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Biallelic pathogenic variants in COX11 are associated with an infantile-onset mitochondrial encephalopathy.

Authors :
Rius R
Bennett NK
Bhattacharya K
Riley LG
Yüksel Z
Formosa LE
Compton AG
Dale RC
Cowley MJ
Gayevskiy V
Al Tala SM
Almehery AA
Ryan MT
Thorburn DR
Nakamura K
Christodoulou J
Source :
Human mutation [Hum Mutat] 2022 Dec; Vol. 43 (12), pp. 1970-1978. Date of Electronic Publication: 2022 Sep 07.
Publication Year :
2022

Abstract

Primary mitochondrial diseases are a group of genetically and clinically heterogeneous disorders resulting from oxidative phosphorylation (OXPHOS) defects. COX11 encodes a copper chaperone that participates in the assembly of complex IV and has not been previously linked to human disease. In a previous study, we identified that COX11 knockdown decreased cellular adenosine triphosphate (ATP) derived from respiration, and that ATP levels could be restored with coenzyme Q <subscript>10</subscript> (CoQ <subscript>10</subscript> ) supplementation. This finding is surprising since COX11 has no known role in CoQ <subscript>10</subscript> biosynthesis. Here, we report a novel gene-disease association by identifying biallelic pathogenic variants in COX11 associated with infantile-onset mitochondrial encephalopathies in two unrelated families using trio genome and exome sequencing. Functional studies showed that mutant COX11 fibroblasts had decreased ATP levels which could be rescued by CoQ <subscript>10</subscript> . These results not only suggest that COX11 variants cause defects in energy production but reveal a potential metabolic therapeutic strategy for patients with COX11 variants.<br /> (© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)

Details

Language :
English
ISSN :
1098-1004
Volume :
43
Issue :
12
Database :
MEDLINE
Journal :
Human mutation
Publication Type :
Academic Journal
Accession number :
36030551
Full Text :
https://doi.org/10.1002/humu.24453