Hedberg-Oldfors, C;
Abramsson, A;
Osborn, DPS;
Danielsson, O;
Fazlinezhad, A;
Nilipour, Y;
Hübbert, L;
... Jamshidi, Y; + view all
(2019)
Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24.
Human Molecular Genetics
, 28
(11)
pp. 1919-1929.
10.1093/hmg/ddz032.
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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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