Journal
CIRCULATION-CARDIOVASCULAR GENETICS
Volume 6, Issue 3, Pages 238-247Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGENETICS.113.000057
Keywords
dilated cardiomyopathy; gene mutations; NKX2-5; transcription factors; UBIQUITIN-proteasome system
Funding
- Sylvia and Charles Viertel Charitable Foundation
- National Health and Medical Research Council [573732]
- National Heart Foundation
- St. Vincent's Clinic Foundation
- Rebecca Cooper Foundation
- Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro
- Howard Hughes Medical Institute
- Australian Government
- State Government of Victoria
- National Health and Medical Research Council Australian Fellowships [546133, 573705]
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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.
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