; Major, Paxton; Achilli, Toni-Marie; Kerson, Abigail G; Wharton, Kristi; Stilwell, Geoff; Reenan, Robert

2017-02-01

Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset motor neuron disease and familial forms can be caused by numerous dominant mutations of the copper-zinc superoxide dismutase 1 (SOD1) gene. Substantial efforts have been invested in studying SOD1-ALS transgenic animal models; yet, the molecular mechanisms by which ALS-mutant SOD1 protein acquires toxicity are not well understood. ALS-like phenotypes in animal models are highly dependent on transgene dosage. Thus, issues of whether the ALS-like phenotypes of these models stem from overexpression of mutant alleles or from aspects of the SOD1 mutation itself are not easily deconvolved. To address concerns about levels of mutant SOD1 in disease pathogenesis, we have genetically engineered four human ALS-causing SOD1 point mutations (G37R, H48R, H71Y, and G85R) into the endogenous locus of Drosophila SOD1 (dsod) via ends-out homologous recombination and analyzed the resulting molecular, biochemical, and behavioral phenotypes. Contrary to previous transgenic models, we have recapitulated ALS-like phenotypes without overexpression of the mutant protein. Drosophila carrying homozygous mutations rendering SOD1 protein enzymatically inactive (G85R, H48R, and H71Y) exhibited neurodegeneration, locomotor deficits, and shortened life span. The mutation retaining enzymatic activity (G37R) was phenotypically indistinguishable from controls. While the observed mutant dsod phenotypes were recessive, a gain-of-function component was uncovered through dosage studies and comparisons with age-matched dsod null animals, which failed to show severe locomotor defects or nerve degeneration. We conclude that the Drosophila knock-in model captures important aspects of human SOD1-based ALS and provides a powerful and useful tool for further genetic studies. Copyright © 2017 by the Genetics Society of America.

Cyclic neutropenia and severe congenital neutropenia in patients with a shared ELANE mutation and paternal haplotype: evidence for phenotype determination by modifying genes.

PubMed

Newburger, Peter E; Pindyck, Talia N; Zhu, Zhiqing; Bolyard, Audrey Anna; Aprikyan, Andrew A G; Dale, David C; Smith, Gary D; Boxer, Laurence A

2010-08-01

Cyclic neutropenia (CN) and severe congenital neutropenia (SCN) are disorders of neutrophil production that differ markedly in disease severity. Mutations of the ELANE gene (the symbol recently replacing ELA2) are considered largely responsible for most cases of CN and SCN, but specific mutations are typically associated with one or the other. We performed ELANE genotyping on all individuals and paternal sperm in an SCN kindred with eight SCN progeny of a sperm donor and six different mothers. One patient with CN had the same S97L ELANE mutation as seven patients with the SCN phenotype. The mutant allele was detected in the donor's spermatozoa, representing 18% of the ELANE gene pool, but not in DNA from his lymphocytes, neutrophils, or buccal mucosa, indicating gonadal mosaicism. The coexistence of CN and SCN phenotypes in this kindred with a shared paternal haplotype strongly suggests both a role for modifying genes in determination of congenital neutropenia disease phenotypes, and the classification of CN and SCN within a spectrum of phenotypes expressing varying degrees of the same disease process. (c) 2010 Wiley-Liss, Inc.

Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis

PubMed Central

Flex, Elisabetta; Jaiswal, Mamta; Pantaleoni, Francesca; Martinelli, Simone; Strullu, Marion; Fansa, Eyad K.; Caye, Aurélie; De Luca, Alessandro; Lepri, Francesca; Dvorsky, Radovan; Pannone, Luca; Paolacci, Stefano; Zhang, Si-Cai; Fodale, Valentina; Bocchinfuso, Gianfranco; Rossi, Cesare; Burkitt-Wright, Emma M.M.; Farrotti, Andrea; Stellacci, Emilia; Cecchetti, Serena; Ferese, Rosangela; Bottero, Lisabianca; Castro, Silvana; Fenneteau, Odile; Brethon, Benoît; Sanchez, Massimo; Roberts, Amy E.; Yntema, Helger G.; Van Der Burgt, Ineke; Cianci, Paola; Bondeson, Marie-Louise; Cristina Digilio, Maria; Zampino, Giuseppe; Kerr, Bronwyn; Aoki, Yoko; Loh, Mignon L.; Palleschi, Antonio; Di Schiavi, Elia; Carè, Alessandra; Selicorni, Angelo; Dallapiccola, Bruno; Cirstea, Ion C.; Stella, Lorenzo; Zenker, Martin; Gelb, Bruce D.; Cavé, Hélène; Ahmadian, Mohammad R.; Tartaglia, Marco

2014-01-01

RASopathies, a family of disorders characterized by cardiac defects, defective growth, facial dysmorphism, variable cognitive deficits and predisposition to certain malignancies, are caused by constitutional dysregulation of RAS signalling predominantly through the RAF/MEK/ERK (MAPK) cascade. We report on two germline mutations (p.Gly39dup and p.Val55Met) in RRAS, a gene encoding a small monomeric GTPase controlling cell adhesion, spreading and migration, underlying a rare (2 subjects among 504 individuals analysed) and variable phenotype with features partially overlapping Noonan syndrome, the most common RASopathy. We also identified somatic RRAS mutations (p.Gly39dup and p.Gln87Leu) in 2 of 110 cases of non-syndromic juvenile myelomonocytic leukaemia, a childhood myeloproliferative/myelodysplastic disease caused by upregulated RAS signalling, defining an atypical form of this haematological disorder rapidly progressing to acute myeloid leukaemia. Two of the three identified mutations affected known oncogenic hotspots of RAS genes and conferred variably enhanced RRAS function and stimulus-dependent MAPK activation. Expression of an RRAS mutant homolog in Caenorhabditis elegans enhanced RAS signalling and engendered protruding vulva, a phenotype previously linked to the RASopathy-causing SHOC2S2G mutant. Overall, these findings provide evidence of a functional link between RRAS and MAPK signalling and reveal an unpredicted role of enhanced RRAS function in human disease. PMID:24705357

hnRNPA2B1 and hnRNPA1 mutations are rare in patients with "multisystem proteinopathy" and frontotemporal lobar degeneration phenotypes.

PubMed

Le Ber, Isabelle; Van Bortel, Inge; Nicolas, Gael; Bouya-Ahmed, Kawtar; Camuzat, Agnès; Wallon, David; De Septenville, Anne; Latouche, Morwena; Lattante, Serena; Kabashi, Edor; Jornea, Ludmila; Hannequin, Didier; Brice, Alexis

2014-04-01

hnRNPA2B1 and hnRNPA1 mutations have been recently identified by exome sequencing in three families presenting with multisystem proteinopathy (MSP), a rare complex phenotype associating frontotemporal lobar degeneration (FTLD), Paget disease of bone (PDB), inclusion body myopathy (IBM), and amyotrophic lateral sclerosis (ALS). No study has evaluated the exact frequency of these genes in cohorts of MSP or FTD patients so far. We sequenced both genes in 17 patients with MSP phenotypes, and in 60 patients with FTLD and FTLD-ALS to test whether mutations could be implicated in the pathogenesis of these disorders. No disease-causing mutation was identified. We conclude that hnRNPA2B1 and hnRNPA1 mutations are rare in MSP and FTLD spectrum of diseases, although further investigations in larger populations are needed. Copyright © 2014 Elsevier Inc. All rights reserved.

Emergence of the P2 Phenotype in Pseudomonas aeruginosa PAO1 Strains Involves Various Mutations in mexT or mexF

PubMed Central

Luong, Preston M.; Shogan, Benjamin D.; Zaborin, Alexander; Belogortseva, Natalia; Shrout, Joshua D.

2014-01-01

We recently demonstrated that Pseudomonas aeruginosa PAO1 undergoes a pronounced phenotypic change when introduced into the intestines of rats during surgical injury. Recovered strains displayed a specific phenotype (termed the P2 phenotype) characterized by altered pyocyanin production, high collagenase activity, high swarming motility, low resistance to chloramphenicol, and increased killing of Caenorhabditis elegans compared to the inoculating strain (termed the P1 phenotype). The aims of this study were to characterize the differences between the P. aeruginosa P1 and P2 phenotypes in quorum sensing and competitiveness. We then determined the presence of the P2 phenotype among PAO1 strains from various laboratories. Results demonstrated that P2 cells display accelerated growth during early exponential phase and early activation of quorum-sensing systems and overcome the growth of P1 cells in a mixed population. Among eight PAO1 strains obtained from different laboratories, four exhibited the P2 phenotype. Of 27 mutants analyzed from the P. aeruginosa MPAO1 transposon library, 25 displayed P2 phenotypes. The P2 phenotype in both cases correlated with a lack of expression of mexE or mexF due to mutations in mexT and mexF genes. In summary, strains possessing the P2 phenotype are distributed among PAO1 strains commonly used across a variety of research laboratories. Genetically, they are characterized by various mutations in mexT or mexF. PMID:24244000

The relative contribution of target-site mutations in complex acaricide resistant phenotypes as assessed by marker assisted backcrossing in Tetranychus urticae.

PubMed

Riga, Maria; Bajda, Sabina; Themistokleous, Christos; Papadaki, Stavrini; Palzewicz, Maria; Dermauw, Wannes; Vontas, John; Leeuwen, Thomas Van

2017-08-23

The mechanisms underlying insecticide and acaricide resistance in insects and mites are often complex, including additive effects of target-site insensitivity, increased metabolism and transport. The extent to which target-site resistance mutations contribute to the resistance phenotype is, however, not well studied. Here, we used marker-assisted backcrossing to create 30 congenic lines carrying nine mutations (alone, or in combination in a few cases) associated with resistance to avermectins, pyrethroids, mite growth inhibitors and mitochondrial complex III inhibitors (QoI) in a polyphagous arthropod pest, the spider mite Tetranychus urticae. Toxicity tests revealed that mutations in the voltage-gated sodium channel, chitin synthase 1 and cytochrome b confer high levels of resistance and, when fixed in a population, these mutations alone can result in field failure of acaricide treatment. In contrast, although we confirmed the implication of mutations in glutamate-gated chloride channels in abamectin and milbemectin insensitivity, these mutations do not lead to the high resistance levels that are often reported in abamectin resistant strains of T. urticae. Overall, this study functionally validates reported target-site resistance mutations in T. urticae, by uncoupling them from additional mechanisms, allowing to finally investigate the strength of the conferred phenotype in vivo.

Vitellogenin Receptor Mutation Leads to the Oogenesis Mutant Phenotype “scanty vitellin” of the Silkworm, Bombyx mori*

PubMed Central

Lin, Ying; Meng, Yan; Wang, Yan-Xia; Luo, Juan; Katsuma, Susumu; Yang, Cong-Wen; Banno, Yutaka; Kusakabe, Takahiro; Shimada, Toru; Xia, Qing-You

2013-01-01

In insects, the vitellogenin receptor (VgR) mediates the uptake of vitellogenin (Vg) from the hemolymph by developing oocytes. The oogenesis mutant scanty vitellin (vit) of Bombyx mori (Bm) lacks vitellin and 30-kDa proteins, but B. mori egg-specific protein and BmVg are normal. The vit eggs are white and smaller compared with the pale yellow eggs of the wild type and are embryonic lethal. This study found that a mutation in the B. mori VgR gene (BmVgR) is responsible for the vit phenotype. We cloned the cDNA sequences encoding WT and vit BmVgR. The functional domains of BmVgR are similar to those of other low-density lipoprotein receptors. When compared with the wild type, a 235-bp genomic sequence in vit BmVgR is substituted for a 7-bp sequence. This mutation has resulted in a 50-amino acid deletion in the third Class B region of the first epidermal growth factor (EGF1) domain. BmVgR is expressed specifically in oocytes, and the transcriptional level is changed dramatically and consistently with maturation of oocytes during the previtellogenic periods. Linkage analysis confirmed that BmVgR is mutated in the vit mutant. The coimmunoprecipitation assay confirmed that mutated BmVgR is able to bind BmVg but that BmVg cannot be dissociated under acidic conditions. The WT phenotype determined by RNA interference was similar to that of the vit phenotype for nutritional deficiency, such as BmVg and 30-kDa proteins. These results showed that BmVgR has an important role in transporting proteins for egg formation and embryonic development in B. mori. PMID:23515308

Ineffectiveness of the presence of H-ras/p53 combination of mutations in squamous cell carcinoma cells to induce a conversion of a nontumorigenic to a tumorigenic phenotype.

PubMed

Lee, H; Li, D; Prior, T; Casto, B C; Weghorst, C M; Shuler, C F; Milo, G E

1997-10-01

Human tumor cells have properties in vitro or in surrogate hosts that are distinct from those of normal cells, such as immortality, anchorage independence, and tumor formation in nude mice. However, different cells from individual tumors may exhibit some, but not all of these features. In previous years, human tumor cell lines derived from different tumor and tissue types have been studied to determine those molecular changes that are associated with the in vitro properties listed above and with tumorigenicity in nude mice. In the present study, seven cell lines derived from human tumors were characterized for p53 and ras mutations that may occur in SCC tumor phenotypes and for tumor formation in nude mice. This investigation was designed to examine whether co-occurrence of mutated ras and p53 lead to a malignant stage in the progression process. None of the seven cell lines contained mutations in the recognized "hot spots" of the p53 tumor suppressor gene, but four had a nonsense/splice mutation in codon 126 and a mutation in codon 12 of the H-ras gene. The remaining three cell lines had p53 mutations in intron 5, in codon 193, and a missense mutation in codon 126, respectively. Four of seven cell lines were nontumorigenic; two of these cell lines contained a nonsense p53-126 mutation and mutated ras; one had a missense mutation at codon 126 but no mutated ras; the the fourth had only a p53 mutation at codon 193. Two of the nontumorigenic cell lines were converted to tumorigenicity after treatment with methyl methanesulfonate or N-methyl-N'-nitro-N-nitrosoguanidine with no apparent additional mutations in either gene. Our analysis revealed that there was a high frequency of genetic diversity and mutations in both p53 and H-ras. There was also a lack of a causal relationship in the presence of mutations in p53 and the cells' ability to exhibit a malignant potential in nude mice.

Identification of a Novel GLA Gene Mutation, p.Ile239Met, in Fabry Disease With a Predominant Cardiac Phenotype.

PubMed

Csányi, Beáta; Hategan, Lidia; Nagy, Viktória; Obál, Izabella; Varga, Edina T; Borbás, János; Tringer, Annamária; Eichler, Sabrina; Forster, Tamás; Rolfs, Arndt; Sepp, Róbert

2017-05-31

Fabry disease (FD) is an X-linked inherited lysosomal storage disorder caused by mutations in the GLA gene, encoding for the enzyme α-galactosidase A. Although hundreds of mutations in the GLA gene have been described, many of them are variants of unknown significance. Here we report a novel GLA mutation, p.Ile239Met, identified in a large Hungarian three-generation family with FD. A 69 year-old female index patient with a clinical history of renal failure, hypertrophic cardiomyopathy, and 2nd degree AV block was screened for mutation in the GLA gene. Genetic screening identified a previously unreported heterozygous mutation in exon 5 of the GLA gene (c.717A>G; p.Ile239Met). Family screening indicated that altogether 6 family members carried the mutation (5 females, 1 male, average age: 55 ± 16 years). Three family members, including the index patient, manifested the cardiac phenotype of hypertrophic cardiomyopathy, while two other family members were diagnosed with left ventricular hypertrophy. Taking affection status as the presence of hypertrophic cardiomyopathy, left ventricular hypertrophy or elevated lyso-Gb3 levels, all affected family members carried the mutation. Linkage analysis of the family gave a two-point LOD score of 2.01 between the affection status and the p.Ile239Met GLA mutation. Lyso-Gb3 levels were elevated in all carrier family members (range: 2.4-13.8 ng/mL; upper limit of normal +2STD: ≤ 1.8 ng/mL). The GLA enzyme level was markedly reduced in the affected male family member (< 0.2 µmol/L/hour; upper limit of normal ± 2STD: ≥ 2.6 µmol/L/hour). We conclude that the p. Ile239Met GLA mutation is a pathogenic mutation for FD associated with predominant cardiac phenotype.

The 80-kb DNA duplication on BTA1 is the only remaining candidate mutation for the polled phenotype of Friesian origin

PubMed Central

2014-01-01

Background The absence of horns, called polled phenotype, is the favored trait in modern cattle husbandry. To date, polled cattle are obtained primarily by dehorning calves. Dehorning is a practice that raises animal welfare issues, which can be addressed by selecting for genetically hornless cattle. In the past 20 years, there have been many studies worldwide to identify unique genetic markers in complete association with the polled trait in cattle and recently, two different alleles at the POLLED locus, both resulting in the absence of horns, were reported: (1) the Celtic allele, which is responsible for the polled phenotype in most breeds and for which a single candidate mutation was detected and (2) the Friesian allele, which is responsible for the polled phenotype predominantly in the Holstein-Friesian breed and in a few other breeds, but for which five candidate mutations were identified in a 260-kb haplotype. Further studies based on genome-wide sequencing and high-density SNP (single nucleotide polymorphism) genotyping confirmed the existence of the Celtic and Friesian variants and narrowed down the causal Friesian haplotype to an interval of 145 kb. Results Almost 6000 animals were genetically tested for the polled trait and we detected a recombinant animal which enabled us to reduce the Friesian POLLED haplotype to a single causal mutation, namely a 80-kb duplication. Moreover, our results clearly disagree with the recently reported perfect co-segregation of the POLLED mutation and a SNP at position 1 390 292 bp on bovine chromosome 1 in the Holstein-Friesian population. Conclusion We conclude that the 80-kb duplication, as the only remaining variant within the shortened Friesian haplotype, represents the most likely causal mutation for the polled phenotype of Friesian origin. PMID:24993890

β-Myosin heavy chain variant Val606Met causes very mild hypertrophic cardiomyopathy in mice, but exacerbates HCM phenotypes in mice carrying other HCM mutations.

PubMed

Blankenburg, Robert; Hackert, Katarzyna; Wurster, Sebastian; Deenen, René; Seidman, J G; Seidman, Christine E; Lohse, Martin J; Schmitt, Joachim P

2014-07-07

Approximately 40% of hypertrophic cardiomyopathy (HCM) is caused by heterozygous missense mutations in β-cardiac myosin heavy chain (β-MHC). Associating disease phenotype with mutation is confounded by extensive background genetic and lifestyle/environmental differences between subjects even from the same family. To characterize disease caused by β-cardiac myosin heavy chain Val606Met substitution (VM) that has been identified in several HCM families with wide variation of clinical outcomes, in mice. Unlike 2 mouse lines bearing the malignant myosin mutations Arg453Cys (RC/+) or Arg719Trp (RW/+), VM/+ mice with an identical inbred genetic background lacked hallmarks of HCM such as left ventricular hypertrophy, disarray of myofibers, and interstitial fibrosis. Even homozygous VM/VM mice were indistinguishable from wild-type animals, whereas RC/RC- and RW/RW-mutant mice died within 9 days after birth. However, hypertrophic effects of the VM mutation were observed both in mice treated with cyclosporine, a known stimulator of the HCM response, and compound VM/RC heterozygous mice, which developed a severe HCM phenotype. In contrast to all heterozygous mutants, both systolic and diastolic function of VM/RC hearts was severely impaired already before the onset of cardiac remodeling. The VM mutation per se causes mild HCM-related phenotypes; however, in combination with other HCM activators it exacerbates the HCM phenotype. Double-mutant mice are suitable for assessing the severity of benign mutations. © 2014 American Heart Association, Inc.

A New COL3A1 Mutation in Ehlers-Danlos Syndrome Vascular Type With Different Phenotypes in the Same Family.

PubMed

Cortini, Francesca; Marinelli, Barbara; Romi, Silvia; Seresini, Agostino; Pesatori, Angela Cecilia; Seia, Manuela; Montano, Nicola; Bassotti, Alessandra

2017-04-01

Vascular Ehlers-Danlos syndrome (vEDS) is a rare and severe connective tissue disorder caused by mutations in the collagen type III alpha I chain ( COL3A1) gene. We describe a pathogenetic heterozygous COL3A1 mutation c.3140 G>A, p. Gly1047Asp, identified using next-generation sequencing, in a 40-year-old Italian female. The genetic test performed on her relatives, which present different clinical phenotypes, confirmed that they carry the same mutation in heterozygous state. This finding confirms that mutations causing vEDS have an incomplete penetrance.

Gtl2lacZ, an insertional mutation on mouse chromosome 12 with parental origin-dependent phenotype.

PubMed

Schuster-Gossler, K; Simon-Chazottes, D; Guenet, J L; Zachgo, J; Gossler, A

1996-01-01

We have produced a transgenic mouse line, Gtl2lacZ (Gene trap locus 2), that carries an insertional mutation with a dominant modified pattern of inheritance:heterozygous Gtl2lacZ mice that inherited the transgene from the father show a proportionate dwarfism phenotype, whereas the penetrance and expressivity of the phenotype is strongly reduced in Gtl2lacZ mice that inherited the transgene from the mother. On a mixed genetic background this pattern of inheritance was reversible upon transmission of the transgene through the germ line of the opposite sex. On a predominantly 129/Sv genetic background, however, transgene passage through the female germ line modified the transgene effect, such that the penetrance of the mutation was drastically reduced and the phenotype was no longer obvious after subsequent male germ line transmission. Expression of the transgene, however, was neither affected by genetic background nor by parental legacy. Gtl2lacZ maps to mouse Chromosome 12 in a region that displays imprinting effects associated with maternal and paternal disomy. Our results suggest that the transgene insertion in Gtl2lacZ mice affects an endogenous gene(s) required for fetal and postnatal growth and that this gene(s) is predominantly paternally expressed.

Mapping Quantitative Trait Loci Associated with Toot Traits Using Sequencing-Based Genotyping Chromosome Segment Substitution Lines Derived from 9311 and Nipponbare in Rice (Oryza sativa L.).

PubMed

Zhou, Yong; Dong, Guichun; Tao, Yajun; Chen, Chen; Yang, Bin; Wu, Yue; Yang, Zefeng; Liang, Guohua; Wang, Baohe; Wang, Yulong

2016-01-01

Identification of quantitative trait loci (QTLs) associated with rice root morphology provides useful information for avoiding drought stress and maintaining yield production under the irrigation condition. In this study, a set of chromosome segment substitution lines derived from 9311 as the recipient and Nipponbare as donor, were used to analysis root morphology. By combining the resequencing-based bin-map with a multiple linear regression analysis, QTL identification was conducted on root number (RN), total root length (TRL), root dry weight (RDW), maximum root length (MRL), root thickness (RTH), total absorption area (TAA) and root vitality (RV), using the CSSL population grown under hydroponic conditions. A total of thirty-eight QTLs were identified: six for TRL, six for RDW, eight for the MRL, four for RTH, seven for RN, two for TAA, and five for RV. Phenotypic effect variance explained by these QTLs ranged from 2.23% to 37.08%, and four single QTLs had more than 10% phenotypic explanations on three root traits. We also detected the correlations between grain yield (GY) and root traits, and found that TRL, RTH and MRL had significantly positive correlations with GY. However, TRL, RDW and MRL had significantly positive correlations with biomass yield (BY). Several QTLs identified in our population were co-localized with some loci for grain yield or biomass. This information may be immediately exploited for improving rice water and fertilizer use efficiency for molecular breeding of root system architectures.

Exome sequencing reveals a de novo POLD1 mutation causing phenotypic variability in mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL).

PubMed

Elouej, Sahar; Beleza-Meireles, Ana; Caswell, Richard; Colclough, Kevin; Ellard, Sian; Desvignes, Jean Pierre; Béroud, Christophe; Lévy, Nicolas; Mohammed, Shehla; De Sandre-Giovannoli, Annachiara

2017-06-01

Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL) is an autosomal dominant systemic disorder characterized by prominent loss of subcutaneous fat, a characteristic facial appearance and metabolic abnormalities. This syndrome is caused by heterozygous de novo mutations in the POLD1 gene. To date, 19 patients with MDPL have been reported in the literature and among them 14 patients have been characterized at the molecular level. Twelve unrelated patients carried a recurrent in-frame deletion of a single codon (p.Ser605del) and two other patients carried a novel heterozygous mutation in exon 13 (p.Arg507Cys). Additionally and interestingly, germline mutations of the same gene have been involved in familial polyposis and colorectal cancer (CRC) predisposition. We describe a male and a female patient with MDPL respectively affected with mild and severe phenotypes. Both of them showed mandibular hypoplasia, a beaked nose with bird-like facies, prominent eyes, a small mouth, growth retardation, muscle and skin atrophy, but the female patient showed such a severe and early phenotype that a first working diagnosis of Hutchinson-Gilford Progeria was made. The exploration was performed by direct sequencing of POLD1 gene exon 15 in the male patient with a classical MDPL phenotype and by whole exome sequencing in the female patient and her unaffected parents. Exome sequencing identified in the latter patient a de novo heterozygous undescribed mutation in the POLD1 gene (NM_002691.3: c.3209T>A), predicted to cause the missense change p.Ile1070Asn in the ZnF2 (Zinc Finger 2) domain of the protein. This mutation was not reported in the 1000 Genome Project, dbSNP and Exome sequencing databases. Furthermore, the Isoleucine1070 residue of POLD1 is highly conserved among various species, suggesting that this substitution may cause a major impairment of POLD1 activity. For the second patient, affected with a typical MDPL phenotype, direct sequencing

The Pleiotropic Phenotype of Apc Mutations in the Mouse: Allele Specificity and Effects of the Genetic Background

PubMed Central

Halberg, Richard B.; Chen, Xiaodi; Amos-Landgraf, James M.; White, Alanna; Rasmussen, Kristin; Clipson, Linda; Pasch, Cheri; Sullivan, Ruth; Pitot, Henry C.; Dove, William F.

2008-01-01

Familial adenomatous polyposis (FAP) is a human cancer syndrome characterized by the development of hundreds to thousands of colonic polyps and extracolonic lesions including desmoid fibromas, osteomas, epidermoid cysts, and congenital hypertrophy of the pigmented retinal epithelium. Afflicted individuals are heterozygous for mutations in the APC gene. Detailed investigations of mice heterozygous for mutations in the ortholog Apc have shown that other genetic factors strongly influence the phenotype. Here we report qualitative and quantitative modifications of the phenotype of Apc mutants as a function of three genetic variables: Apc allele, p53 allele, and genetic background. We have found major differences between the Apc alleles Min and 1638N in multiplicity and regionality of intestinal tumors, as well as in incidence of extracolonic lesions. By contrast, Min mice homozygous for either of two different knockout alleles of p53 show similar phenotypic effects. These studies illustrate the classic principle that functional genetics is enriched by assessing penetrance and expressivity with allelic series. The mouse permits study of an allelic gene series on multiple genetic backgrounds, thereby leading to a better understanding of gene action in a range of biological processes. PMID:18723878

The pleiotropic phenotype of Apc mutations in the mouse: allele specificity and effects of the genetic background.

PubMed

Halberg, Richard B; Chen, Xiaodi; Amos-Landgraf, James M; White, Alanna; Rasmussen, Kristin; Clipson, Linda; Pasch, Cheri; Sullivan, Ruth; Pitot, Henry C; Dove, William F

2008-09-01

Familial adenomatous polyposis (FAP) is a human cancer syndrome characterized by the development of hundreds to thousands of colonic polyps and extracolonic lesions including desmoid fibromas, osteomas, epidermoid cysts, and congenital hypertrophy of the pigmented retinal epithelium. Afflicted individuals are heterozygous for mutations in the APC gene. Detailed investigations of mice heterozygous for mutations in the ortholog Apc have shown that other genetic factors strongly influence the phenotype. Here we report qualitative and quantitative modifications of the phenotype of Apc mutants as a function of three genetic variables: Apc allele, p53 allele, and genetic background. We have found major differences between the Apc alleles Min and 1638N in multiplicity and regionality of intestinal tumors, as well as in incidence of extracolonic lesions. By contrast, Min mice homozygous for either of two different knockout alleles of p53 show similar phenotypic effects. These studies illustrate the classic principle that functional genetics is enriched by assessing penetrance and expressivity with allelic series. The mouse permits study of an allelic gene series on multiple genetic backgrounds, thereby leading to a better understanding of gene action in a range of biological processes.

Convergent Loss of Awn in Two Cultivated Rice Species Oryza sativa and Oryza glaberrima Is Caused by Mutations in Different Loci.

PubMed

Furuta, Tomoyuki; Komeda, Norio; Asano, Kenji; Uehara, Kanako; Gamuyao, Rico; Angeles-Shim, Rosalyn B; Nagai, Keisuke; Doi, Kazuyuki; Wang, Diane R; Yasui, Hideshi; Yoshimura, Atsushi; Wu, Jianzhong; McCouch, Susan R; Ashikari, Motoyuki

2015-09-02

A long awn is one of the distinct morphological features of wild rice species. This organ is thought to aid in seed dispersal and prevent predation by animals. Most cultivated varieties of Oryza sativa and Oryza glaberrima, however, have lost the ability to form long awns. The causal genetic factors responsible for the loss of awn in these two rice species remain largely unknown. Here, we evaluated three sets of chromosome segment substitution lines (CSSLs) in a common O. sativa genetic background (cv. Koshihikari) that harbor genomic fragments from Oryza nivara, Oryza rufipogon, and Oryza glaberrima donors. Phenotypic analyses of these libraries revealed the existence of three genes, Regulator of Awn Elongation 1 (RAE1), RAE2, and RAE3, involved in the loss of long awns in cultivated rice. Donor segments at two of these genes, RAE1 and RAE2, induced long awn formation in the CSSLs whereas an O. sativa segment at RAE3 induced long awn formation in O. glaberrima. These results suggest that the two cultivated rice species, O. sativa and O. glaberrima, have taken independent paths to become awnless. Copyright © 2015 Furuta et al.

Novel mutation in TSPAN12 leads to autosomal recessive inheritance of congenital vitreoretinal disease with intra-familial phenotypic variability.

PubMed

Gal, Moran; Levanon, Erez Y; Hujeirat, Yasir; Khayat, Morad; Pe'er, Jacob; Shalev, Stavit

2014-12-01

Developmental malformations of the vitreoretinal vasculature are a heterogeneous group of conditions with various modes of inheritance, and include familial exudative vitreoretinopathy (FEVR), persistent fetal vasculature (PFV), and Norrie disease. We investigated a large consanguineous kindred with multiple affected individuals exhibiting variable phenotypes of abnormal vitreoretinal vasculature, consistent with the three above-mentioned conditions and compatible with autosomal recessive inheritance. Exome sequencing identified a novel c.542G > T (p.C181F) apparently mutation in the TSPAN12 gene that segregated with the ocular disease in the family. The TSPAN12 gene was previously reported to cause dominant and recessive FEVR, but has not yet been associated with other vitreoretinal manifestations. The intra-familial clinical variability caused by a single mutation in the TSPAN12 gene underscores the complicated phenotype-genotype correlation of mutations in this gene, and suggests that there are additional genetic and environmental factors involved in the complex process of ocular vascularization during embryonic development. Our study supports considering PFV, FEVR, and Norrie disease a spectrum of disorders, with clinical and genetic overlap, caused by mutations in distinct genes acting in the Norrin/β-catenin signaling pathway. © 2014 Wiley Periodicals, Inc.

Unusual phenotypic expression of an XLRS1 mutation in X-linked juvenile retinoschisis.

PubMed

Dodds, Jodi A; Srivastava, Anand K; Holden, Kenton R

2006-04-01

X-linked juvenile retinoschisis is a rare progressive vitreoretinal degenerative process that appears in early childhood, results in decreased visual acuity and blindness (if severe), and is caused by various mutations within the XLRS1 gene at Xp22.2. We report an affected family of Western European ancestry with X-linked juvenile retinoschisis. The family was found to carry a 304C-->T substitution in exon 4 of the XLRS1 gene, resulting in an Arg102Trp amino acid substitution. Two of the four available clinical cases in this family were found to carry the mutation. All available mothers of affected males were found to be unaffected carriers of the mutation, a typical feature of X-linked diseases. Two new female carriers, sisters of affected males, were identified and counseled accordingly. Questionnaires on visual functioning were given to the affected family members to examine the psychologic and sociologic impact of X-linked juvenile retinoschisis, which documented an associated stigma even when affected with a "mild" phenotype.

Novel mutations in IBA57 are associated with leukodystrophy and variable clinical phenotypes.

PubMed

Torraco, Alessandra; Ardissone, Anna; Invernizzi, Federica; Rizza, Teresa; Fiermonte, Giuseppe; Niceta, Marcello; Zanetti, Nadia; Martinelli, Diego; Vozza, Angelo; Verrigni, Daniela; Di Nottia, Michela; Lamantea, Eleonora; Diodato, Daria; Tartaglia, Marco; Dionisi-Vici, Carlo; Moroni, Isabella; Farina, Laura; Bertini, Enrico; Ghezzi, Daniele; Carrozzo, Rosalba

2017-01-01

Defects of the Fe/S cluster biosynthesis represent a subgroup of diseases affecting the mitochondrial energy metabolism. In the last years, mutations in four genes (NFU1, BOLA3, ISCA2 and IBA57) have been related to a new group of multiple mitochondrial dysfunction syndromes characterized by lactic acidosis, hyperglycinemia, multiple defects of the respiratory chain complexes, and impairment of four lipoic acid-dependent enzymes: α-ketoglutarate dehydrogenase complex, pyruvic dehydrogenase, branched-chain α-keto acid dehydrogenase complex and the H protein of the glycine cleavage system. Few patients have been reported with mutations in IBA57 and with variable clinical phenotype. Herein, we describe four unrelated patients carrying novel mutations in IBA57. All patients presented with combined or isolated defect of complex I and II. Clinical features varied widely, ranging from fatal infantile onset of the disease to acute and severe psychomotor regression after the first year of life. Brain MRI was characterized by cavitating leukodystrophy. The identified mutations were never reported previously and all had a dramatic effect on IBA57 stability. Our study contributes to expand the array of the genotypic variation of IBA57 and delineates the leukodystrophic pattern of IBA57 deficient patients.

Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis.

PubMed

Gripp, Karen W; Zand, Dina J; Demmer, Laurie; Anderson, Carol E; Dobyns, William B; Zackai, Elaine H; Denenberg, Elizabeth; Jenny, Kim; Stabley, Deborah L; Sol-Church, Katia

2013-10-01

Noonan syndrome is a heterogenous rasopathy typically presenting with short stature, characteristic facial features, cardiac abnormalities including pulmonic valve stenosis, ASD and hypertrophic cardiomyopathy (HCM), cryptorchidism, ectodermal abnormalities, and learning differences. The phenotype is variable, and limited genotype phenotype correlation exists with SOS1 mutations often associated with normal cognition and stature, RAF1 mutations entailing a high HCM risk, and certain PTPN11 mutations predisposing to juvenile myelomonocytic leukemia. The recently identified SHOC2 mutation (p.Ser2Gly) causes Noonan syndrome with loose anagen hair. We report five patients with this mutation. All had skin hyperpigmentation, sparse light colored hair, increased fine wrinkles, ligamentous laxity, developmental delay, and 4/4 had a structural cardiac anomaly. Hypotonia and macrocephaly occurred in 4/5 (80%); 3/5 (60%) had polyhydramnios, increased birth weight or required use of a feeding tube. Distinctive brain abnormalities included relative megalencephaly and enlarged subarachnoid spaces suggestive of benign external hydrocephalus, and a relatively small posterior fossa as indicated by a vertical tentorium. The combination of a large brain with a small posterior fossa likely resulted in the high rate of cerebellar tonsillar ectopia (3/4; 75%). Periventricular nodular heterotopia was seen in one patient with a thick and dysplastic corpus callosum. We report on the first hematologic neoplasm, myelofibrosis, in a 2-year-old patient with SHOC2 mutation. Myelofibrosis is exceedingly rare in children and young adults. The absence of a somatic JAK2 mutation, seen in the majority of patients with myelofibrosis, is noteworthy as it suggests that germline or somatic SHOC2 mutations are causally involved in myelofibrosis. Copyright © 2013 Wiley Periodicals, Inc.

A strong loss-of-function mutation in RAN1 results in constitutive activation of the ethylene response pathway as well as a rosette-lethal phenotype

NASA Technical Reports Server (NTRS)

Woeste, K. E.; Kieber, J. J.; Evans, M. L. (Principal Investigator)

2000-01-01

A recessive mutation was identified that constitutively activated the ethylene response pathway in Arabidopsis and resulted in a rosette-lethal phenotype. Positional cloning of the gene corresponding to this mutation revealed that it was allelic to responsive to antagonist1 (ran1), a mutation that causes seedlings to respond in a positive manner to what is normally a competitive inhibitor of ethylene binding. In contrast to the previously identified ran1-1 and ran1-2 alleles that are morphologically indistinguishable from wild-type plants, this ran1-3 allele results in a rosette-lethal phenotype. The predicted protein encoded by the RAN1 gene is similar to the Wilson and Menkes disease proteins and yeast Ccc2 protein, which are integral membrane cation-transporting P-type ATPases involved in copper trafficking. Genetic epistasis analysis indicated that RAN1 acts upstream of mutations in the ethylene receptor gene family. However, the rosette-lethal phenotype of ran1-3 was not suppressed by ethylene-insensitive mutants, suggesting that this mutation also affects a non-ethylene-dependent pathway regulating cell expansion. The phenotype of ran1-3 mutants is similar to loss-of-function ethylene receptor mutants, suggesting that RAN1 may be required to form functional ethylene receptors. Furthermore, these results suggest that copper is required not only for ethylene binding but also for the signaling function of the ethylene receptors.

Why is golden rice golden (yellow) instead of red?

PubMed

Schaub, Patrick; Al-Babili, Salim; Drake, Rachel; Beyer, Peter

2005-05-01

The endosperm of Golden Rice (Oryza sativa) is yellow due to the accumulation of beta-carotene (provitamin A) and xanthophylls. The product of the two carotenoid biosynthesis transgenes used in Golden Rice, phytoene synthase (PSY) and the bacterial carotene desaturase (CRTI), is lycopene, which has a red color. The absence of lycopene in Golden Rice shows that the pathway proceeds beyond the transgenic end point and thus that the endogenous pathway must also be acting. By using TaqMan real-time PCR, we show in wild-type rice endosperm the mRNA expression of the relevant carotenoid biosynthetic enzymes encoding phytoene desaturase, zeta-carotene desaturase, carotene cis-trans-isomerase, beta-lycopene cyclase, and beta-carotene hydroxylase; only PSY mRNA was virtually absent. We show that the transgenic phenotype is not due to up-regulation of expression of the endogenous rice pathway in response to the transgenes, as was suggested to be the case in tomato (Lycopersicon esculentum) fruit, where CRTI expression resulted in a similar carotenoid phenomenon. This means that beta-carotene and xanthophyll formation in Golden Rice relies on the activity of constitutively expressed intrinsic rice genes (carotene cis-trans-isomerase, alpha/beta-lycopene cyclase, beta-carotene hydroxylase). PSY needs to be supplemented and the need for the CrtI transgene in Golden Rice is presumably due to insufficient activity of the phytoene desaturase and/or zeta-carotene desaturase enzyme in endosperm. The effect of CRTI expression was also investigated in leaves of transgenic rice and Arabidopsis (Arabidopsis thaliana). Here, again, the mRNA levels of intrinsic carotenogenic enzymes remained unaffected; nevertheless, the carotenoid pattern changed, showing a decrease in lutein, while the beta-carotene-derived xanthophylls increased. This shift correlated with CRTI-expression and is most likely governed at the enzyme level by lycopene-cis-trans-isomerism. Possible implications are

Neutral lipid-storage disease with myopathy and extended phenotype with novel PNPLA2 mutation.

PubMed

Massa, Roberto; Pozzessere, Simone; Rastelli, Emanuele; Serra, Laura; Terracciano, Chiara; Gibellini, Manuela; Bozzali, Marco; Arca, Marcello

2016-04-01

Neutral lipid-storage disease with myopathy is caused by mutations in PNPLA2, which produce skeletal and cardiac myopathy. We report a man with multiorgan neutral lipid storage and unusual multisystem clinical involvement, including cognitive impairment. Quantitative brain MRI with voxel-based morphometry and extended neuropsychological assessment were performed. In parallel, the coding sequences and intron/exon boundaries of the PNPLA2 gene were screened by direct sequencing. Neuropsychological assessment revealed global cognitive impairment, and brain MRI showed reduced gray matter volume in the temporal lobes. Molecular characterization revealed a novel homozygous mutation in exon 5 of PNPLA2 (c.714C>A), resulting in a premature stop codon (p.Cys238*). Some PNPLA2 mutations, such as the one described here, may present with an extended phenotype, including brain involvement. In these cases, complete neuropsychological testing, combined with quantitative brain MRI, may help to characterize and quantify cognitive impairment. © 2016 Wiley Periodicals, Inc.

Whole exome analysis identifies dominant COL4A1 mutations in patients with complex ocular phenotypes involving microphthalmia.

PubMed

Deml, B; Reis, L M; Maheshwari, M; Griffis, C; Bick, D; Semina, E V

2014-11-01

Anophthalmia/microphthalmia (A/M) is a developmental ocular malformation defined as complete absence or reduction in size of the eye. A/M is a heterogenous disorder with numerous causative genes identified; however, about half the cases lack a molecular diagnosis. We undertook whole exome sequencing in an A/M family with two affected siblings, two unaffected siblings, and unaffected parents; the ocular phenotype was isolated with only mild developmental delay/learning difficulties reported and a normal brain magnetic resonance imaging (MRI) in the proband at 16 months. No pathogenic mutations were identified in 71 known A/M genes. Further analysis identified a shared heterozygous mutation in COL4A1, c.2317G>A, p.(Gly773Arg) that was not seen in the unaffected parents and siblings. Analysis of 24 unrelated A/M exomes identified a novel c.2122G>A, p.(Gly708Arg) mutation in an additional patient with unilateral microphthalmia, bilateral microcornea and Peters anomaly; the mutation was absent in the unaffected mother and the unaffected father was not available. Mutations in COL4A1 have been linked to a spectrum of human disorders; the most consistent feature is cerebrovascular disease with variable ocular anomalies, kidney and muscle defects. This study expands the spectrum of COL4A1 phenotypes and indicates screening in patients with A/M regardless of MRI findings or presumed inheritance pattern. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Mutations in the Human Laminin β2 (LAMB2) Gene and the Associated Phenotypic Spectrum

PubMed Central

Matejas, Verena; Hinkes, Bernward; Alkandari, Faisal; Al-Gazali, Lihadh; Annexstad, Ellen; Aytac, Mehmet B.; Barrow, Margaret; Bláhová, Kvĕta; Bockenhauer, Detlef; Cheong, Hae Il; Maruniak-Chudek, Iwona; Cochat, Pierre; Dötsch, Jörg; Gajjar, Priya; Hennekam, Raoul C.; Janssen, Françoise; Kagan, Mikhail; Kariminejad, Ariana; Kemper, Markus J.; Koenig, Jens; Kogan, Jillene; Kroes, Hester Y.; Kuwertz-Bröking, Eberhard; Lewanda, Amy F.; Medeira, Ana; Muscheites, Jutta; Niaudet, Patrick; Pierson, Michel; Saggar, Anand; Seaver, Laurie; Suri, Mohnish; Tsygin, Alexey; Wühl, Elke; Zurowska, Aleksandra; Uebe, Steffen; Hildebrandt, Friedhelm; Antignac, Corinne; Zenker, Martin

2010-01-01

Mutations of LAMB2 typically cause autosomal recessive Pierson syndrome, a disorder characterized by congenital nephrotic syndrome, ocular and neurologic abnormalities, but may occasionally be associated with milder or oligosymptomatic disease variants. LAMB2 encodes the basement membrane protein laminin β2 which is incorporated in specific heterotrimeric laminin isoforms and has an expression pattern corresponding to the pattern of organ manifestations in Pierson syndrome. Herein we review all previously reported and several novel LAMB2 mutations in relation to the associated phenotype in patients from 39 unrelated families. The majority of disease-causing LAMB2 mutations are truncating, consistent with the hypothesis that loss of laminin β2 function is the molecular basis of Pierson syndrome. While truncating mutations are distributed across the entire gene, missense mutations are clearly clustered in the N-terminal LN domain, which is important for intermolecular interactions. There is an association of missense mutations and small in frame deletions with a higher mean age at onset of renal disease and with absence of neurologic abnormalities, thus suggesting that at least some of these may represent hypomorphic alleles. Nevertheless, genotype alone does not appear to explain the full range of clinical variability, and therefore hitherto unidentified modifiers are likely to exist. PMID:20556798

Phenotypic spectrum and prevalence of INPP5E mutations in Joubert syndrome and related disorders.

PubMed

Travaglini, Lorena; Brancati, Francesco; Silhavy, Jennifer; Iannicelli, Miriam; Nickerson, Elizabeth; Elkhartoufi, Nadia; Scott, Eric; Spencer, Emily; Gabriel, Stacey; Thomas, Sophie; Ben-Zeev, Bruria; Bertini, Enrico; Boltshauser, Eugen; Chaouch, Malika; Cilio, Maria Roberta; de Jong, Mirjam M; Kayserili, Hulya; Ogur, Gonul; Poretti, Andrea; Signorini, Sabrina; Uziel, Graziella; Zaki, Maha S; Johnson, Colin; Attié-Bitach, Tania; Gleeson, Joseph G; Valente, Enza Maria

2013-10-01

Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain-hindbrain malformation known as the 'molar tooth sign'. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS fetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus.

Phenotypic characterization of the Komeda miniature rat Ishikawa, an animal model of dwarfism caused by a mutation in Prkg2.

PubMed

Tsuchida, Atsuko; Yokoi, Norihide; Namae, Misako; Fuse, Masanori; Masuyama, Taku; Sasaki, Masashi; Kawazu, Shoji; Komeda, Kajuro

2008-12-01

The Komeda miniature rat Ishikawa (KMI) is a spontaneous animal model of dwarfism caused by a mutation in Prkg2, which encodes cGMP-dependent protein kinase type II (cGKII). This strain has been maintained as a segregating inbred strain for the mutated allele mri. In this study, we characterized the phenotype of the KMI strain, particularly growth traits, craniofacial measurements, and organ weights. The homozygous mutant (mri/mri) animals were approximately 70% to 80% of the size of normal, heterozygous (mri/+) animals in regard to body length, weight, and naso-occipital length of the calvarium, and the retroperitoneal fat of mri/mri rats was reduced greatly. In addition, among progeny of the (BNxKMI-mri/mri)F1xKMI-mri/mri backcross, animals with the KMI phenotype (mri/mri) were easily distinguished from those showing the wild-type phenotype (mri/+) by using growth traits such as body length and weight. Genetic analysis revealed that all of the backcrossed progeny exhibiting the KMI phenotype were homozygous for the KMI allele in the 1.2-cM region between D14Rat5 and D14Rat80 on chromosome 14, suggesting strongly that mri acts in a completely recessive manner. The KMI strain is the first and only rat model with a confirmed mutation in Prkg2 and is a valuable model for studying dwarfism and longitudinal growth traits in humans and for functional studies of cGKII.

Phenotypic Characterization of the Komeda Miniature Rat Ishikawa, an Animal Model of Dwarfism Caused by a Mutation in Prkg2

PubMed Central

Tsuchida, Atsuko; Yokoi, Norihide; Namae, Misako; Fuse, Masanori; Masuyama, Taku; Sasaki, Masashi; Kawazu, Shoji; Komeda, Kajuro

2008-01-01

The Komeda miniature rat Ishikawa (KMI) is a spontaneous animal model of dwarfism caused by a mutation in Prkg2, which encodes cGMP-dependent protein kinase type II (cGKII). This strain has been maintained as a segregating inbred strain for the mutated allele mri. In this study, we characterized the phenotype of the KMI strain, particularly growth traits, craniofacial measurements, and organ weights. The homozygous mutant (mri/mri) animals were approximately 70% to 80% of the size of normal, heterozygous (mri/+) animals in regard to body length, weight, and naso-occipital length of the calvarium, and the retroperitoneal fat of mri/mri rats was reduced greatly. In addition, among progeny of the (BN×KMI-mri/mri)F1×KMI-mri/mri backcross, animals with the KMI phenotype (mri/mri) were easily distinguished from those showing the wild-type phenotype (mri/+) by using growth traits such as body length and weight. Genetic analysis revealed that all of the backcrossed progeny exhibiting the KMI phenotype were homozygous for the KMI allele in the 1.2-cM region between D14Rat5 and D14Rat80 on chromosome 14, suggesting strongly that mri acts in a completely recessive manner. The KMI strain is the first and only rat model with a confirmed mutation in Prkg2 and is a valuable model for studying dwarfism and longitudinal growth traits in humans and for functional studies of cGKII. PMID:19149413

Short communication: Phenotypic protease inhibitor resistance and cross-resistance in the clinic from 2006 to 2008 and mutational prevalences in HIV from patients with discordant tipranavir and darunavir susceptibility phenotypes.

PubMed

Bethell, Richard; Scherer, Joseph; Witvrouw, Myriam; Paquet, Agnes; Coakley, Eoin; Hall, David

2012-09-01

To test tipranavir (TPV) or darunavir (DRV) as treatment options for patients with phenotypic resistance to protease inhibitors (PIs), including lopinavir, saquinavir, atazanavir, and fosamprenavir, the PhenoSense GT database was analyzed for susceptibility to DRV or TPV among PI-resistant isolates. The Monogram Biosciences HIV database (South San Francisco, CA) containing 7775 clinical isolates (2006-2008) not susceptible to at least one first-generation PI was analyzed. Phenotypic responses [resistant (R), partially susceptible (PS), or susceptible (S)] were defined by upper and lower clinical cut-offs to each PI. Genotypes were screened for amino acid substitutions associated with TPV-R/DRV-S and TPV-S/DRV-R phenotypes. In all, 4.9% (378) of isolates were resistant to all six PIs and 31.0% (2407) were resistant to none. Among isolates resistant to all four first-generation PIs, DRV resistance increased from 21.2% to 41.9% from 2006 to 2008, respectively, and resistance to TPV remained steady (53.9 to 57.3%, respectively). Higher prevalence substitutions in DRV-S/TPV-R isolates versus DRV-R/TPV-S isolates, respectively, were 82L/T (44.4% vs. 0%) and 83D (5.8% vs. 0%). Higher prevalence substitutions in DRV-R/TPV-S virus were 50V (0.0% vs. 28.9%), 54L (1.0% vs. 36.1%), and 76V (0.4% vs. 15.5%). Mutations to help predict discordant susceptibility to DRV and TPV in isolates with reduced susceptibility to other PIs were identified. DRV resistance mutations associated with improved virologic response to TPV were more prevalent in DRV-R/TPV-S isolates. TPV resistance mutations were more prevalent in TPV-R and DRV-S isolates. These results confirm the impact of genotype on phenotype, illustrating how HIV genotype and phenotype data assist regimen optimization.

Turning rice meiosis into mitosis

PubMed Central

Mieulet, Delphine; Jolivet, Sylvie; Rivard, Maud; Cromer, Laurence; Vernet, Aurore; Mayonove, Pauline; Pereira, Lucie; Droc, Gaëtan; Courtois, Brigitte; Guiderdoni, Emmanuel; Mercier, Raphael

2016-01-01

Introduction of clonal reproduction through seeds (apomixis) in crops has the potential to revolutionize agriculture by allowing self-propagation of any elite variety, in particular F1 hybrids. In the sexual model plant Arabidopsis thaliana synthetic clonal reproduction through seeds can be artificially implemented by (i) combining three mutations to turn meiosis into mitosis (MiMe) and (ii) crossing the obtained clonal gametes with a line expressing modified CENH3 and whose genome is eliminated in the zygote. Here we show that additional combinations of mutations can turn Arabidopsis meiosis into mitosis and that a combination of three mutations in rice (Oryza sativa) efficiently turns meiosis into mitosis, leading to the production of male and female clonal diploid gametes in this major crop. Successful implementation of the MiMe technology in the phylogenetically distant eudicot Arabidopsis and monocot rice opens doors for its application to any flowering plant and paves the way for introducing apomixis in crop species. PMID:27767093

Phenotype-genotype analysis of cryopyrin-associated periodic syndromes (CAPS): description of a rare non-exon 3 and a novel CIAS1 missense mutation.

PubMed

Jesus, Adriana A; Silva, Clovis A; Segundo, Gesmar R; Aksentijevich, Ivona; Fujihira, Erika; Watanabe, Mônica; Carneiro-Sampaio, Magda; Duarte, Alberto J S; Oliveira, João B

2008-03-01

We describe in this paper the phenotype-genotype analysis of a Brazilian cohort of patients with cryopyrin-associated periodic syndromes (CAPS). Patient 1 presented with an urticarial rash and recurrent fever exacerbated by cold weather, arthritis, and anterior uveitis, thus, receiving a clinical diagnosis of familial cold autoinflammatory syndrome. CIAS1 sequencing identified the T436I mutation, previously associated to a clinical phenotype of chronic infantile neurological cutaneous and articular/neonatal onset multisystem inflammatory disease. Patient 2 developed a papular exanthema with daily fever shortly after birth, frontal bossing, patellae enlargement, and cognitive and motor impairments. Sequencing identified the exceedingly rare G755R CIAS1 mutation in exon 4. Patient 3 developed skin rash and articular symptoms 6 h after birth, followed by aseptic meningitis. He was found to have the novel C148Y missense mutation in CIAS1. This report expands the spectrum of CIAS1 mutations associated to clinical disease, suggests that the same mutation can be associated with different clinical syndromes, and supports the evidence that CAPS patients should always be screened for mutations outside exon 3.

Constitutive expression of transgenes encoding derivatives of the synthetic antimicrobial peptide BP100: impact on rice host plant fitness

PubMed Central

2012-01-01

Background The Biopeptide BP100 is a synthetic and strongly cationic α-helical undecapeptide with high, specific antibacterial activity against economically important plant-pathogenic bacteria, and very low toxicity. It was selected from a library of synthetic peptides, along with other peptides with activities against relevant bacterial and fungal species. Expression of the BP100 series of peptides in plants is of major interest to establish disease-resistant plants and facilitate molecular farming. Specific challenges were the small length, peptide degradation by plant proteases and toxicity to the host plant. Here we approached the expression of the BP100 peptide series in plants using BP100 as a proof-of-concept. Results Our design considered up to three tandemly arranged BP100 units and peptide accumulation in the endoplasmic reticulum (ER), analyzing five BP100 derivatives. The ER retention sequence did not reduce the antimicrobial activity of chemically synthesized BP100 derivatives, making this strategy possible. Transformation with sequences encoding BP100 derivatives (bp100der) was over ten-fold less efficient than that of the hygromycin phosphotransferase (hptII) transgene. The BP100 direct tandems did not show higher antimicrobial activity than BP100, and genetically modified (GM) plants constitutively expressing them were not viable. In contrast, inverted repeats of BP100, whether or not elongated with a portion of a natural antimicrobial peptide (AMP), had higher antimicrobial activity, and fertile GM rice lines constitutively expressing bp100der were produced. These GM lines had increased resistance to the pathogens Dickeya chrysanthemi and Fusarium verticillioides, and tolerance to oxidative stress, with agronomic performance comparable to untransformed lines. Conclusions Constitutive expression of transgenes encoding short cationic α-helical synthetic peptides can have a strong negative impact on rice fitness. However, GM plants expressing, for

Complex phenotype linked to a mutation in exon 11 of the lamin A/C gene: Hypertrophic cardiomyopathy, atrioventricular block, severe dyslipidemia and diabetes.

PubMed

Francisco, Ana Rita G; Santos Gonçalves, Inês; Veiga, Fátima; Mendes Pedro, Mónica; Pinto, Fausto J; Brito, Dulce

2017-09-01

The lamin A/C (LMNA) gene encodes lamins A and C, which have an important role in nuclear cohesion and chromatin organization. Mutations in this gene usually lead to the so-called laminopathies, the primary cardiac manifestations of which are dilated cardiomyopathy and intracardiac conduction defects. Some mutations, associated with lipodystrophy but not cardiomyopathy, have been linked to metabolic abnormalities such as diabetes and severe dyslipidemia. Herein we describe a new phenotype associated with a mutation in exon 11 of the LMNA gene: hypertrophic cardiomyopathy, atrioventricular block, severe dyslipidemia and diabetes. A 64-year-old woman with hypertrophic cardiomyopathy and a point mutation in exon 11 of the LMNA gene (c.1718C>T, Ser573Leu) presented with severe symptomatic ventricular hypertrophy and left ventricular outflow tract obstruction. She underwent septal alcohol ablation, followed by Morrow myectomy. The patient was also diagnosed with severe dyslipidemia, diabetes and obesity, and fulfilled diagnostic criteria for metabolic syndrome. No other characteristics of LMNA mutation-related phenotypes were identified. The development of type III atrioventricular block with no apparent cause, and mildly depressed systolic function, prompted referral for cardiac resynchronization therapy. In conclusion, the association between LMNA mutations and different phenotypes is complex and not fully understood, and can present with a broad spectrum of severity. Copyright © 2017 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

Epilepsy caused by CDKL5 mutations.

PubMed

Castrén, Maija; Gaily, Eija; Tengström, Carola; Lähdetie, Jaana; Archer, Hayley; Ala-Mello, Sirpa

2011-01-01

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been identified in female patients with early onset epileptic encephalopathy and severe mental retardation with a Rett-like phenotype. Subsequently CDKL5 mutations were shown to be associated with more diverse phenotypes including mild epilepsy and autism without epilepsy. Furthermore, CDKL5 mutations were found in patients with Angelman-like phenotype. The severity of epilepsy associated with CDKL5 mutations was recently shown to correlate with the type of CDKL5 mutations and epilepsy was identified to involve three distinct sequential stages. Here, we describe the phenotype of a severe form of neurodevelopmental disease in a female patient with a de novo nonsense mutation of the CDKL5 gene c.175C > T (p.R59X) affecting the catalytic domain of CDKL5 protein. Mutations in the CDKL5 gene are less common in males and can be associated with a genomic deletion as found in our male patient with a deletion of 0.3 Mb at Xp22.13 including the CDKL5 gene. We review phenotypes associated with CDKL5 mutations and examine putative relationships between the clinical epilepsy phenotype and the type of the mutation in the CDKL5 gene. © 2010 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.