SCO2 mutations cause early-onset axonal Charcot-Marie-Tooth disease associated with cellular copper deficiency

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 L Zuchner, Michael E. Shy

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)662-672
Number of pages11
JournalBrain
Volume141
Issue number3
DOIs
StatePublished - Mar 1 2018

Fingerprint

Charcot-Marie-Tooth Disease
Copper
Mutation
Oxidoreductases
Polyneuropathies
Electron Transport Complex IV
Missense Mutation
Heterozygote
Cardiomyopathies
Cause of Death
Fibroblasts
Genes
Proteins

Keywords

  • Charcot-Marie-Tooth disease
  • Copper deficiency
  • SCO2

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Rebelo, A. P., Saade, D., Pereira, C. V., Farooq, A., Huff, T. C., Abreu, L., ... Shy, M. E. (2018). SCO2 mutations cause early-onset axonal Charcot-Marie-Tooth disease associated with cellular copper deficiency. Brain, 141(3), 662-672. https://doi.org/10.1093/brain/awx369

SCO2 mutations cause early-onset axonal Charcot-Marie-Tooth disease associated with cellular copper deficiency. / Rebelo, Adriana P.; Saade, Dimah; Pereira, Claudia V.; Farooq, Amjad; Huff, Tyler C.; Abreu, Lisa; Moraes, Carlos T; Mnatsakanova, Diana; Mathews, Kathy; Yang, Hua; Schon, Eric A.; Zuchner, Stephan L; Shy, Michael E.

In: Brain, Vol. 141, No. 3, 01.03.2018, p. 662-672.

Research output: Contribution to journalArticle

Rebelo, AP, Saade, D, Pereira, CV, Farooq, A, Huff, TC, Abreu, L, Moraes, CT, Mnatsakanova, D, Mathews, K, Yang, H, Schon, EA, Zuchner, SL & Shy, ME 2018, 'SCO2 mutations cause early-onset axonal Charcot-Marie-Tooth disease associated with cellular copper deficiency', Brain, vol. 141, no. 3, pp. 662-672. https://doi.org/10.1093/brain/awx369
Rebelo, Adriana P. ; Saade, Dimah ; Pereira, Claudia V. ; Farooq, Amjad ; Huff, Tyler C. ; Abreu, Lisa ; Moraes, Carlos T ; Mnatsakanova, Diana ; Mathews, Kathy ; Yang, Hua ; Schon, Eric A. ; Zuchner, Stephan L ; Shy, Michael E. / SCO2 mutations cause early-onset axonal Charcot-Marie-Tooth disease associated with cellular copper deficiency. In: Brain. 2018 ; Vol. 141, No. 3. pp. 662-672.
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