title: A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55).
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.
authors.affiliation: Division of Neurology, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Haruo
authors.initials: H
authors.lastname: Shimazaki
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Takiyama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ishiura
authors.forename: Chika
authors.initials: C
authors.lastname: Sakai
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Matsushima
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Hatakeyama
authors.forename: Junko
authors.initials: J
authors.lastname: Honda
authors.forename: Kumi
authors.initials: K
authors.lastname: Sakoe
authors.forename: Tametou
authors.initials: T
authors.lastname: Naoi
authors.forename: Michito
authors.initials: M
authors.lastname: Namekawa
authors.forename: Yoko
authors.initials: Y
authors.lastname: Fukuda
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Jun
authors.initials: J
authors.lastname: Goto
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
authors.forename: Yu-ichi
authors.initials: Y
authors.lastname: Goto
authors.forename: Imaharu
authors.initials: I
authors.lastname: Nakano
mesh_terms: D000328:Adult; D001483:Base Sequence; D056915:DNA Copy Number Variations; D059472:Exome; D008040:Genetic Linkage; D006720:Homozygote; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins; D009154:Mutation; D009896:Optic Atrophy / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010454:Peptide Termination Factors / Q000235:genetics*; D010523:Peripheral Nervous System Diseases / Q000235:genetics* / Q000378:metabolism; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000378:metabolism
chemical_list: D024101:Mitochondrial Proteins; D010454:Peptide Termination Factors; C551030:MTRFR protein, human