Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

A novel homozygous COX6A1 variant causes axonal charcot-marie-tooth disease, developmental delays and mitochondrial dysfunction

Journal of Human Genetics (2025)Cite this article

Subjects

Abstract

Mitochondrial complex IV (cytochrome c oxidase, COX) is essential for oxidative phosphorylation, and pathogenic variants of COX-related genes, such as COX6A1, are associated with neuromuscular disorders. While recessive COX6A1 variants are linked to Charcot-Marie-Tooth disease (CMT), the phenotypic spectrum and molecular mechanism remain incompletely understood. Here we report a 2-year-4-month-old girl who presented with global developmental delay, axonal CMT disease, and elevated lactate levels. WES revealed a rare homozygous COX6A1 variant (NM_004373.4: c.329 A > T, p.110Leuext41) that is absent in population databases. This variant is 41 amino acids longer than the wild-type protein. Functional assays demonstrated significantly reduced mutant protein levels (p < 0.01), supporting the pathogenicity of this mutation. The patient experienced rapid decompensation and died following febrile illness at the age of 3.5 years. This study revealed a novel pathogenic COX6A1 variant that causes developmental delay and mitochondrial dysfunction, highlighting stop-loss mutations as a mechanism of disease. We report the first COX6A1 stop-loss variant, and our findings expand the phenotypic and genetic spectrum of COX6A1-related disorders.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Brain magnetic resonance imaging showing bilateral abnormal signals around the posterior horns of lateral ventricles.
Fig. 2: Identification and characterization of the COX6A1 c.329 A > T variant in our patient.
Fig. 3: Functional validation of the COX6A1 c.329 A > T variant.

Similar content being viewed by others

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Valnot I, von Kleist-Retzow JC, Barrientos A, Gorbatyuk M, Taanman JW, Mehaye B, et al. A mutation in the human heme A:farnesyltransferase gene (COX10) causes cytochrome c oxidase deficiency. Hum Mol Genet. 2000;9:1245–9.

    Article  CAS  PubMed  Google Scholar 

  2. Alfadhel M, Lillquist YP, Waters PJ, Sinclair G, Struys E, McFadden D, et al. Infantile cardioencephalopathy due to a COX15 gene defect: report and review. Am J Med Genet A. 2011;155a:840–4.

    Article  PubMed  Google Scholar 

  3. Szklarczyk R, Wanschers BF, Nijtmans LG, Rodenburg RJ, Zschocke J, Dikow N, et al. A mutation in the FAM36A gene, the human ortholog of COX20, impairs cytochrome c oxidase assembly and is associated with ataxia and muscle hypotonia. Hum Mol Genet. 2013;22:656–67.

    Article  CAS  PubMed  Google Scholar 

  4. Dong HL, Ma Y, Yu H, Wei Q, Li JQ, Liu GL, et al. Bi-allelic loss of function variants in COX20 gene cause autosomal recessive sensory neuronopathy. Brain. 2021;144:2457–70.

    Article  PubMed  Google Scholar 

  5. Tamiya G, Makino S, Hayashi M, Abe A, Numakura C, Ueki M, et al. A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease. Am J Hum Genet. 2014;95:294–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Laššuthová P, Beharka R, Krůtová M, Neupauerová J, Seeman P. COX6A1 mutation causes axonal hereditary motor and sensory neuropathy - the confirmation of the primary report. Clin Genet. 2016;89:512–4.

    Article  PubMed  Google Scholar 

  7. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:1754–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Mills JF, Heiland LD, Nguyen SA, Close MF, Meyer TA. Charcot-marie-tooth disease and hearing loss: a systematic review with meta-analysis. Otol Neurotol. 2024;45:732–9.

    Article  PubMed  Google Scholar 

  11. Laurá M, Pipis M, Rossor AM, Reilly MM. Charcot-Marie-Tooth disease and related disorders: an evolving landscape. Curr Opin Neurol. 2019;32:641–50.

    Article  PubMed  Google Scholar 

  12. Ross JM, Öberg J, Brené S, Coppotelli G, Terzioglu M, Pernold K, et al. High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio. Proc Natl Acad Sci USA. 2010;107:20087–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Morena J, Gupta A, Hoyle JC. Charcot-marie-tooth: from molecules to therapy. Int J Mol Sci. 2019;20:3419.

  14. Rossor AM, Carr AS, Devine H, Chandrashekar H, Pelayo-Negro AL, Pareyson D, et al. Peripheral neuropathy in complex inherited diseases: an approach to diagnosis. J Neurol Neurosurg Psychiatry. 2017;88:846–63.

    Article  PubMed  Google Scholar 

  15. Parkinson MH, Bartmann AP, Clayton LMS, Nethisinghe S, Pfundt R, Chapple JP, et al. Optical coherence tomography in autosomal recessive spastic ataxia of Charlevoix-Saguenay. Brain. 2018;141:989–99.

    Article  PubMed  Google Scholar 

  16. Baumann M, Schreiber H, Schlotter-Weigel B, Löscher WN, Stucka R, Karall D, et al. MPV17 mutations in juvenile- and adult-onset axonal sensorimotor polyneuropathy. Clin Genet. 2019;95:182–6.

    Article  CAS  PubMed  Google Scholar 

  17. Tomaselli PJ, Rossor AM, Horga A, Laura M, Blake JC, Houlden H, et al. A de novo dominant mutation in KIF1A associated with axonal neuropathy, spasticity and autism spectrum disorder. J Peripher Nerv Syst. 2017;22:460–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pitceathly RD, Murphy SM, Cottenie E, Chalasani A, Sweeney MG, Woodward C, et al. Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease. Neurology. 2012;79:1145–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Comi GP, Bordoni A, Salani S, Franceschina L, Sciacco M, Prelle A, et al. Cytochrome c oxidase subunit I microdeletion in a patient with motor neuron disease. Ann Neurol. 1998;43:110–6.

    Article  CAS  PubMed  Google Scholar 

  20. Liu W, Gnanasambandam R, Benjamin J, Kaur G, Getman PB, Siegel AJ, et al. Mutations in cytochrome c oxidase subunit VIa cause neurodegeneration and motor dysfunction in Drosophila. Genetics. 2007;176:937–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Brischigliaro M, Zeviani M. Cytochrome c oxidase deficiency. Biochim Biophys Acta Bioenerg. 2021;1862:148335.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to the patient and the family members who participated in this study. We also thank CIPHER GENE for their support of the WES.

Author information

Authors and Affiliations

  1. Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China

    Qianyun Cai, Haijiao Wang & Rong Luo

  2. Department of Pediatrics, Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of the Ministry of Education, Sichuan University, Chengdu, Sichuan, China

    Qianyun Cai, Haijiao Wang & Rong Luo

  3. Department of Pediatrics, Key Laboratory of Development and Maternal and Child Diseases of Sichuan Province, Sichuan University, Chengdu, Sichuan, China

    Qianyun Cai, Haijiao Wang & Rong Luo

  4. Cipher Gene LLC, Beijing, China

    Xiao Qian

  5. Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Zhongjie Zhou

Authors
  1. Qianyun Cai
    View author publications

    Search author on:PubMed Google Scholar

  2. Haijiao Wang
    View author publications

    Search author on:PubMed Google Scholar

  3. Rong Luo
    View author publications

    Search author on:PubMed Google Scholar

  4. Xiao Qian
    View author publications

    Search author on:PubMed Google Scholar

  5. Zhongjie Zhou
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Zhongjie Zhou.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The author first listed made the greatest contribution to the paper.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cai, Q., Wang, H., Luo, R. et al. A novel homozygous COX6A1 variant causes axonal charcot-marie-tooth disease, developmental delays and mitochondrial dysfunction. J Hum Genet (2025). https://doi.org/10.1038/s10038-025-01411-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s10038-025-01411-4

Search

Advanced search

Quick links