ArticleCirculation. Cardiovascular genetics2013
Functional characterization of a novel mutation in NKX2-5 associated with congenital heart disease and adult-onset cardiomyopathy.
Article in Circulation. Cardiovascular genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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45 citing papers in PubMed, 88 citations in OpenAlex.
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- The cardiac conduction system: development, function and therapeutic targets.Nature reviews. Cardiology · 2026Review
- Discovery ofDiagnostics (Basel, Switzerland) · 2025Article
- Sudden cardiac death in congenital heart disease-a narrative review and update.Frontiers in cardiovascular medicine · 2025Review
- Unveiling the Spectrum of Minor Genes in Cardiomyopathies: A Narrative Review.International journal of molecular sciences · 2024Review
- Modeling a variant of unknown significance in the Drosophila ortholog of the human cardiogenic gene NKX2.5.Disease models & mechanisms · 2023Article
- Application of 4-D ultrasound-derived regional strain and proteomics analysis inAmerican journal of physiology. Heart and circulatory physiology · 2023Article
- Alternative polyadenylation regulation in cardiac development and cardiovascular disease.Cardiovascular research · 2023Review
- Identification ofDiagnostics (Basel, Switzerland) · 2023Article
- Modeling congenital heart disease: lessons from mice, hPSC-based models, and organoids.Genes & development · 2022Review
- Predisposition to atrioventricular septal defects may be caused by SOX7 variants that impair interaction with GATA4.Molecular genetics and genomics : MGG · 2022Article
- A heterozygous p.S143P mutation inFrontiers in cell and developmental biology · 2022Article
- New Insights into the Development and Morphogenesis of the Cardiac Purkinje Fiber Network: Linking Architecture and Function.Journal of cardiovascular development and disease · 2021Review
- Machine Learning Driven Contouring of High-Frequency Four-Dimensional Cardiac Ultrasound Data.Applied sciences (Basel, Switzerland) · 2021Article
- An update on the CHDGKB for the systematic understanding of risk factors associated with non-syndromic congenital heart disease.Computational and structural biotechnology journal · 2021Article
- Nkx2-5 defines distinct scaffold and recruitment phases during formation of the murine cardiac Purkinje fiber network.Nature communications · 2020Article
- Genetic architecture of left ventricular noncompaction in adults.Human genome variation · 2020Article
- Defects in Trabecular Development Contribute to Left Ventricular Noncompaction.Pediatric cardiology · 2019Review
- Identification and Functional Characterization of an ISL1 Mutation Predisposing to Dilated Cardiomyopathy.Journal of cardiovascular translational research · 2019Article
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Authors and funding
23 authors at 9 institutions in 2 countries.
Funding
Abstract
backgroundThe 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
resultsMutation 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.
conclusionsCertain 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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