A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55)

Haruo Shimazaki, Yoshihisa Takiyama, Hiroyuki Ishiura, Chika Sakai, Yuichi Matsushima, Hideyuki Hatakeyama, Junko Honda, Kumi Sakoe, Tametou Naoi, Michito Namekawa, Yoko Fukuda, Yuji Takahashi, Jun Goto, Shoji Tsuji, Yu Ichi Goto, Imaharu Nakano

研究成果: ジャーナルへの寄稿学術誌査読

62 被引用数 (Scopus)

抄録

Background: Autosomal recessive hereditary spastic paraplegias (AR-HSP) constitute a heterogeneous group of neurodegenerative diseases involving pyramidal tracts dysfunction. The genes responsible for many types of AR-HSPs remain unknown. We attempted to identify the gene responsible for AR-HSP with optic atrophy and neuropathy. Methods: The present study involved two patients in a consanguineous Japanese family. Neurologic examination and DNA analysis were performed for both patients, and a skin biopsy for one. We performed genome-wide linkage analysis involving single nucleotide polymorphism arrays, copy-number variation analysis, and exome sequencing. To clarify the mitochondrial functional alteration resulting from the identified mutation, we performed immunoblot analysis, mitochondrial protein synthesis assaying, blue native polyacrylamide gel electrophoresis (BN-PAGE) analysis, and respiratory enzyme activity assaying of cultured fibroblasts of the patient and a control. Results: We identified a homozygous nonsense mutation (c.394C>T, p.R132X) in C12orf65 in the two patients in this family. This C12orf65 mutation was not found in 74 Japanese AR-HSP index patients without any mutations in previously known HSP genes. This mutation resulted in marked reduction of mitochondrial protein synthesis, followed by functional and structural defects in respiratory complexes I and IV. Conclusions: This novel nonsense mutation in C12orf65 could cause AR-HSP with optic atrophy and neuropathy, resulting in a premature stop codon. The truncated C12orf65 protein must lead to a defect in mitochondrial protein synthesis and a reduction in the respiratory complex enzyme activity. Thus, dysfunction of mitochondrial translation could be one of the pathogenic mechanisms underlying HSPs.

本文言語英語
ページ(範囲)777-784
ページ数8
ジャーナルJournal of medical genetics
49
12
DOI
出版ステータス出版済み - 12月 2012
外部発表はい

!!!All Science Journal Classification (ASJC) codes

  • 遺伝学
  • 遺伝学(臨床)

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