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Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24

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. Green open access

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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.

Type: Article
Title: Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/hmg/ddz032
Publisher version: https://doi.org/10.1093/hmg/ddz032
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: cardiac arrhythmia, hypertrophic cardiomyopathy, heart transplantation, cardiovascular diseases, cardiomyopathy, genetic linkage analysis, mutation, heart failure, biopsy, adult, desmin, genes, genome, homozygote, intermediate filaments, ligase, skeletal muscles, ubiquitin, zebrafish, genetics, heart, cardiac development, whole exome sequencing
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10075239
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