2. Academic Validation
  3. COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency

COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency

  • Ann Neurol. 2019 Aug;86(2):193-202. doi: 10.1002/ana.25517.
Michio Inoue 1 2 3,  Shumpei Uchino 4 5,  Aritoshi Iida 3,  Satoru Noguchi 1 3,  Shinichiro Hayashi 1 3,  Tsutomu Takahashi 6,  Katsunori Fujii 7,  Hirofumi Komaki 4 8,  Eri Takeshita 4 8,  Ikuya Nonaka 1,  Yukinori Okada 9,  Takuya Yoshizawa 10,  Leentje Van Lommel 11,  Frans Schuit 11,  Yu-Ichi Goto 3 4 8,  Masakazu Mimaki 4 5,  Ichizo Nishino 1 3
Affiliations

Affiliations

  • 1 Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
  • 2 Integrated Graduate School of Medicine, Engineering, and Agricultural Science, University of Yamanashi, Yamanashi, Japan.
  • 3 Medical Genome Center, National Center of Neurology and Psychiatry, Tokyo, Japan.
  • 4 Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
  • 5 Department of Pediatrics, Teikyo University School of Medicine, Tokyo, Japan.
  • 6 Department of Pediatrics, Saiseikai Utsunomiya Hospital, Tochigi, Japan.
  • 7 Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba, Japan.
  • 8 Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.
  • 9 Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan.
  • 10 College of Life Sciences, Ritsumeikan University, Kusatsu, Japan.
  • 11 Department of Cellular and Molecular Medicine, Faculty of Medicine, KU Leuven, Leuven, Belgium.
PMID: 31155743 DOI: 10.1002/ana.25517
Abstract

Objective: Cytochrome c oxidase (COX) deficiency is a major mitochondrial respiratory chain defect that has vast genetic and phenotypic heterogeneity. This study aims to identify novel causative genes of COX deficiency with only striated muscle-specific symptoms.

Methods: Whole exome sequencing was performed in 2 unrelated individuals who were diagnosed with congenital myopathy and presented COX deficiency in muscle pathology. We assessed the COX6A2 variants using measurements of enzymatic activities and assembly of mitochondrial respiratory chain complexes in the samples from the patients and knockout mice.

Results: Both patients presented muscle weakness and hypotonia in 4 limbs along with facial muscle weakness. One patient had cardiomyopathy. Neither patient exhibited involvement from other organs. Whole exome sequencing identified biallelic missense variants in COX6A2, which is expressed only in the skeletal muscle and heart. The variants detected were homozygous c.117C > A (p.Ser39Arg) and compound heterozygous c.117C > A (p.Ser39Arg) and c.127T > C (p.Cys43Arg). We found specific reductions in complex IV activities in the skeletal muscle of both individuals. Assembly of complex IV and its supercomplex formation were impaired in the muscle.

Interpretation: This study indicates that biallelic variants in COX6A2 cause a striated muscle-specific form of COX deficiency. ANN NEUROL 2019;86:193-202.

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