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J Med Genet 49:777-784 doi:10.1136/jmedgenet-2012-101212
  • Genotype-phenotype correlations

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

  1. and Japan Spastic Paraplegia Research Consortium (JASPAC)
  1. 1Division of Neurology, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan
  2. 2Department of Neurology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan
  3. 3Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
  4. 4Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
  1. Correspondence to Dr Yoshihisa Takiyama, Department of Neurology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi 409-3898, Japan; ytakiyama{at}yamanashi.ac.jp
  • Received 11 August 2012
  • Revised 27 September 2012
  • Accepted 5 October 2012

Abstract

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.