Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24.
Hum Mol Genet
; 28(11): 1919-1929, 2019 06 01.
Article
en En
| MEDLINE
| ID: mdl-30715372
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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Arritmias Cardíacas
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Proteínas Represoras
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Cardiomiopatía Hipertrófica
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Insuficiencia Cardíaca
Tipo de estudio:
Prognostic_studies
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Risk_factors_studies
Límite:
Adult
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Animals
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Female
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Humans
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Male
Idioma:
En
Año:
2019
Tipo del documento:
Article