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

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

Research output: Contribution to journal › Article › Research › peer-review

7 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1970-1978
Number of pages	9
Journal	Human Mutation
Volume	43
Issue number	12
DOIs	https://doi.org/10.1002/humu.24453
Publication status	Published - Dec 2022

Keywords

coenzyme Q
COX11
mitochondrial disorders
OXPHOS

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/humu.24453Licence: CC BY-NC-ND

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Rius, R., Bennett, N. K., Bhattacharya, K., Riley, L. G., Yüksel, Z., Formosa, L. E., Compton, A. G., Dale, R. C., Cowley, M. J., Gayevskiy, V., Al Tala, S. M., Almehery, A. A., Ryan, M. T., Thorburn, D. R., Nakamura, K., & Christodoulou, J. (2022). Biallelic pathogenic variants in COX11 are associated with an infantile-onset mitochondrial encephalopathy. Human Mutation, 43(12), 1970-1978. https://doi.org/10.1002/humu.24453

@article{357488bb01b54942a802f13a7500dd0d,

title = "Biallelic pathogenic variants in COX11 are associated with an infantile-onset mitochondrial encephalopathy",

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 = "coenzyme Q, COX11, mitochondrial disorders, OXPHOS",

author = "Rocio Rius and Bennett, {Neal K.} and Kaustuv Bhattacharya and Riley, {Lisa G.} and Zafer Y{\"u}ksel and Formosa, {Luke E.} and Compton, {Alison G.} and Dale, {Russell C.} and Cowley, {Mark J.} and Velimir Gayevskiy and {Al Tala}, {Saeed M.} and Almehery, {Abdulrahman A.} and Ryan, {Michael T.} and Thorburn, {David R.} and Ken Nakamura and John Christodoulou",

note = "Funding Information: The Chair in Genomic Medicine awarded to J. C. is generously supported by The Royal Children's Hospital Foundation. We are grateful to the Crane, Perkins and Miller families for their generous financial support. We thank the Kinghorn Center for Clinical Genomics for assistance with production and processing of genome sequencing data. L. E. F. acknowledges support from the Mito Foundation. M. J. C. acknowledges support from the Luminesce Alliance. We thank Dr. Michio Hirano for providing fibroblasts from healthy individuals for controls. K. N. and N. K. B. were supported by NIH R01AG065428 to K. N. N. K. B. was also supported by NIH award F32 AG063457‐01, and a Berkelhammer Award for Excellence in Neuroscience. This researchstudy was supported by a New South Wales Office of Health and Medical Research Council Sydney Genomics Collaborative grant (J. C.). We acknowledge funding from the National Health and Medical Research Council (NHMRC): Project Grants GNT1165217 (M. T. R.) and GNT1164479 (D. R. T.), Principal Research Fellowship GNT1155244 (D. R. T.), and Investigator Grant 2010149 to L. E. F. The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program. Open access publishing facilitated by The University of Melbourne, as part of the Wiley ‐ The University of Melbourne agreement via the Council of Australian University Librarians. Publisher Copyright: {\textcopyright} 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.",

year = "2022",

month = dec,

doi = "10.1002/humu.24453",

language = "English",

volume = "43",

pages = "1970--1978",

journal = "Human Mutation",

issn = "1059-7794",

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number = "12",

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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 2022, 'Biallelic pathogenic variants in COX11 are associated with an infantile-onset mitochondrial encephalopathy', Human Mutation, vol. 43, no. 12, pp. 1970-1978. https://doi.org/10.1002/humu.24453

TY - JOUR

T1 - Biallelic pathogenic variants in COX11 are associated with an infantile-onset mitochondrial encephalopathy

AU - Rius, Rocio

AU - Bennett, Neal K.

AU - Bhattacharya, Kaustuv

AU - Riley, Lisa G.

AU - Yüksel, Zafer

AU - Formosa, Luke E.

AU - Compton, Alison G.

AU - Dale, Russell C.

AU - Cowley, Mark J.

AU - Gayevskiy, Velimir

AU - Al Tala, Saeed M.

AU - Almehery, Abdulrahman A.

AU - Ryan, Michael T.

AU - Thorburn, David R.

AU - Nakamura, Ken

AU - Christodoulou, John

N1 - Funding Information: The Chair in Genomic Medicine awarded to J. C. is generously supported by The Royal Children's Hospital Foundation. We are grateful to the Crane, Perkins and Miller families for their generous financial support. We thank the Kinghorn Center for Clinical Genomics for assistance with production and processing of genome sequencing data. L. E. F. acknowledges support from the Mito Foundation. M. J. C. acknowledges support from the Luminesce Alliance. We thank Dr. Michio Hirano for providing fibroblasts from healthy individuals for controls. K. N. and N. K. B. were supported by NIH R01AG065428 to K. N. N. K. B. was also supported by NIH award F32 AG063457‐01, and a Berkelhammer Award for Excellence in Neuroscience. This researchstudy was supported by a New South Wales Office of Health and Medical Research Council Sydney Genomics Collaborative grant (J. C.). We acknowledge funding from the National Health and Medical Research Council (NHMRC): Project Grants GNT1165217 (M. T. R.) and GNT1164479 (D. R. T.), Principal Research Fellowship GNT1155244 (D. R. T.), and Investigator Grant 2010149 to L. E. F. The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program. Open access publishing facilitated by The University of Melbourne, as part of the Wiley ‐ The University of Melbourne agreement via the Council of Australian University Librarians. Publisher Copyright: © 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

KW - coenzyme Q

KW - COX11

KW - mitochondrial disorders

KW - OXPHOS

UR - http://www.scopus.com/inward/record.url?scp=85137458221&partnerID=8YFLogxK

U2 - 10.1002/humu.24453

DO - 10.1002/humu.24453

M3 - Article

C2 - 36030551

AN - SCOPUS:85137458221

SN - 1059-7794

VL - 43

SP - 1970

EP - 1978

JO - Human Mutation

JF - Human Mutation

IS - 12

ER -

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

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Understanding complex I assembly for better diagnosis and future treatment

Defining molecular pathways for COX2 maturation in mitochondrial Complex IV

Cite this

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

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Projects

Understanding complex I assembly for better diagnosis and future treatment

Defining molecular pathways for COX2 maturation in mitochondrial Complex IV

Cite this