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Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24

Journal article
Authors Carola Oldfors Hedberg
Alexandra Abramsson
D. P. S. Osborn
O. Danielsson
A. Fazlinezhad
Y. Nilipour
L. Hubbert
I. Nennesmo
Kittichate Visuttijai
J. Bharj
E. Petropoulou
A. Shoreim
B. Vona
N. Ahangari
Marcela Davila Lopez
M. Doosti
Rakesh Kumar Banote
R. Maroofian
Malin Edling
M. Taherpour
Henrik Zetterberg
E. G. Karimiani
Anders Oldfors
Y. Jamshidi
Published in Hum Mol Genet
Volume 28
Issue 11
Pages 1919-1929
ISSN 0964-6906
Publication year 2019
Published at Institute of Biomedicine, Department of Medical and Clinical Genetics
Institute of Biomedicine, Department of Pathology
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Core Facilities, Bioinformatics
Pages 1919-1929
Language en
Links dx.doi.org/10.1093/hmg/ddz032
Keywords kelch-repeat superfamily, hypertrophic cardiomyopathy, ubiquitin ligase, mutations, proteins, myopathy, desmin, expression, Biochemistry & Molecular Biology, Genetics & Heredity
Subject categories Cardiac and Cardiovascular Systems

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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