학술논문
Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24
Document Type
Author
Oldfors Hedberg, Carola, 1969; Abramsson, Alexandra, 1973; Osborn, D. P. S.; Danielsson, O.; Fazlinezhad, A.; Nilipour, Y.; Hubbert, L.; Nennesmo, I.; Visuttijai, Kittichate; Bharj, J.; Petropoulou, E.; Shoreim, A.; Vona, B.; Ahangari, N.; Davila Lopez, Marcela; Doosti, M.; Banote, Rakesh Kumar; Maroofian, R.; Edling, Malin; Taherpour, M.; Zetterberg, Henrik, 1973; Karimiani, E. G.; Oldfors, Anders, 1951; Jamshidi, Y.
Source
Human Molecular Genetics. 28(11):1919-1929
Subject
Language
English
ISSN
0964-6906
1460-2083
1460-2083
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.