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, 28 (11).
pp. 1919-1929.
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
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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, Ehsan Ghayoor Karimiani, Anders Oldfors, Yalda Jamshidi, Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24, Human Molecular Genetics, Volume 28, Issue 11, 1 June 2019, Pages 1919–1929 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: |
Date | Event |
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1 June 2019 | Published | 1 February 2019 | Published Online | 28 January 2019 | Accepted |
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Publisher License: |
Publisher's own licence |
Projects: |
Project ID | Funder | Funder ID |
---|
2012-2014 | Swedish Research Council | UNSPECIFIED | 2013-2546 | Swedish Research Council | UNSPECIFIED | 20180236 | Swedish Heart-Lung Foundation | UNSPECIFIED |
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URI: |
https://openaccess.sgul.ac.uk/id/eprint/110611 |
Publisher's version: |
https://doi.org/10.1093/hmg/ddz032 |
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