Journal article
SCO2 mutations cause early-onset axonal Charcot-Marie-Tooth disease associated with cellular copper deficiency
Brain (London, England : 1878), Vol.141(3), pp.662-672
03/01/2018
DOI: 10.1093/brain/awx369
PMCID: PMC5837310
PMID: 29351582
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.
Details
- Title: Subtitle
- SCO2 mutations cause early-onset axonal Charcot-Marie-Tooth disease associated with cellular copper deficiency
- Creators
- Adriana P Rebelo - Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USADimah Saade - Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, USAClaudia V Pereira - Department of Neurology, University of Miami, Miami, USAAmjad Farooq - Biochemistry Department, University of Miami Miller School of Medicine, Miami, USATyler C Huff - Department of Neurology, University of Miami, Miami, USALisa Abreu - Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USACarlos T Moraes - Department of Neurology, University of Miami, Miami, USADiana Mnatsakanova - Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, USAKathy Mathews - Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, USAHua Yang - Department of Neurology, Columbia University Medical Center, New York, USAEric A Schon - Department of Genetics and Development, Columbia University Medical Center, New York, USAStephan Zuchner - Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USAMichael E Shy - Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, USA
- Resource Type
- Journal article
- Publication Details
- Brain (London, England : 1878), Vol.141(3), pp.662-672
- Publisher
- England
- DOI
- 10.1093/brain/awx369
- PMID
- 29351582
- PMCID
- PMC5837310
- ISSN
- 0006-8950
- eISSN
- 1460-2156
- Grant note
- R01 NS075764 / NINDS NIH HHS U54 NS065712 / NINDS NIH HHS
- Language
- English
- Date published
- 03/01/2018
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
- Record Identifier
- 9984070388902771
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