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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; Nennesmo, I; Visuttijai, K; Bharj, J; et al. Hedberg-Oldfors, C; Abramsson, A; Osborn, DPS; Danielsson, O; Fazlinezhad, A; Nilipour, Y; Hübbert, L; Nennesmo, I; Visuttijai, K; Bharj, J; Petropoulou, E; Shoreim, A; Vona, B; Ahangari, N; López, MD; Doosti, M; Banote, RK; Maroofian, R; Edling, M; Taherpour, M; Zetterberg, H; Karimiani, EG; Oldfors, A; Jamshidi, Y (2019) Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24. HUMAN MOLECULAR GENETICS. ISSN 0964-6906 https://doi.org/10.1093/hmg/ddz032
SGUL Authors: Jamshidi, Yalda

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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 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.

Item Type: Article
Additional Information: This is a pre-copyedited, author-produced version of an article accepted for publication in Human Molecular Genetics following peer review. The version of record Carola Hedberg-Oldfors, Alexandra Abramsson, Daniel P S Osborn, Olof Danielsson, Afsoon Fazlinezhad, Yalda Nilipour, Laila Hübbert, Inger Nennesmo, Kittichate Visuttijai, Jaipreet Bharj, Evmorfia Petropoulou, Azza Shoreim, Barbara Vona, Najmeh Ahangari, Marcela Dávila López, Mohammad Doosti, Rakesh Kumar Banote, Reza Maroofian, Malin Edling, Mehdi Taherpour, Henrik Zetterberg MD, Ehsan Ghayoor Karimiani, Anders Oldfors, Yalda Jamshidi; Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24, Human Molecular Genetics, , ddz032 is available online at: https://doi.org/10.1093/hmg/ddz032
Keywords: 06 Biological Sciences, 11 Medical And Health Sciences, Genetics & Heredity
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: HUMAN MOLECULAR GENETICS
ISSN: 0964-6906
Dates:
DateEvent
1 February 2019Published Online
28 January 2019Accepted
Publisher License: Publisher's own licence
Projects:
Project IDFunderFunder ID
2012-2014Swedish Research CouncilUNSPECIFIED
2013-2546Swedish Research CouncilUNSPECIFIED
20180236Swedish Heart-Lung FoundationUNSPECIFIED
URI: http://openaccess.sgul.ac.uk/id/eprint/110611
Publisher's version: https://doi.org/10.1093/hmg/ddz032

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