SCO2 Mutations Cause Early-onset Axonal Charcot-Marie-Tooth Disease Associated with Cellular Copper Deficiency

Overview

Journal Brain

Publisher Oxford University Press

Specialty Neurology

Date 2018 Jan 20

PMID 29351582

Citations 26

Authors

Adriana P Rebelo

Dimah Saade

Claudia V Pereira

Amjad Farooq

Tyler C Huff

Lisa Abreu

Carlos T Moraes

Diana Mnatsakanova

Kathy Mathews

Hua Yang

Eric A Schon

Stephan Zuchner

Michael E Shy

Affiliations

Soon will be listed here.

Abstract

Recessive mutations in the mitochondrial copper-binding protein SCO2, cytochrome c oxidase (COX) assembly protein, have been reported in several cases with fatal infantile cardioencephalomyopathy with COX deficiency. Significantly expanding the known phenotypic spectrum, we identified compound heterozygous variants in SCO2 in two unrelated patients with axonal polyneuropathy, also known as Charcot-Marie-Tooth disease type 4. Different from previously described cases, our patients developed predominantly motor neuropathy, they survived infancy, and they have not yet developed the cardiomyopathy that causes death in early infancy in reported patients. Both of our patients harbour missense mutations near the conserved copper-binding motif (CXXXC), including the common pathogenic variant E140K and a novel change D135G. In addition, each patient carries a second mutation located at the same loop region, resulting in compound heterozygote changes E140K/P169T and D135G/R171Q. Patient fibroblasts showed reduced levels of SCO2, decreased copper levels and COX deficiency. Given that another Charcot-Marie-Tooth disease gene, ATP7A, is a known copper transporter, our findings further underline the relevance of copper metabolism in Charcot-Marie-Tooth disease.

Citing Articles

Alternative splicing expands the clinical spectrum of NDUFS6-related mitochondrial disorders.

Armirola-Ricaurte C, Zonnekein N, Koutsis G, Amor-Barris S, Pelayo-Negro A, Atkinson D Genet Med. 2024; 26(6):101117.

PMID: 38459834 PMC: 11180951. DOI: 10.1016/j.gim.2024.101117.

Hepatic depletion of nucleolar protein mDEF causes excessive mitochondrial copper accumulation associated with p53 and NRF1 activation.

Wei J, Wang S, Zhu H, Cui W, Gao J, Gao C iScience. 2023; 26(7):107220.

PMID: 37456842 PMC: 10339200. DOI: 10.1016/j.isci.2023.107220.

Construction of a risk model and prediction of prognosis and immunotherapy based on cuproptosis-related LncRNAs in the urinary system pan-cancer.

Ma Z, Liang H, Cui R, Ji J, Liu H, Liu X Eur J Med Res. 2023; 28(1):198.

PMID: 37370148 PMC: 10294367. DOI: 10.1186/s40001-023-01173-9.

Identification of an 85-kb Heterozygous 4p Microdeletion With Full Genome Analysis in Autosomal Dominant Charcot-Marie-Tooth Disease.

Hsueh H, Kao H, Chao C, Hsueh S, Huang Y, Lin W Neurol Genet. 2023; 9(4):e200078.

PMID: 37346931 PMC: 10281236. DOI: 10.1212/NXG.0000000000200078.

Biallelic variants in COQ7 cause distal hereditary motor neuropathy with upper motor neuron signs.

Rebelo A, Tomaselli P, Medina J, Wang Y, Dohrn M, Nyvltova E Brain. 2023; 146(10):4191-4199.

PMID: 37170631 PMC: 10545612. DOI: 10.1093/brain/awad158.

References

Strickland A, Rebelo A, Zhang F, Price J, Bolon B, Silva J . Characterization of the mitofusin 2 R94W mutation in a knock-in mouse model. J Peripher Nerv Syst. 2014; 19(2):152-64. DOI: 10.1111/jns5.12066. View

Zuchner S, Mersiyanova I, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali E . Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet. 2004; 36(5):449-51. DOI: 10.1038/ng1341. View

Stiburek L, Vesela K, Hansikova H, Pecina P, Tesarova M, cerna L . Tissue-specific cytochrome c oxidase assembly defects due to mutations in SCO2 and SURF1. Biochem J. 2005; 392(Pt 3):625-32. PMC: 1316303. DOI: 10.1042/BJ20050807. View

Sievers F, Wilm A, Dineen D, Gibson T, Karplus K, Li W . Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol. 2011; 7:539. PMC: 3261699. DOI: 10.1038/msb.2011.75. View

Kennerson M, Nicholson G, Kaler S, Kowalski B, Mercer J, Tang J . Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy. Am J Hum Genet. 2010; 86(3):343-52. PMC: 2833394. DOI: 10.1016/j.ajhg.2010.01.027. View

Leary S, Kaufman B, Pellecchia G, Guercin G, Mattman A, Jaksch M . Human SCO1 and SCO2 have independent, cooperative functions in copper delivery to cytochrome c oxidase. Hum Mol Genet. 2004; 13(17):1839-48. DOI: 10.1093/hmg/ddh197. View

Barrientos A, Barros M, Valnot I, Rotig A, Rustin P, Tzagoloff A . Cytochrome oxidase in health and disease. Gene. 2002; 286(1):53-63. DOI: 10.1016/s0378-1119(01)00803-4. View

Valnot I, Osmond S, Gigarel N, Mehaye B, Amiel J, Cormier-Daire V . Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy. Am J Hum Genet. 2000; 67(5):1104-9. PMC: 1288552. DOI: 10.1016/S0002-9297(07)62940-1. View

Pronicki M, Kowalski P, Piekutowska-Abramczuk D, Taybert J, Karkucinska-Wieckowska A, Szymanska-Debinska T . A homozygous mutation in the SCO2 gene causes a spinal muscular atrophy like presentation with stridor and respiratory insufficiency. Eur J Paediatr Neurol. 2009; 14(3):253-60. DOI: 10.1016/j.ejpn.2009.09.008. View

10.

Horng Y, Leary S, Cobine P, Young F, George G, Shoubridge E . Human Sco1 and Sco2 function as copper-binding proteins. J Biol Chem. 2005; 280(40):34113-22. DOI: 10.1074/jbc.M506801200. View

11.

Soto I, Fontanesi F, Liu J, Barrientos A . Biogenesis and assembly of eukaryotic cytochrome c oxidase catalytic core. Biochim Biophys Acta. 2011; 1817(6):883-97. PMC: 3262112. DOI: 10.1016/j.bbabio.2011.09.005. View

12.

Williams J, Sue C, Banting G, Yang H, Glerum D, Hendrickson W . Crystal structure of human SCO1: implications for redox signaling by a mitochondrial cytochrome c oxidase "assembly" protein. J Biol Chem. 2005; 280(15):15202-11. DOI: 10.1074/jbc.M410705200. View

13.

Weihl C, Lopate G . Motor neuron disease associated with copper deficiency. Muscle Nerve. 2006; 34(6):789-93. DOI: 10.1002/mus.20631. View

14.

Leary S, Cobine P, Kaufman B, Guercin G, Mattman A, Palaty J . The human cytochrome c oxidase assembly factors SCO1 and SCO2 have regulatory roles in the maintenance of cellular copper homeostasis. Cell Metab. 2006; 5(1):9-20. DOI: 10.1016/j.cmet.2006.12.001. View

15.

Stuart A, Fiser A, Sanchez R, Melo F, Sali A . Comparative protein structure modeling of genes and genomes. Annu Rev Biophys Biomol Struct. 2000; 29:291-325. DOI: 10.1146/annurev.biophys.29.1.291. View

16.

Echaniz-Laguna A, Ghezzi D, Chassagne M, Mayencon M, Padet S, Melchionda L . SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease. Neurology. 2013; 81(17):1523-30. PMC: 3888171. DOI: 10.1212/WNL.0b013e3182a4a518. View

17.

Yang H, Brosel S, Acin-Perez R, Slavkovich V, Nishino I, Khan R . Analysis of mouse models of cytochrome c oxidase deficiency owing to mutations in Sco2. Hum Mol Genet. 2009; 19(1):170-80. PMC: 2792155. DOI: 10.1093/hmg/ddp477. View

18.

Seburn K, Morelli K, Jordanova A, Burgess R . Lack of neuropathy-related phenotypes in hint1 knockout mice. J Neuropathol Exp Neurol. 2014; 73(7):693-701. PMC: 4098130. DOI: 10.1097/NEN.0000000000000085. View

19.

Papadopoulou L, Sue C, Davidson M, Tanji K, Nishino I, Sadlock J . Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene. Nat Genet. 1999; 23(3):333-7. DOI: 10.1038/15513. View

20.

Leary S, Antonicka H, Sasarman F, Weraarpachai W, Cobine P, Pan M . Novel mutations in SCO1 as a cause of fatal infantile encephalopathy and lactic acidosis. Hum Mutat. 2013; 34(10):1366-70. DOI: 10.1002/humu.22385. View