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1.
iScience ; 26(5): 106701, 2023 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-37207277

RESUMO

Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.

2.
Orphanet J Rare Dis ; 17(1): 440, 2022 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-36528660

RESUMO

PURPOSE: NGLY1 Deficiency is an ultra-rare, multisystemic disease caused by biallelic pathogenic NGLY1 variants. The aims of this study were to (1) characterize the variants and clinical features of the largest cohort of NGLY1 Deficiency patients reported to date, and (2) estimate the incidence of this disorder. METHODS: The Grace Science Foundation collected genotypic data from 74 NGLY1 Deficiency patients, of which 37 also provided phenotypic data. We analyzed NGLY1 variants and clinical features and estimated NGLY1 disease incidence in the United States (U.S.). RESULTS: Analysis of patient genotypes, including 10 previously unreported NGLY1 variants, showed strong statistical enrichment for missense variants in the transglutaminase-like domain of NGLY1 (p < 1.96E-11). Caregivers reported global developmental delay, movement disorder, and alacrima in over 85% of patients. Some phenotypic differences were noted between males and females. Regression was reported for all patients over 14 years old by their caregivers. The calculated U.S. incidence of NGLY1 Deficiency was ~ 12 individuals born per year. CONCLUSION: The estimated U.S. incidence of NGLY1 indicates the disease may be more common than the number of patients reported in the literature suggests. Given the low frequency of most variants and proportion of compound heterozygotes, genotype/phenotype correlations were not distinguishable.


Assuntos
Defeitos Congênitos da Glicosilação , Feminino , Humanos , Masculino , Defeitos Congênitos da Glicosilação/genética , Genótipo , Incidência , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase , Doenças Raras , Sistema de Registros
3.
Cancer Res ; 80(18): 3841-3854, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32690724

RESUMO

Inactivation of SMARCA4/BRG1, the core ATPase subunit of mammalian SWI/SNF complexes, occurs at very high frequencies in non-small cell lung cancers (NSCLC). There are no targeted therapies for this subset of lung cancers, nor is it known how mutations in BRG1 contribute to lung cancer progression. Using a combination of gain- and loss-of-function approaches, we demonstrate that deletion of BRG1 in lung cancer leads to activation of replication stress responses. Single-molecule assessment of replication fork dynamics in BRG1-deficient cells revealed increased origin firing mediated by the prelicensing protein, CDC6. Quantitative mass spectrometry and coimmunoprecipitation assays showed that BRG1-containing SWI/SNF complexes interact with RPA complexes. Finally, BRG1-deficient lung cancers were sensitive to pharmacologic inhibition of ATR. These findings provide novel mechanistic insight into BRG1-mutant lung cancers and suggest that their dependency on ATR can be leveraged therapeutically and potentially expanded to BRG1-mutant cancers in other tissues. SIGNIFICANCE: These findings indicate that inhibition of ATR is a promising therapy for the 10% of non-small cell lung cancer patients harboring mutations in SMARCA4/BRG1. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/18/3841/F1.large.jpg.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/genética , DNA Helicases/genética , Deleção de Genes , Neoplasias Pulmonares/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Animais , Proteínas de Ciclo Celular/metabolismo , Proteínas Cromossômicas não Histona , DNA Helicases/deficiência , Progressão da Doença , Feminino , Fatores de Transcrição Forkhead , Edição de Genes , Humanos , Imunoprecipitação , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Proteínas Nucleares/deficiência , Proteínas Nucleares/metabolismo , Análise de Sequência de RNA , Fatores de Transcrição/deficiência
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