Costa, Mauro W and Guo, Guanglan and Wolstein, Orit and Vale, Molly and Castro, Maria L and Wang, Libin and Otway, Robyn and Riek, Peter and Cochrane, Natalie and Furtado, Milena B and Semsarian, Christopher and Weintraub, Robert G and Yeoh, Thomas and Hayward, Christopher S and Keogh, Anne and Macdonald, Peter S and Feneley, Michael P and Graham, Robert M and Seidman, Jonathan G and Seidman, Christine E and Rosenthal, Nadia and Fatkin, Diane and Harvey, Richard P (2013) Functional characterization of a novel mutation in NKX2-5 associated with congenital heart disease and adult-onset cardiomyopathy. Circulation: Cardiovascular Genetics, 6 (3). pp.238-47. ISSN 1942-3268 (PMC OA)
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Abstract
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.
(NHMRC grants 573732,546133 and 573705, National Heart Foundation, St Vincent’s Clinic Foundation).
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 22 Dec 2015 03:46 |
| Last Modified: | 19 Apr 2016 07:23 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/60 |
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