Abstract
Cytochrome c oxidase 20 (COX20)/FAM36A encodes a conserved protein that is important for the assembly of COX, complex IV of the mitochondrial respiratory chain. A homozygous mutation (p.Thr52Pro) in COX20 gene has been previously described to cause muscle hypotonia and ataxia. In this study, we describe two patients from a non-consanguineous family exhibiting autosomal recessive sensory-dominant axonal neuropathy and static encephalopathy. The whole-exome sequencing analysis revealed that both patients harbored compound heterozygous mutations (p.Lys14Arg and p.Trp74Cys) of COX20 gene. The pathogenicity of the variants was further supported by morphological alternations of mitochondria observed in sural nerve and decreased COX20 protein level of peripheral blood leucocytes derived from the patients. In conclusion, COX20 might be considered as a candidate gene for the complex inherited disease. This observation broadens the clinical and genetic spectrum of COX20-related disease. However, due to the limitation of a single-family study, additional cases and studies are definitely needed to further confirm the association.
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References
Antonicka H, Leary SC, Guercin GH, Agar JN, Horvath R, Kennaway NG, Harding CO, Jaksch M, Shoubridge EA (2003) Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency. Hum Mol Genet 12:2693–2702. https://doi.org/10.1093/hmg/ddg284
Baxter RV, Ben Othmane K, Rochelle JM, Stajich JE, Hulette C, Dew-Knight S, Hentati F, Ben Hamida M, Bel S, Stenger JE, Gilbert JR, Pericak-Vance MA, Vance JM (2002) Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21. Nat Genet 30:21–22. https://doi.org/10.1038/ng796
Bourens M, Barrientos A (2017) Human mitochondrial cytochrome c oxidase assembly factor COX18 acts transiently as a membrane insertase within the subunit 2 maturation module. J Biol Chem 292:7774–7783. https://doi.org/10.1074/jbc.M117.778514
Bourens M, Boulet A, Leary SC, Barrientos A (2014) Human COX20 cooperates with SCO1 and SCO2 to mature COX2 and promote the assembly of cytochrome c oxidase. Hum Mol Genet 23:2901–2913. https://doi.org/10.1093/hmg/ddu003
Bruno C, Biancheri R, Garavaglia B, Biedi C, Rossi A, Lamba LD, Bado M, Greco M, Zeviani M, Minetti C (2002) A novel mutation in the SURF1 gene in a child with Leigh disease, peripheral neuropathy, and cytochrome-c oxidase deficiency. J Child Neurol 17:233–236. https://doi.org/10.1177/088307380201700318
Cassereau J, Codron P, Funalot B (2014) Inherited peripheral neuropathies due to mitochondrial disorders. Rev Neurol (Paris) 170:366–374. https://doi.org/10.1016/j.neurol.2013.11.005
Crimella C, Baschirotto C, Arnoldi A, Tonelli A, Tenderini E, Airoldi G, Martinuzzi A, Trabacca A, Losito L, Scarlato M, Benedetti S, Scarpini E, Spinicci G, Bresolin N, Bassi MT (2012) Mutations in the motor and stalk domains of KIF5A in spastic paraplegia type 10 and in axonal Charcot-Marie-Tooth type 2. Clin Genet 82:157–164. https://doi.org/10.1111/j.1399-0004.2011.01717.x
Cuesta A, Pedrola L, Sevilla T, Garcia-Planells J, Chumillas MJ, Mayordomo F, LeGuern E, Marin I, Vilchez JJ, Palau F (2002) The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease. Nat Genet 30:22–25. https://doi.org/10.1038/ng798
Del Bo R, Moggio M, Rango M, Bonato S, D’Angelo MG, Ghezzi S, Airoldi G, Bassi MT, Guglieri M, Napoli L, Lamperti C, Corti S, Federico A, Bresolin N, Comi GP (2008) Mutated mitofusin 2 presents with intrafamilial variability and brain mitochondrial dysfunction. Neurology 71:1959–1966. https://doi.org/10.1212/01.wnl.0000327095.32005.a4
Dennerlein S, Rehling P (2015) Human mitochondrial COX1 assembly into cytochrome c oxidase at a glance. J Cell Sci 128:833–837. https://doi.org/10.1242/jcs.161729
Doss S, Lohmann K, Seibler P, Arns B, Klopstock T, Zuhlke C, Freimann K, Winkler S, Lohnau T, Drungowski M, Nurnberg P, Wiegers K, Lohmann E, Naz S, Kasten M, Bohner G, Ramirez A, Endres M, Klein C (2014) Recessive dystonia-ataxia syndrome in a Turkish family caused by a COX20 (FAM36A) mutation. J Neurol 261:207–212. https://doi.org/10.1007/s00415-013-7177-7
Fernandez-Vizarra E, Tiranti V, Zeviani M (2009) Assembly of the oxidative phosphorylation system in humans: what we have learned by studying its defects. Biochim Biophys Acta 1793:200–211. https://doi.org/10.1016/j.bbamcr.2008.05.028
Hamamoto T, Takumida M, Hirakawa K, Tatsukawa T, Ishibashi T (2009) Localization of transient receptor potential vanilloid (TRPV) in the human larynx. Acta Otolaryngol 129:560–568. https://doi.org/10.1080/00016480802273108
Herrmann JM, Funes S (2005) Biogenesis of cytochrome oxidase-sophisticated assembly lines in the mitochondrial inner membrane. Gene 354:43–52. https://doi.org/10.1016/j.gene.2005.03.017
Liu YT, Laura M, Hersheson J, Horga A, Jaunmuktane Z, Brandner S, Pittman A, Hughes D, Polke JM, Sweeney MG, Proukakis C, Janssen JC, Auer-Grumbach M, Zuchner S, Shields KG, Reilly MM, Houlden H (2014) Extended phenotypic spectrum of KIF5A mutations: from spastic paraplegia to axonal neuropathy. Neurology 83:612–619. https://doi.org/10.1212/WNL.0000000000000691
Mick DU, Fox TD, Rehling P (2011) Inventory control: cytochrome c oxidase assembly regulates mitochondrial translation. Nat Rev Mol Cell Biol 12:14–20. https://doi.org/10.1038/nrm3029
Ott M, Amunts A, Brown A (2016) Organization and regulation of mitochondrial protein synthesis. Annu Rev Biochem 85:77–101. https://doi.org/10.1146/annurev-biochem-060815-014334
Pecina P, Houstkova H, Hansikova H, Zeman J, Houstek J (2004) Genetic defects of cytochrome c oxidase assembly. Physiol Res 53(Suppl 1):S213–S223
Rak M, Benit P, Chretien D, Bouchereau J, Schiff M, El-Khoury R, Tzagoloff A, Rustin P (2016) Mitochondrial cytochrome c oxidase deficiency. Clin Sci (Lond) 130:393–407. https://doi.org/10.1042/CS20150707
Rebelo AP, Saade D, Pereira CV, Farooq A, Huff TC, Abreu L, Moraes CT, Mnatsakanova D, Mathews K, Yang H, Schon EA, Zuchner S, Shy ME (2018) SCO2 mutations cause early-onset axonal Charcot-Marie-Tooth disease associated with cellular copper deficiency. Brain 141:662–672. https://doi.org/10.1093/brain/awx369
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, Committee ALQA (2015) 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 17:405–424. https://doi.org/10.1038/gim.2015.30
Richter-Dennerlein R, Dennerlein S, Rehling P (2015) Integrating mitochondrial translation into the cellular context. Nat Rev Mol Cell Biol 16:586–592
Rossor AM, Carr AS, Devine H, Chandrashekar H, Pelayo-Negro AL, Pareyson D, Shy ME, Scherer SS, Reilly MM (2017) Peripheral neuropathy in complex inherited diseases: an approach to diagnosis. J Neurol Neurosurg Psychiatry 88:846–863. https://doi.org/10.1136/jnnp-2016-313960
Soto IC, Fontanesi F, Liu J, Barrientos A (2012) Biogenesis and assembly of eukaryotic cytochrome c oxidase catalytic core. Biochim Biophys Acta 1817:883–897. https://doi.org/10.1016/j.bbabio.2011.09.005
Szklarczyk R, Wanschers BF, Nijtmans LG, Rodenburg RJ, Zschocke J, Dikow N, van den Brand MA, Hendriks-Franssen MG, Gilissen C, Veltman JA, Nooteboom M, Koopman WJ, Willems PH, Smeitink JA, Huynen MA, van den Heuvel LP (2013) 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 22:656–667. https://doi.org/10.1093/hmg/dds473
Tamiya G, Makino S, Hayashi M, Abe A, Numakura C, Ueki M, Tanaka A, Ito C, Toshimori K, Ogawa N, Terashima T, Maegawa H, Yanagisawa D, Tooyama I, Tada M, Onodera O, Hayasaka K (2014) A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease. Am J Hum Genet 95:294–300. https://doi.org/10.1016/j.ajhg.2014.07.013
Valnot I, Osmond S, Gigarel N, Mehaye B, Amiel J, Cormier-Daire V, Munnich A, Bonnefont JP, Rustin P, Rotig A (2000) Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy. Am J Hum Genet 67:1104–1109. https://doi.org/10.1016/S0002-9297(07)62940-1
Zuchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, Zappia M, Nelis E, Patitucci A, Senderek J, Parman Y, Evgrafov O, Jonghe PD, Takahashi Y, Tsuji S, Pericak-Vance MA, Quattrone A, Battaloglu E, Polyakov AV, Timmerman V, Schroder JM, Vance JM (2004) Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet 36:449–451. https://doi.org/10.1038/ng1341
Acknowledgements
We sincerely thank the participants for their cooperation and unwavering dedication to this study and the anonymous reviewers whose help improved this manuscript.
Funding
This work was supported by the following grants: The Young Scientists Fund of the National Natural Science Foundation of China (Grant No. 81601093); The Young Scientists Fund of the First Affiliated Hospital of Zhengzhou University (2015, Director: Hongliang Xu).
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XHL and JT wrote the paper. XHL, JT and LYJ conceived the idea and evaluated the patients. XHL and JT analyzed the genetic results. XHL and LS performed the sural nerve biopsy. XHL, JT, YYH and DXB evaluated the pathological findings. CX, WSY and XHL performed the Western blotting. LYJ supervised the diagnosis and treatment. All authors approved the final version of the manuscript.
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Written informed consent was obtained from the patients and/or their guardians prior to sample collection and open sural nerve biopsy.
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This study was approved by the ethics committee of the Zhengzhou University First Hospital and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
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Xu, H., Ji, T., Lian, Y. et al. Observation of novel COX20 mutations related to autosomal recessive axonal neuropathy and static encephalopathy. Hum Genet 138, 749–756 (2019). https://doi.org/10.1007/s00439-019-02026-4
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DOI: https://doi.org/10.1007/s00439-019-02026-4