Identification of the causative gene for autosomal recessive spastic paraplegia with optic atrophy and neuropathy. Homo sapiens

Objective: To identify the causative gene responsive to autosomal recessive spastic paraplegia (AR-HSP) with optic atrophy and neuropathy. Methods: This study included two patients in a consanguineous family. Two patients underwent neurological examination and DNA analysis. We performed genomewide linkage analysis with SNP array, copy-number variation analysis and whole-exome sequencing. Results: We identified a homozygous nonsense mutation (c.394C>T, p.R132X) in Chromosome 12 open reading flame 65 (C12orf65) gene in two patients. C12orf65 gene mutation was not found in 74 Japanese AR-HSP patients without known HSP gene substitutions. Interpretation: The novel nonsense mutation in C12orf65 could be causative for AR-HSP with optic atrophy and neuropathy, resulting in a premature stop codon. Truncated C12orf65 protein would lead to the mitochondrial protein synthesis defect and respiratory complex enzyme activity reduction. Mitochondrial translation dysfunction could be one of the pathogenic mechanisms for the AR-HSP.