| Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy. | |
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MedLine Citation:
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PMID: 19712804 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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OBJECTIVES: We sought to identify a novel gene for dilated cardiomyopathy (DCM). BACKGROUND: DCM is a heritable, genetically heterogeneous disorder that remains idiopathic in the majority of patients. Familial cases provide an opportunity to discover unsuspected molecular bases of DCM, enabling pre-clinical risk detection. METHODS: Two large families with autosomal-dominant DCM were studied. Genome-wide linkage analysis was used to identify a disease locus, followed by fine mapping and positional candidate gene sequencing. Mutation scanning was then performed in 278 unrelated subjects with idiopathic DCM, prospectively identified at the Mayo Clinic. RESULTS: Overlapping loci for DCM were independently mapped to chromosome 10q25-q26. Deoxyribonucleic acid sequencing of affected individuals in each family revealed distinct heterozygous missense mutations in exon 9 of RBM20, encoding ribonucleic acid (RNA) binding motif protein 20. Comprehensive coding sequence analyses identified missense mutations clustered within this same exon in 6 additional DCM families. Mutations segregated with DCM (peak composite logarithm of the odds score >11.49), were absent in 480 control samples, and altered residues within a highly conserved arginine/serine (RS)-rich region. Expression of RBM20 messenger RNA was confirmed in human heart tissue. CONCLUSIONS: Our findings establish RBM20 as a DCM gene and reveal a mutation hotspot in the RS domain. RBM20 is preferentially expressed in the heart and encodes motifs prototypical of spliceosome proteins that regulate alternative pre-messenger RNA splicing, thus implicating a functionally distinct gene in human cardiomyopathy. RBM20 mutations are associated with young age at diagnosis, end-stage heart failure, and high mortality. |
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Authors:
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Katharine M Brauch; Margaret L Karst; Kathleen J Herron; Mariza de Andrade; Patricia A Pellikka; Richard J Rodeheffer; Virginia V Michels; Timothy M Olson |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of the American College of Cardiology Volume: 54 ISSN: 1558-3597 ISO Abbreviation: J. Am. Coll. Cardiol. Publication Date: 2009 Sep |
Date Detail:
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Created Date: 2009-08-28 Completed Date: 2009-09-23 Revised Date: 2010-09-07 |
Medline Journal Info:
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Nlm Unique ID: 8301365 Medline TA: J Am Coll Cardiol Country: United States |
Other Details:
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Languages: eng Pagination: 930-41 Citation Subset: AIM; IM |
Affiliation:
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Cardiovascular Genetics Laboratory, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adolescent Adult Aged Cardiomyopathy, Dilated / genetics*, metabolism Child, Preschool Female Genome-Wide Association Study Genotype Heterozygote Humans Linkage (Genetics) Lod Score Male Middle Aged Mutation, Missense* Myocardium / metabolism Pedigree Phenotype RNA, Messenger / metabolism RNA-Binding Proteins / genetics* Spliceosomes / genetics Young Adult |
| Grant Support | |
ID/Acronym/Agency:
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R01 HL071225/HL/NHLBI NIH HHS; R01 HL071225-06/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/RNA, Messenger; 0/RNA-Binding Proteins; 0/ribonucleic acid binding motif protein 20, human |
| Comments/Corrections | |
Comment In:
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J Am Coll Cardiol. 2009 Sep 1;54(10):942-3
[PMID:
19712805
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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