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http://purl.uniprot.org/citations/23661673http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/23661673http://www.w3.org/2000/01/rdf-schema#comment"

Background

The transcription factor NKX2-5 is crucial for heart development, and mutations in this gene have been implicated in diverse congenital heart diseases and conduction defects in mouse models and humans. Whether NKX2-5 mutations have a role in adult-onset heart disease is unknown.

Methods and results

Mutation screening was performed in 220 probands with adult-onset dilated cardiomyopathy. Six NKX2-5 coding sequence variants were identified, including 3 nonsynonymous variants. A novel heterozygous mutation, I184M, located within the NKX2-5 homeodomain, was identified in 1 family. A subset of family members had congenital heart disease, but there was an unexpectedly high prevalence of dilated cardiomyopathy. Functional analysis of I184M in vitro demonstrated a striking increase in protein expression when transfected into COS-7 cells or HL-1 cardiomyocytes because of reduced degradation by the Ubiquitin-proteasome system. In functional assays, DNA-binding activity of I184M was reduced, resulting in impaired activation of target genes despite increased expression levels of mutant protein.

Conclusions

Certain NKX2-5 homeodomain mutations show abnormal protein degradation via the Ubiquitin-proteasome system and partially impaired transcriptional activity. We propose that this class of mutation can impair heart development and mature heart function and contribute to NKX2-5-related cardiomyopathies with graded severity."xsd:string
http://purl.uniprot.org/citations/23661673http://purl.org/dc/terms/identifier"doi:10.1161/circgenetics.113.000057"xsd:string
http://purl.uniprot.org/citations/23661673http://purl.uniprot.org/core/author"Macdonald P."xsd:string
http://purl.uniprot.org/citations/23661673http://purl.uniprot.org/core/author"Wang L."xsd:string
http://purl.uniprot.org/citations/23661673http://purl.uniprot.org/core/author"Guo G."xsd:string
http://purl.uniprot.org/citations/23661673http://purl.uniprot.org/core/author"Seidman C.E."xsd:string
http://purl.uniprot.org/citations/23661673http://purl.uniprot.org/core/author"Seidman J.G."xsd:string
http://purl.uniprot.org/citations/23661673http://purl.uniprot.org/core/author"Hayward C."xsd:string
http://purl.uniprot.org/citations/23661673http://purl.uniprot.org/core/author"Graham R.M."xsd:string
http://purl.uniprot.org/citations/23661673http://purl.uniprot.org/core/author"Harvey R.P."xsd:string
http://purl.uniprot.org/citations/23661673http://purl.uniprot.org/core/author"Semsarian C."xsd:string
http://purl.uniprot.org/citations/23661673http://purl.uniprot.org/core/author"Rosenthal N."xsd:string
http://purl.uniprot.org/citations/23661673http://purl.uniprot.org/core/author"Vale M."xsd:string
http://purl.uniprot.org/citations/23661673http://purl.uniprot.org/core/author"Fatkin D."xsd:string
http://purl.uniprot.org/citations/23661673http://purl.uniprot.org/core/author"Keogh A."xsd:string
http://purl.uniprot.org/citations/23661673http://purl.uniprot.org/core/author"Furtado M."xsd:string
http://purl.uniprot.org/citations/23661673http://purl.uniprot.org/core/author"Costa M.W."xsd:string
http://purl.uniprot.org/citations/23661673http://purl.uniprot.org/core/author"Otway R."xsd:string
http://purl.uniprot.org/citations/23661673http://purl.uniprot.org/core/author"Weintraub R.G."xsd:string
http://purl.uniprot.org/citations/23661673http://purl.uniprot.org/core/author"Yeoh T."xsd:string
http://purl.uniprot.org/citations/23661673http://purl.uniprot.org/core/author"Wolstein O."xsd:string
http://purl.uniprot.org/citations/23661673http://purl.uniprot.org/core/author"Castro M.L."xsd:string
http://purl.uniprot.org/citations/23661673http://purl.uniprot.org/core/author"Riek P."xsd:string
http://purl.uniprot.org/citations/23661673http://purl.uniprot.org/core/author"Feneley M."xsd:string
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