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1.
Ann Neurol ; 88(2): 348-362, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32515017

RESUMO

OBJECTIVE: Pathogenic variants in SCN3A, encoding the voltage-gated sodium channel subunit Nav1.3, cause severe childhood onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A-related neurodevelopmental disorder. METHODS: Patients were ascertained via an international collaborative network. We compared sodium channels containing wild-type versus variant Nav1.3 subunits coexpressed with ß1 and ß2 subunits using whole-cell voltage clamp electrophysiological recordings in a heterologous mammalian system (HEK-293T cells). RESULTS: Of 22 patients with pathogenic SCN3A variants, most had treatment-resistant epilepsy beginning in the first year of life (16/21, 76%; median onset, 2 weeks), with severe or profound developmental delay (15/20, 75%). Many, but not all (15/19, 79%), exhibited malformations of cortical development. Pathogenic variants clustered in transmembrane segments 4 to 6 of domains II to IV. Most pathogenic missense variants tested (10/11, 91%) displayed gain of channel function, with increased persistent current and/or a leftward shift in the voltage dependence of activation, and all variants associated with malformation of cortical development exhibited gain of channel function. One variant (p.Ile1468Arg) exhibited mixed effects, with gain and partial loss of function. Two variants demonstrated loss of channel function. INTERPRETATION: Our study defines SCN3A-related neurodevelopmental disorder along a spectrum of severity, but typically including epilepsy and severe or profound developmental delay/intellectual disability. Malformations of cortical development are a characteristic feature of this unusual channelopathy syndrome, present in >75% of affected individuals. Gain of function at the channel level in developing neurons is likely an important mechanism of disease pathogenesis. ANN NEUROL 2020;88:348-362.

2.
Am J Hum Genet ; 105(6): 1126-1147, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31735293

RESUMO

The redox state of the neural progenitors regulates physiological processes such as neuronal differentiation and dendritic and axonal growth. The relevance of endoplasmic reticulum (ER)-associated oxidoreductases in these processes is largely unexplored. We describe a severe neurological disorder caused by bi-allelic loss-of-function variants in thioredoxin (TRX)-related transmembrane-2 (TMX2); these variants were detected by exome sequencing in 14 affected individuals from ten unrelated families presenting with congenital microcephaly, cortical polymicrogyria, and other migration disorders. TMX2 encodes one of the five TMX proteins of the protein disulfide isomerase family, hitherto not linked to human developmental brain disease. Our mechanistic studies on protein function show that TMX2 localizes to the ER mitochondria-associated membranes (MAMs), is involved in posttranslational modification and protein folding, and undergoes physical interaction with the MAM-associated and ER folding chaperone calnexin and ER calcium pump SERCA2. These interactions are functionally relevant because TMX2-deficient fibroblasts show decreased mitochondrial respiratory reserve capacity and compensatory increased glycolytic activity. Intriguingly, under basal conditions TMX2 occurs in both reduced and oxidized monomeric form, while it forms a stable dimer under treatment with hydrogen peroxide, recently recognized as a signaling molecule in neural morphogenesis and axonal pathfinding. Exogenous expression of the pathogenic TMX2 variants or of variants with an in vitro mutagenized TRX domain induces a constitutive TMX2 polymerization, mimicking an increased oxidative state. Altogether these data uncover TMX2 as a sensor in the MAM-regulated redox signaling pathway and identify it as a key adaptive regulator of neuronal proliferation, migration, and organization in the developing brain.


Assuntos
Encefalopatias/patologia , Encéfalo/anormalidades , Deficiências do Desenvolvimento/patologia , Proteínas de Membrana/metabolismo , Mitocôndrias/metabolismo , Tiorredoxinas/metabolismo , Adolescente , Adulto , Encefalopatias/genética , Encefalopatias/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/metabolismo , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas de Membrana/genética , Mitocôndrias/patologia , Oxirredução , Prognóstico , Pele/metabolismo , Pele/patologia , Tiorredoxinas/genética , Transcriptoma
4.
Nat Genet ; 51(3): 481-493, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804560

RESUMO

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function-associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.


Assuntos
Predisposição Genética para Doença/genética , Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Fumar/genética
6.
Am J Hum Genet ; 103(5): 786-793, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30343942

RESUMO

PCGF2 encodes the polycomb group ring finger 2 protein, a transcriptional repressor involved in cell proliferation, differentiation, and embryogenesis. PCGF2 is a component of the polycomb repressive complex 1 (PRC1), a multiprotein complex which controls gene silencing through histone modification and chromatin remodelling. We report the phenotypic characterization of 13 patients (11 unrelated individuals and a pair of monozygotic twins) with missense mutations in PCGF2. All the mutations affected the same highly conserved proline in PCGF2 and were de novo, excepting maternal mosaicism in one. The patients demonstrated a recognizable facial gestalt, intellectual disability, feeding problems, impaired growth, and a range of brain, cardiovascular, and skeletal abnormalities. Computer structural modeling suggests the substitutions alter an N-terminal loop of PCGF2 critical for histone biding. Mutant PCGF2 may have dominant-negative effects, sequestering PRC1 components into complexes that lack the ability to interact efficiently with histones. These findings demonstrate the important role of PCGF2 in human development and confirm that heterozygous substitutions of the Pro65 residue of PCGF2 cause a recognizable syndrome characterized by distinctive craniofacial, neurological, cardiovascular, and skeletal features.

7.
Brain ; 141(3): 698-712, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29365063

RESUMO

Polymicrogyria is a malformation of cortical development. The aetiology of polymicrogyria remains poorly understood. Using whole-exome sequencing we found de novo heterozygous missense GRIN1 mutations in 2 of 57 parent-offspring trios with polymicrogyria. We found nine further de novo missense GRIN1 mutations in additional cortical malformation patients. Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy. GRIN1 encodes GluN1, the essential subunit of the N-methyl-d-aspartate receptor. The polymicrogyria-associated GRIN1 mutations tended to cluster in the S2 region (part of the ligand-binding domain of GluN1) or the adjacent M3 helix. These regions are rarely mutated in the normal population or in GRIN1 patients without polymicrogyria. Using two-electrode and whole-cell voltage-clamp analysis, we showed that the polymicrogyria-associated GRIN1 mutations significantly alter the in vitro activity of the receptor. Three of the mutations increased agonist potency while one reduced proton inhibition of the receptor. These results are striking because previous GRIN1 mutations have generally caused loss of function, and because N-methyl-d-aspartate receptor agonists have been used for many years to generate animal models of polymicrogyria. Overall, our results expand the phenotypic spectrum associated with GRIN1 mutations and highlight the important role of N-methyl-d-aspartate receptor signalling in the pathogenesis of polymicrogyria.


Assuntos
Mutação/genética , Proteínas do Tecido Nervoso/genética , Polimicrogiria/genética , Receptores de N-Metil-D-Aspartato/genética , Animais , Criança , Pré-Escolar , Análise Mutacional de DNA , Agonistas de Aminoácidos Excitatórios/farmacologia , Saúde da Família , Feminino , Ácido Glutâmico/farmacologia , Glicina/metabolismo , Glicina/farmacologia , Células HEK293 , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Potenciais da Membrana/genética , Modelos Moleculares , Mutagênese/genética , N-Metilaspartato/farmacologia , Técnicas de Patch-Clamp , Polimicrogiria/diagnóstico por imagem , Ratos , Transfecção
8.
Mov Disord Clin Pract ; 4(2): 249-253, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-30838261

RESUMO

We report on a white Afrikaans family from eastern South Africa with three members affected with North Sea progressive myoclonus epilepsy, resulting from a homozygous founder GOSR2 mutation (c.430G>T, p.Gly144Trp). The mutation was identified by exomic sequencing in a research study investigating childhood onset ataxias. All three subjects presented with ataxia, tremor, early gait difficulties, and myoclonic and generalized tonic clonic (GTC) epilepsy. Each patient underwent deep brain stimulation of the caudal Zona Incerta before coming to the attention of the authors. In each case there was a reduction in GTC seizures, and two patients exhibited a reduction in involuntary movements, as evaluated during long-term follow-up. In one case there was an improvement in gait and stance when assessed while the stimulation was on.

9.
PLoS One ; 11(9): e0160483, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27603668

RESUMO

The question of whether any species except humans exhibits culture has generated much debate, partially due to the difficulty of providing conclusive evidence from observational studies in the wild. A starting point for demonstrating the existence of culture that has been used for many species including chimpanzees and orangutans is to show that there is geographic variation in the occurrence of particular behavioral traits inferred to be a result of social learning and not ecological or genetic influences. Gorillas live in a wide variety of habitats across Africa and they exhibit flexibility in diet, behavior, and social structure. Here we apply the 'method of exclusion' to look for the presence/absence of behaviors that could be considered potential cultural traits in well-habituated groups from five study sites of the two species of gorillas. Of the 41 behaviors considered, 23 met the criteria of potential cultural traits, of which one was foraging related, nine were environment related, seven involved social interactions, five were gestures, and one was communication related. There was a strong positive correlation between behavioral dissimilarity and geographic distance among gorilla study sites. Roughly half of all variation in potential cultural traits was intraspecific differences (i.e. variability among sites within a species) and the other 50% of potential cultural traits were differences between western and eastern gorillas. Further research is needed to investigate if the occurrence of these traits is influenced by social learning. These findings emphasize the importance of investigating cultural traits in African apes and other species to shed light on the origin of human culture.


Assuntos
Cultura , Comportamento Alimentar/fisiologia , Gorilla gorilla/fisiologia , Comportamento Social , África , Animais , Ecologia , Feminino , Gorilla gorilla/genética , Relações Interpessoais , Pan troglodytes , Fenótipo , Pongo , Pongo pygmaeus
10.
Brain ; 138(Pt 7): 1817-32, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25981959

RESUMO

Cerebral palsy is a sporadic disorder with multiple likely aetiologies, but frequently considered to be caused by birth asphyxia. Genetic investigations are rarely performed in patients with cerebral palsy and there is little proven evidence of genetic causes. As part of a large project investigating children with ataxia, we identified four patients in our cohort with a diagnosis of ataxic cerebral palsy. They were investigated using either targeted next generation sequencing or trio-based exome sequencing and were found to have mutations in three different genes, KCNC3, ITPR1 and SPTBN2. All the mutations were de novo and associated with increased paternal age. The mutations were shown to be pathogenic using a combination of bioinformatics analysis and in vitro model systems. This work is the first to report that the ataxic subtype of cerebral palsy can be caused by de novo dominant point mutations, which explains the sporadic nature of these cases. We conclude that at least some subtypes of cerebral palsy may be caused by de novo genetic mutations and patients with a clinical diagnosis of cerebral palsy should be genetically investigated before causation is ascribed to perinatal asphyxia or other aetiologies.


Assuntos
Ataxia/genética , Paralisia Cerebral/genética , Doenças Genéticas Inatas/genética , Receptores de Inositol 1,4,5-Trifosfato/genética , Mutação Puntual , Canais de Potássio Shaw/genética , Espectrina/genética , Sequência de Bases , Criança , Pré-Escolar , Análise Mutacional de DNA , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Masculino , Técnicas de Patch-Clamp , Análise de Sequência de DNA
11.
Bioinformatics ; 30(9): 1290-1, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24395753

RESUMO

Computational genomics seeks to draw biological inferences from genomic datasets, often by integrating and contextualizing next-generation sequencing data. CGAT provides an extensive suite of tools designed to assist in the analysis of genome scale data from a range of standard file formats. The toolkit enables filtering, comparison, conversion, summarization and annotation of genomic intervals, gene sets and sequences. The tools can both be run from the Unix command line and installed into visual workflow builders, such as Galaxy.


Assuntos
Genômica/métodos , Bases de Dados Genéticas , Sequenciamento de Nucleotídeos em Larga Escala , Software , Fluxo de Trabalho
12.
Am J Hum Genet ; 93(5): 976-83, 2013 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-24207122

RESUMO

Spinal muscular atrophies (SMAs) are a heterogeneous group of inherited disorders characterized by degeneration of anterior horn cells and progressive muscle weakness. In two unrelated families affected by a distinct form of autosomal-dominant distal SMA initially manifesting with calf weakness, we identified by genetic linkage analysis and exome sequencing a heterozygous missense mutation, c.616T>C (p.Cys206Arg), in F-box protein 38 (FBXO38). FBXO38 is a known coactivator of the transcription factor Krüppel-like factor 7 (KLF7), which regulates genes required for neuronal axon outgrowth and repair. The p.Cys206Arg substitution did not alter the subcellular localization of FBXO38 but did impair KLF7-mediated transactivation of a KLF7-responsive promoter construct and endogenous KLF7 target genes in both heterologously expressing human embryonic kidney 293T cells and fibroblasts derived from individuals with the FBXO38 missense mutation. This transcriptional dysregulation was associated with an impairment of neurite outgrowth in primary motor neurons. Together, these results suggest that a transcriptional regulatory pathway that has a well-established role in axonal development could also be critical for neuronal maintenance and highlight the importance of FBXO38 and KLF7 activity in motor neurons.


Assuntos
Proteínas F-Box/genética , Atrofia Muscular Espinal/genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Células do Corno Anterior/metabolismo , Células do Corno Anterior/patologia , Axônios/metabolismo , Axônios/patologia , Exoma , Feminino , Fibroblastos/citologia , Fibroblastos/patologia , Ligação Genética , Células HEK293 , Humanos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Atrofia Muscular Espinal/patologia , Linhagem , Adulto Jovem
13.
J Neurol Neurosurg Psychiatry ; 83(12): 1204-9, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22851605

RESUMO

BACKGROUND: TRPV4 mutations have been identified in Charcot-Marie-Tooth type 2 (CMT2), scapuloperoneal spinal muscular atrophy and distal hereditary motor neuropathy (dHMN). OBJECTIVE: We aimed to screen the TRPV4 gene in 422 British patients with inherited neuropathy for potentially pathogenic mutations. METHODS: We sequenced TRPV4 coding regions and splice junctions in 271 patients with CMT2 and 151 patients with dHMN. Mutations were clinically and genetically characterised and screened in ≥345 matched controls. RESULTS: 13 missense and nonsense variants were identified, of which five were novel and absent from controls (G20R, E218K, N302Y, Y567X and T701I). N302Y and T701I mutations were present in typical CMT2 cases and are potentially pathogenic based on in silico analyses. G20R was detected in a patient with dHMN and her asymptomatic father and is possibly pathogenic with variable expressivity. The Y567X variant segregated with disease in a family with severe CMT2 but also with a MFN2 mutation reported to cause a mild CMT2 phenotype. Although Y567X caused nonsense mediated mRNA decay, the amount of TRPV4 protein on western blotting of patient lymphoblasts was no different to control. Y567X is therefore unlikely to be pathogenic. E218K is unlikely to be pathogenic based on segregation. CONCLUSIONS: In this comprehensive analysis of the TRPV4 gene, we identified mutations in <1% of patients with CMT2/dHMN. We found that TRPV4 likely harbours many missense and nonsense non-pathogenic variants that should be analysed in detail to prove pathogenicity before results are given to patients.


Assuntos
Neuropatia Hereditária Motora e Sensorial/genética , Canais de Cátion TRPV/genética , Adulto , Idoso , Western Blotting , Células Cultivadas , Doença de Charcot-Marie-Tooth/genética , Códon sem Sentido , Estudos de Coortes , Éxons , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Reação em Cadeia da Polimerase , Isoformas de Proteínas
14.
Trends Genet ; 26(6): 266-74, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20381893

RESUMO

In 2007, an association of single nucleotide polymorphisms (SNPs) in the fat mass and obesity-associated (FTO) gene region with body mass index (BMI) and risk of obesity was identified in multiple populations, making FTO the first locus unequivocally associated with adiposity. At the time, FTO was a gene of unknown function and it was not known whether these SNPs exerted their effect on adiposity by affecting FTO or neighboring genes. Therefore, this breakthrough association inspired a wealth of in silico, in vitro, and in vivo analyses in model organisms and humans to improve knowledge of FTO function. These studies suggested that FTO plays a role in controlling feeding behavior and energy expenditure. Here, we review the approaches taken that provide a blueprint for the study of other obesity-associated genes in the hope that this strategy will result in increased understanding of the biological mechanisms underlying body weight regulation.


Assuntos
Obesidade/genética , Proteínas/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Animais , Biologia Computacional , Modelos Animais de Doenças , Estudos de Associação Genética , Humanos , Polimorfismo de Nucleotídeo Único
15.
Diabetes ; 59(3): 741-6, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20028947

RESUMO

OBJECTIVE: Wolfram syndrome 1 (WFS1) single nucleotide polymorphisms (SNPs) are associated with risk of type 2 diabetes. In this study we aimed to refine this association and investigate the role of low-frequency WFS1 variants in type 2 diabetes risk. RESEARCH DESIGN AND METHODS: For fine-mapping, we sequenced WFS1 exons, splice junctions, and conserved noncoding sequences in samples from 24 type 2 diabetic case and 68 control subjects, selected tagging SNPs, and genotyped these in 959 U.K. type 2 diabetic case and 1,386 control subjects. The same genomic regions were sequenced in samples from 1,235 type 2 diabetic case and 1,668 control subjects to compare the frequency of rarer variants between case and control subjects. RESULTS: Of 31 tagging SNPs, the strongest associated was the previously untested 3' untranslated region rs1046320 (P = 0.008); odds ratio 0.84 and P = 6.59 x 10(-7) on further replication in 3,753 case and 4,198 control subjects. High correlation between rs1046320 and the original strongest SNP (rs10010131) (r2 = 0.92) meant that we could not differentiate between their effects in our samples. There was no difference in the cumulative frequency of 82 rare (minor allele frequency [MAF] <0.01) nonsynonymous variants between type 2 diabetic case and control subjects (P = 0.79). Two intermediate frequency (MAF 0.01-0.05) nonsynonymous changes also showed no statistical association with type 2 diabetes. CONCLUSIONS: We identified six highly correlated SNPs that show strong and comparable associations with risk of type 2 diabetes, but further refinement of these associations will require large sample sizes (>100,000) or studies in ethnically diverse populations. Low frequency variants in WFS1 are unlikely to have a large impact on type 2 diabetes risk in white U.K. populations, highlighting the complexities of undertaking association studies with low-frequency variants identified by resequencing.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Variação Genética , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Mapeamento Cromossômico , Éxons/genética , Haplótipos , Heterozigoto , Humanos , Sítios de Splice de RNA/genética , Fatores de Risco , Reino Unido/epidemiologia
16.
Proc Natl Acad Sci U S A ; 106(23): 9350-5, 2009 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-19470471

RESUMO

Tre-2, BUB2, CDC16, 1 domain family member 4 (TBC1D4) (AS160) is a Rab-GTPase activating protein implicated in insulin-stimulated glucose transporter 4 (GLUT4) translocation in adipocytes and myotubes. To determine whether loss-of-function mutations in TBC1D4 might impair GLUT4 translocation and cause insulin resistance in humans, we screened the coding regions of this gene in 156 severely insulin-resistant patients. A female presenting at age 11 years with acanthosis nigricans and extreme postprandial hyperinsulinemia was heterozygous for a premature stop mutation (R363X) in TBC1D4. After demonstrating reduced expression of wild-type TBC1D4 protein and expression of the truncated protein in lymphocytes from the proband, we further characterized the biological effects of the truncated protein in 3T3L1 adipocytes. Prematurely truncated TBC1D4 protein tended to increase basal cell membrane GLUT4 levels (P = 0.053) and significantly reduced insulin-stimulated GLUT4 cell membrane translocation (P < 0.05). When coexpressed with wild-type TBC1D4, the truncated protein dimerized with full-length TBC1D4, suggesting that the heterozygous truncated variant might interfere with its wild-type counterpart in a dominant negative fashion. Two overweight family members with the mutation also manifested normal fasting glucose and insulin levels but disproportionately elevated insulin levels following an oral glucose challenge. This family provides unique genetic evidence of TBC1D4 involvement in human insulin action.


Assuntos
Acantose Nigricans/genética , Proteínas Ativadoras de GTPase/genética , Hiperinsulinismo/genética , Códon sem Sentido , Feminino , Transportador de Glucose Tipo 4/genética , Humanos , Masculino , Linhagem , Mutação Puntual
17.
Diabetes ; 57(9): 2527-33, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18591397

RESUMO

OBJECTIVE: Loss of lipin 1 activity causes lipodystrophy and insulin resistance in the fld mouse, and LPIN1 expression and common genetic variation were recently suggested to influence adiposity and insulin sensitivity in humans. We aimed to conduct a comprehensive association study to clarify the influence of common LPIN1 variation on adiposity and insulin sensitivity in U.K. populations and to examine the role of LPIN1 mutations in insulin resistance syndromes. RESEARCH DESIGN AND METHOD: Twenty-two single nucleotide polymorphisms tagging common LPIN1 variation were genotyped in Medical Research Council (MRC) Ely (n = 1,709) and Hertfordshire (n = 2,901) population-based cohorts. LPIN1 exons, exon/intron boundaries, and 3' untranslated region were sequenced in 158 patients with idiopathic severe insulin resistance (including 23 lipodystrophic patients) and 48 control subjects. RESULTS: We found no association between LPIN1 single nucleotide polymorphisms and fasting insulin but report a nominal association between rs13412852 and BMI (P = 0.042) in a meta-analysis of 8,504 samples from in-house and publicly available studies. Three rare nonsynonymous variants (A353T, R552K, and G582R) were detected in severely insulin-resistant patients. However, these did not cosegregate with disease in affected families, and Lipin1 protein expression and phosphorylation in patients with variants were indistinguishable from those in control subjects. CONCLUSIONS: Our data do not support a major effect of common LPIN1 variation on metabolic traits and suggest that mutations in LPIN1 are not a common cause of lipodystrophy in humans. The nominal associations with BMI and other metabolic traits in U.K. cohorts require replication in larger cohorts.


Assuntos
Peso Corporal/genética , Resistência à Insulina/genética , Lipodistrofia/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Estudos de Coortes , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Hibridização de Ácido Nucleico , Linhagem , Fosfatidato Fosfatase , Reino Unido
18.
Nat Genet ; 39(8): 951-3, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17603484

RESUMO

We studied genes involved in pancreatic beta cell function and survival, identifying associations between SNPs in WFS1 and diabetes risk in UK populations that we replicated in an Ashkenazi population and in additional UK studies. In a pooled analysis comprising 9,533 cases and 11,389 controls, SNPs in WFS1 were strongly associated with diabetes risk. Rare mutations in WFS1 cause Wolfram syndrome; using a gene-centric approach, we show that variation in WFS1 also predisposes to common type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Humanos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/fisiologia
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