Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24

Hedberg-Oldfors, C. and Abramsson, A. and Osborn, D. P. S. and Danielsson, O. and Fazlinezhad, A. and Nilipour, Y. and Hübbert, L. and Nennesmo, I. and Visuttijai, K. and Bharj, J. and Petropoulou, E. and Shoreim, A. and Vona, B. and Ahangari, N. and López, M. D. and Doosti, M. and Banote, R. K. and Maroofian, R. and Edling, M. and Taherpour, M. and Zetterberg, H. and Karimiani, E. G. and Oldfors, A. and Jamshidi, Y. (2019) Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24. Human Molecular Genetics, 28 (11). pp. 1919-1929.

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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. © The Author(s) 2019. Published by Oxford University Press.

Item Type: Article
Additional Information: Cited By :3 Export Date: 16 February 2020 CODEN: HMGEE Correspondence Address: Oldfors, A.; Department of Pathology and Genetics, Institute of Biomedicine, University of Gothenburg, Gula street 8, Sweden; email: anders.oldfors@gu.se
Uncontrolled Keywords: cullin desmin ubiquitin protein ligase E3 kelch-like protein 24, human repressor protein adolescent adult amino acid substitution animal experiment animal model animal tissue Article autosomal recessive disorder clinical article consanguineous marriage controlled study female gene gene function gene inactivation genetic association heart arrhythmia heart development heart failure heart muscle biopsy heart transplantation histopathology homozygosity homozygote human human tissue hypertrophic cardiomyopathy intermediate filament klhl24 gene linkage analysis loss of function mutation male missense mutation molecular genetics nonhuman nonsense mutation pedigree priority journal skeletal muscle whole exome sequencing zebra fish animal disease model genetic linkage genetics mortality mutation pathology pathophysiology phenotype sudden cardiac death Animals Arrhythmias, Cardiac Cardiomyopathy, Hypertrophic Death, Sudden, Cardiac Disease Models, Animal Humans Repressor Proteins Zebrafish
Subjects: QZ pathology-neoplasms-Genetics
Divisions: Mashhad University of Medical Sciences
Depositing User: mr lib1 lib1
Date Deposited: 21 Jun 2020 06:34
Last Modified: 21 Jun 2020 06:34
URI: http://eprints.mums.ac.ir/id/eprint/18408

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