Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24
Carola Hedberg-Oldfors1, Alexandra Abramsson2, Daniel P S Osborn3
1Department of Pathology and Genetics, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
Insights
Mutations in KLHL24 cause hypertrophic cardiomyopathy (HCM), a common inherited heart condition. This discovery identifies a new genetic cause for HCM and highlights KLHL24
Area of Science:
- Genetics
- Cardiovascular Medicine
- Molecular Biology
Background:
- Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiovascular disease.
- The genetic underpinnings of up to 50% of HCM cases remain unidentified.
- Understanding the genetic basis of HCM is crucial for diagnosis and treatment.
Purpose of the Study:
- To identify novel genetic causes of hypertrophic cardiomyopathy (HCM).
- To investigate the role of KLHL24 gene mutations in human HCM.
- To elucidate the molecular mechanisms underlying KLHL24-associated HCM.
Main Methods:
- Genome-wide linkage analysis and exome sequencing were employed to identify causative genes.
- Genetic analysis was performed on DNA from two consanguineous families affected by HCM.
- Zebrafish models were used to study the functional consequences of klhl24a knockdown.
Main Results:
- Homozygous mutations in the KLHL24 gene were identified in families with HCM.
- Affected individuals exhibited severe clinical manifestations, including sudden death and heart failure.
- Muscle biopsies revealed desmin intermediate filament accumulation, and zebrafish klhl24a knockdown caused heart defects.
Conclusions:
- Mutations in KLHL24 represent a novel genetic cause of hypertrophic cardiomyopathy (HCM).
- KLHL24 plays a critical role in cardiac development and function.
- These findings expand the genetic landscape of HCM and offer new avenues for research.
Abstract:
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, yet the genetic cause of up to 50% of cases remains unknown. Here, we show that mutations in KLHL24 cause HCM in humans. Using genome-wide linkage analysis and exome sequencing, we identified homozygous mutations in KLHL24 in two consanguineous families with HCM. Of the 11 young affected adults identified, 3 died suddenly and 1 had a cardiac transplant due to heart failure. KLHL24 is a member of the Kelch-like protein family, which acts as substrate-specific adaptors to Cullin E3 ubiquitin ligases. Endomyocardial and skeletal muscle biopsies from affected individuals of both families demonstrated characteristic alterations, including accumulation of desmin intermediate filaments. Knock-down of the zebrafish homologue klhl24a results in heart defects similar to that described for other HCM-linked genes providing additional support for KLHL24 as a HCM-associated gene. Our findings reveal a crucial role for KLHL24 in cardiac development and function.
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