Format

Send to

Choose Destination
Hum Mol Genet. 2019 Feb 1. doi: 10.1093/hmg/ddz032. [Epub ahead of print]

Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24.

Author information

1
Department of Pathology and Genetics, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
2
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
3
Genetics Research Centre, Molecular and Clinical Sciences Institute, St George's University of London, Cranmer Terrace, London, UK.
4
Department of Neurology, and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
5
Razavi Cancer Research Center, Razavi Hospital, Imam Reza International University, Mashhad, Iran.
6
Pediatric Pathology Research Center, Research Institute for Children Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
7
Department of Medical and Health Sciences, Linkoping University, Linkoping Sweden.
8
Department of Pathology, Karolinska University Hospital, Stockholm, Sweden.
9
Institute of Human Genetics, Julius Maximilians University Würzburg, Würzburg, Germany.
10
Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
11
Bioinformatics Core Facilities, Sahlgrenska Academy, University of Gothenburg, Sweden.
12
Next Generation Genetic Polyclinic, Mashhad, Iran.
13
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
14
Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.
15
Innovative Medical Research Center, Faculty of Medicine, Mashhad Branch, Islamic Azad University, Mashhad, Iran.

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 hypertrophic cardiomyopathy in humans. Using genome-wide linkage analysis and exome sequencing we identified homozygous mutations in KLHL24 in two consanguineous families with HCM. Of the eleven young affected adults identified, three died suddenly and one had a cardiac transplant due to heart failure. KLHL24 is a member of the kelch-like protein family, which act as substrate-specific adaptors 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.

PMID:
30715372
DOI:
10.1093/hmg/ddz032

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center