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

Rocio Rius; Neal K Bennett; Kaustuv Bhattacharya; Lisa G Riley; Zafer Yüksel; Luke E Formosa; Alison G Compton; Russell C Dale; Mark J Cowley; Velimir Gayevskiy; Saeed M Al Tala; Abdulrahman A Almehery; Michael T Ryan; David R Thorburn; Ken Nakamura; John Christodoulou

doi:10.1002/humu.24453

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

Hum Mutat. 2022 Dec;43(12):1970-1978. doi: 10.1002/humu.24453. Epub 2022 Sep 7.

Authors

Rocio Rius^{1

2}, Neal K Bennett³, Kaustuv Bhattacharya^{4

5}, Lisa G Riley^{6

7}, Zafer Yüksel⁸, Luke E Formosa⁹, Alison G Compton^{1

2}, Russell C Dale¹⁰, Mark J Cowley¹¹, Velimir Gayevskiy¹², Saeed M Al Tala¹³, Abdulrahman A Almehery¹³, Michael T Ryan⁸, David R Thorburn^{1

2

14}, Ken Nakamura^{3

15

16}, John Christodoulou^{1

2

5}

Affiliations

¹ Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia.
² Department of Paediatrics, University of Melbourne, Melbourne, Australia.
³ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, California, USA.
⁴ Genetic Metabolic Disorders Service, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
⁵ Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
⁶ Specialty of Child & Adolescent Health, University of Sydney, Sydney, Australia.
⁷ Rare Diseases Functional Genomics, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
⁸ Department of Human Genetics, Bioscientia Healthcare GmbH, Ingelheim, Germany.
⁹ Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.
¹⁰ Department of Paediatric Neurology and Clinical school, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
¹¹ Children's Cancer Institute & School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia.
¹² Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
¹³ Pediatric Directorate, Neonatal NICU, Armed Forces Hospital SR, Khamis Mushayt, Saudi Arabia.
¹⁴ Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, Victoria, Australia.
¹⁵ Department of Neurology, University of California, San Francisco, California, USA.
¹⁶ Graduate Programs in Biomedical Sciences and Neuroscience, University of California, San Francisco, California, USA.

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 Q₁₀ (CoQ₁₀ ) supplementation. This finding is surprising since COX11 has no known role in CoQ₁₀ 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 CoQ₁₀ . 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.

Keywords: COX11; OXPHOS; coenzyme Q; mitochondrial disorders.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / metabolism
Copper Transport Proteins / metabolism
Electron Transport Chain Complex Proteins / metabolism
Humans
Mitochondria / metabolism
Mitochondrial Diseases* / genetics
Mitochondrial Diseases* / metabolism
Mitochondrial Encephalomyopathies* / genetics
Mitochondrial Encephalomyopathies* / metabolism
Mitochondrial Proteins / genetics
Mitochondrial Proteins / metabolism

Substances

Adenosine Triphosphate
COX11 protein, human
Copper Transport Proteins
Mitochondrial Proteins
Electron Transport Chain Complex Proteins

Supplementary concepts

Mitochondrial encephalopathy

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding