PUBLICATION
Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24
- Authors
- Hedberg-Oldfors, C., Abramsson, A., Osborn, D.P.S., Danielsson, O., Fazlinezhad, A., Nilipour, Y., Hübbert, L., Nennesmo, I., Visuttijai, K., Bharj, J., Petropoulou, E., Shoreim, A., Vona, B., Ahangari, N., López, M.D., Doosti, M., Banote, R.K., Maroofian, R., Edling, M., Taherpour, M., Zetterberg Md, H., Karimiani, E.G., Oldfors, A., Jamshidi, Y.
- ID
- ZDB-PUB-190205-8
- Date
- 2019
- Source
- Human molecular genetics 28(11): 1919-1929 (Journal)
- Registered Authors
- Zetterberg, Henrik
- Keywords
- none
- MeSH Terms
-
- Adult
- Animals
- Arrhythmias, Cardiac/genetics*
- Arrhythmias, Cardiac/mortality
- Arrhythmias, Cardiac/physiopathology
- Cardiomyopathy, Hypertrophic/genetics
- Cardiomyopathy, Hypertrophic/mortality*
- Cardiomyopathy, Hypertrophic/pathology
- Death, Sudden, Cardiac/pathology
- Desmin/genetics
- Disease Models, Animal
- Female
- Genetic Linkage/genetics
- Heart Failure/genetics*
- Heart Failure/mortality
- Heart Failure/physiopathology
- Homozygote
- Humans
- Male
- Mutation
- Pedigree
- Phenotype
- Repressor Proteins/genetics*
- Zebrafish/genetics
- PubMed
- 30715372 Full text @ Hum. Mol. Genet.
Citation
Hedberg-Oldfors, C., Abramsson, A., Osborn, D.P.S., Danielsson, O., Fazlinezhad, A., Nilipour, Y., Hübbert, L., Nennesmo, I., Visuttijai, K., Bharj, J., Petropoulou, E., Shoreim, A., Vona, B., Ahangari, N., López, M.D., Doosti, M., Banote, R.K., Maroofian, R., Edling, M., Taherpour, M., Zetterberg Md, H., Karimiani, E.G., Oldfors, A., Jamshidi, Y. (2019) Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24. Human molecular genetics. 28(11):1919-1929.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping