Abstract:
:Dilated cardiomyopathy (DCM) is a highly heterogeneous trait with sarcomeric gene mutations predominating. The cause of a substantial percentage of DCMs remains unknown, and no gene-specific therapy is available. On the basis of resequencing of 513 DCM cases and 1,150 matched controls from various cohorts of distinct ancestry, we discovered rare, functional RAF1 mutations in 3 of the cohorts (South Indian, North Indian and Japanese). The prevalence of RAF1 mutations was ~9% in childhood-onset DCM cases in these three cohorts. Biochemical studies showed that DCM-associated RAF1 mutants had altered kinase activity, resulting in largely unaltered ERK activation but in AKT that was hyperactivated in a BRAF-dependent manner. Constitutive expression of these mutants in zebrafish embryos resulted in a heart failure phenotype with AKT hyperactivation that was rescued by treatment with rapamycin. These findings provide new mechanistic insights and potential therapeutic targets for RAF1-associated DCM and further expand the clinical spectrum of RAF1-related human disorders.
journal_name
Nat Genetjournal_title
Nature geneticsauthors
Dhandapany PS,Razzaque MA,Muthusami U,Kunnoth S,Edwards JJ,Mulero-Navarro S,Riess I,Pardo S,Sheng J,Rani DS,Rani B,Govindaraj P,Flex E,Yokota T,Furutani M,Nishizawa T,Nakanishi T,Robbins J,Limongelli G,Hajjar RJ,Ldoi
10.1038/ng.2963subject
Has Abstractpub_date
2014-06-01 00:00:00pages
635-639issue
6eissn
1061-4036issn
1546-1718journal_volume
46pub_type
杂志文章相关文献
NATURE GENETICS文献大全abstract::Using transgenic mice expressing human cystatin C (encoded by CST3), we show that cystatin C binds soluble amyloid-beta peptide and inhibits cerebral amyloid deposition in amyloid-beta precursor protein (APP) transgenic mice. Cystatin C expression twice that of the endogenous mouse cystatin C was sufficient to substan...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.2007.29
更新日期:2007-12-01 00:00:00
abstract::Genomic imprinting is an epigenetic modification that results in expression from only one of the two parental copies of a gene. Differences in methylation between the two parental chromosomes are often observed at or near imprinted genes. Beckwith-Wiedemann syndrome (BWS), which predisposes to cancer and excessive gro...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng988
更新日期:2002-11-01 00:00:00
abstract::Notch and the m9/10 gene (groucho) of the Enhancer of split (E(spI)) complex are members of the "Notch group" of genes, which is required for a variety of cell fate choices in Drosophila. We have characterized human cDNA clones encoding a family of proteins, designated TLE, that are homologous to the E(spI) m9/10 gene...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng1092-119
更新日期:1992-10-01 00:00:00
abstract::We introduce an approach to identify disease-relevant tissues and cell types by analyzing gene expression data together with genome-wide association study (GWAS) summary statistics. Our approach uses stratified linkage disequilibrium (LD) score regression to test whether disease heritability is enriched in regions sur...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/s41588-018-0081-4
更新日期:2018-04-01 00:00:00
abstract::Hypotrichosis simplex is a group of nonsyndromic human alopecias. We mapped an autosomal recessive form of this disorder to chromosome 13q14.11-13q21.33, and identified homozygous truncating mutations in P2RY5, which encodes an orphan G protein-coupled receptor. Furthermore, we identified oleoyl-L-alpha-lysophosphatid...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.84
更新日期:2008-03-01 00:00:00
abstract::The cardiac homeobox protein Nkx2-5 is essential in cardiac development, and mutations in Csx (which encodes Nkx2-5) cause various congenital heart diseases. Using the yeast two-hybrid system with Nkx2-5 as the 'bait', we isolated the T-box-containing transcription factor Tbx5; mutations in TBX5 cause heart and limb m...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/90123
更新日期:2001-07-01 00:00:00
abstract::Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 ad...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.686
更新日期:2010-11-01 00:00:00
abstract::We identified three distinct mutations and six mutant alleles in GDAP1 in three families with axonal Charcot-Marie-Tooth (CMT) neuropathy and vocal cord paresis, which were previously linked to the CMT4A locus on chromosome 8q21.1. These results establish the molecular etiology of CMT4A (MIM 214400) and suggest that i...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng798
更新日期:2002-01-01 00:00:00
abstract::The degree to which genetic factors influence human intelligence remains a matter of some controversy. However, there is little doubt that single gene mutations can significantly alter brain development and function. For example, mutations affecting the FMR1 gene cause the fragile X syndrome, the most prevalent known ...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng1195-331
更新日期:1995-11-01 00:00:00
abstract::Loss of tight association between epidermis and dermis underlies several blistering disorders and is frequently caused by impaired function of extracellular matrix (ECM) proteins. Here we describe a new protein in mouse, Fras1, that is specifically detected in a linear fashion underlying the epidermis and the basal su...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng1168
更新日期:2003-06-01 00:00:00
abstract::Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] famil...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng1985
更新日期:2007-03-01 00:00:00
abstract::It is now feasible to map disease genes by screening the genome for linkage disequilibrium between the disease and marker alleles. This report presents the first application of this approach for a previously unmapped locus. A gene for benign recurrent intrahepatic cholestasis (BRIC) was mapped to chromosome 18 by sear...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng1294-380
更新日期:1994-12-01 00:00:00
abstract::The Human Genome Project and its spin-offs are making it increasingly feasible to determine the genetic basis of complex traits using genome-wide association studies. The statistical challenge of analyzing such studies stems from the severe multiple-comparison problem resulting from the analysis of thousands of SNPs. ...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng1582
更新日期:2005-07-01 00:00:00
abstract::Pancreatic cancer has the lowest survival rate among human cancers, and there are no effective markers for its screening and early diagnosis. To identify genetic susceptibility markers for this cancer, we carried out a genome-wide association study on 981 individuals with pancreatic cancer (cases) and 1,991 cancer-fre...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.1020
更新日期:2011-12-11 00:00:00
abstract::Human cystic fibrosis transmembrane conductance regulator (CFTR) was expressed in transgenic mice under the control of transcriptional elements derived from the human surfactant protein C (SP-C) gene. The hCFTR mRNA was expressed in lungs and testes: in the lung, we found hCFTR mRNA in bronchiolar and alveolar epithel...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng0992-13
更新日期:1992-09-01 00:00:00
abstract::We report the first annotated chromosome-level reference genome assembly for pea, Gregor Mendel's original genetic model. Phylogenetics and paleogenomics show genomic rearrangements across legumes and suggest a major role for repetitive elements in pea genome evolution. Compared to other sequenced Leguminosae genomes,...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/s41588-019-0480-1
更新日期:2019-09-01 00:00:00
abstract::Despite advances in sequencing, the goal of obtaining a comprehensive view of genetic variation in populations is still far from reached. We sequenced 180 lines of A. thaliana from Sweden to obtain as complete a picture as possible of variation in a single region. Whereas simple polymorphisms in the unique portion of ...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.2678
更新日期:2013-08-01 00:00:00
abstract::In a recent genome-wide association study of generalized vitiligo, we identified ten confirmed susceptibility loci. By testing additional loci that showed suggestive association in the genome-wide study, using two replication cohorts of European descent, we observed replicated association of generalized vitiligo with ...
journal_title:Nature genetics
pub_type: 杂志文章,多中心研究
doi:10.1038/ng.602
更新日期:2010-07-01 00:00:00
abstract::Recent studies of human oocytes have demonstrated an enrichment for distal exchanges among meiosis I (MI) nondisjunction events and for proximal exchanges among meiosis II (MII) events. Our characterization of 103 cases of spontaneous X chromosome nondisjunction in Drosophila oocytes strongly parallels these observati...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng1296-406
更新日期:1996-12-01 00:00:00
abstract::Pelger-Huët anomaly (PHA; OMIM *169400) is an autosomal dominant disorder characterized by abnormal nuclear shape and chromatin organization in blood granulocytes. Affected individuals show hypolobulated neutrophil nuclei with coarse chromatin. Presumed homozygous individuals have ovoid neutrophil nuclei, as well as v...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng925
更新日期:2002-08-01 00:00:00
abstract::Most candidate drugs currently fail later-stage clinical trials, largely due to poor prediction of efficacy on early target selection1. Drug targets with genetic support are more likely to be therapeutically valid2,3, but the translational use of genome-scale data such as from genome-wide association studies for drug ...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/s41588-019-0456-1
更新日期:2019-07-01 00:00:00
abstract::To shed light on the peopling of South Asia and the origins of the morphological adaptations found there, we analyzed whole-genome sequences from 10 Andamanese individuals and compared them with sequences for 60 individuals from mainland Indian populations with different ethnic histories and with publicly available da...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.3621
更新日期:2016-09-01 00:00:00
abstract::Graves' disease is a common autoimmune disorder characterized by thyroid stimulating hormone receptor autoantibodies (TRAb) and hyperthyroidism. To investigate the genetic architecture of Graves' disease, we conducted a genome-wide association study in 1,536 individuals with Graves' disease (cases) and 1,516 controls....
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.898
更新日期:2011-08-14 00:00:00
abstract::In the past decade, bioinformatics has become an integral part of research and development in the biomedical sciences. Bioinformatics now has an essential role both in deciphering genomic, transcriptomic and proteomic data generated by high-throughput experimental technologies and in organizing information gathered fr...
journal_title:Nature genetics
pub_type: 历史文章,杂志文章,评审
doi:10.1038/ng1109
更新日期:2003-03-01 00:00:00
abstract::Lafora's disease (LD; OMIM 254780) is an autosomal recessive form of progressive myoclonus epilepsy characterized by seizures and cumulative neurological deterioration. Onset occurs during late childhood and usually results in death within ten years of the first symptoms. With few exceptions, patients follow a homogen...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/2470
更新日期:1998-10-01 00:00:00
abstract::Restless legs syndrome (RLS) is a frequent neurological disorder characterized by an imperative urge to move the legs during night, unpleasant sensation in the lower limbs, disturbed sleep and increased cardiovascular morbidity. In a genome-wide association study we found highly significant associations between RLS an...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng2099
更新日期:2007-08-01 00:00:00
abstract::High rates of APOBEC-signature mutations are found in many tumors, but factors affecting this mutation pattern are not well understood. Here we explored the contribution of two common germline variants in the APOBEC3 region. SNP rs1014971 was associated with bladder cancer risk, increased APOBEC3B expression, and enri...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.3670
更新日期:2016-11-01 00:00:00
abstract::We report germline missense mutations in ETV6 segregating with the dominant transmission of thrombocytopenia and hematologic malignancy in three unrelated kindreds, defining a new hereditary syndrome featuring thrombocytopenia with susceptibility to diverse hematologic neoplasms. Two variants, p.Arg369Gln and p.Arg399...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.3177
更新日期:2015-02-01 00:00:00
abstract::Tumor mutational burden correlates with response to immune checkpoint blockade in multiple solid tumors, although in microsatellite-stable tumors this association is of uncertain clinical utility. Here we uniformly analyzed whole-exome sequencing (WES) of 249 tumors and matched normal tissue from patients with clinica...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/s41588-018-0200-2
更新日期:2018-09-01 00:00:00
abstract::The approach to annotating a genome critically affects the number and accuracy of genes identified in the genome sequence. Genome annotation based on stringent gene identification is prone to underestimate the complement of genes encoded in a genome. In contrast, over-prediction of putative genes followed by exhaustiv...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/85922
更新日期:2001-03-01 00:00:00