RT Journal Article SR Electronic T1 A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55) JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 777 OP 784 DO 10.1136/jmedgenet-2012-101212 VO 49 IS 12 A1 Shimazaki, Haruo A1 Takiyama, Yoshihisa A1 Ishiura, Hiroyuki A1 Sakai, Chika A1 Matsushima, Yuichi A1 Hatakeyama, Hideyuki A1 Honda, Junko A1 Sakoe, Kumi A1 Naoi, Tametou A1 Namekawa, Michito A1 Fukuda, Yoko A1 Takahashi, Yuji A1 Goto, Jun A1 Tsuji, Shoji A1 Goto, Yu-ichi A1 Nakano, Imaharu A1 and Japan Spastic Paraplegia Research Consortium (JASPAC) YR 2012 UL http://jmg.bmj.com/content/49/12/777.abstract AB 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.