Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy

Brain. 2018 Jun 1;141(6):1622-1636. doi: 10.1093/brain/awy104.

Yujiro Higuchi ¹, Ryuta Okunushi ², Taichi Hara ³ ⁴, Akihiro Hashiguchi ¹, Junhui Yuan ¹, Akiko Yoshimura ¹, Kei Murayama ⁵, Akira Ohtake ⁶ ⁷, Masahiro Ando ¹, Yu Hiramatsu ¹, Satoshi Ishihara ¹ ⁸, Hajime Tanabe ¹, Yuji Okamoto ¹, Eiji Matsuura ¹, Takehiro Ueda ⁹, Tatsushi Toda ⁹ ¹⁰, Sumimasa Yamashita ¹¹, Kenichiro Yamada ¹², Takashi Koide ¹³, Hiroaki Yaguchi ¹⁴, Jun Mitsui ¹⁰, Hiroyuki Ishiura ¹⁰, Jun Yoshimura ¹⁵, Koichiro Doi ¹⁵, Shinichi Morishita ¹⁵, Ken Sato ⁴, Masanori Nakagawa ¹⁶, Masamitsu Yamaguchi ², Shoji Tsuji ¹⁰, Hiroshi Takashima ¹

Affiliations

1 Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
2 Department of Applied Biology and The Center for Advanced Insect Research, Kyoto Institute of Technology, Japan.
3 Laboratory of Cellular Regulation, Faculty of Human Sciences, Waseda University, Mikajima, Tokorozawa, Saitama 359-1192, Japan.
4 Laboratory of Molecular Traffic, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan.
5 Department of Metabolism, Chiba Children's Hospital, Chiba, Japan.
6 Department of Pediatrics, Faculty of Medicine, Saitama Medical University, Saitama, Japan.
7 Center for Intractable Diseases, Saitama Medical University Hospital, Saitama, Japan.
8 Department of Cardiovascular medicine, Nephrology and Neurology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
9 Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan.
10 Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
11 Department of Neurology, Kanagawa Children's Medical Center, Japan.
12 Department of Pediatrics, Hiratsuka City Hospital, Hiratsuka City, Kanagawa, Japan.
13 Department of Neurology, Hiratsuka City Hospital, Hiratsuka City, Kanagawa, Japan.
14 Department of Neurology, Brain Center, Sapporo City General Hospital, Sapporo, Hokkaido, Japan.
15 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
16 Director of North Medical Center, Kyoto Prefectural University of Medicine, Kyoto, Japan.

PMID: 29718187 DOI: 10.1093/brain/awy104

Abstract

Several genes related to mitochondrial functions have been identified as causative genes of neuropathy or ataxia. Cytochrome c oxidase assembly factor 7 (COA7) may have a role in assembling mitochondrial respiratory chain complexes that function in Oxidative Phosphorylation. Here we identified four unrelated patients with recessive mutations in COA7 among a Japanese case series of 1396 patients with Charcot-Marie-Tooth disease (CMT) or Other inherited peripheral neuropathies, including complex forms of CMT. We also found that all four patients had characteristic neurological features of peripheral neuropathy and ataxia with cerebellar atrophy, and some patients showed leukoencephalopathy or spinal cord atrophy on MRI scans. Validated mutations were located at highly conserved residues among different species and segregated with the disease in each family. Nerve conduction studies showed axonal sensorimotor neuropathy. Sural nerve biopsies showed chronic axonal degeneration with a marked loss of large and medium myelinated fibres. An immunohistochemical assay with an anti-COA7 antibody in the sural nerve from the control patient showed the positive expression of COA7 in the cytoplasm of Schwann cells. We also observed mildly elevated serum creatine kinase levels in all patients and the presence of a few ragged-red fibres and some cytochrome c oxidase-negative fibres in a muscle biopsy obtained from one patient, which was suggestive of subclinical mitochondrial myopathy. Mitochondrial respiratory chain Enzyme assay in skin fibroblasts from the three patients showed a definitive decrease in complex I or complex IV. Immunocytochemical analysis of subcellular localization in HeLa cells indicated that mutant COA7 proteins as well as wild-type COA7 were localized in mitochondria, which suggests that mutant COA7 does not affect the mitochondrial recruitment and may affect the stability or localization of COA7 interaction partners in the mitochondria. In addition, Drosophila COA7 (dCOA7) knockdown models showed rough eye phenotype, reduced lifespan, impaired locomotive ability and shortened synaptic branches of motor neurons. Our results suggest that loss-of-function COA7 mutation is responsible for the phenotype of the presented patients, and this new entity of disease would be referred to as spinocerebellar ataxia with axonal neuropathy type 3.

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