Mutations in a Gene Encoding a Mitochondrial Protein as a First Cause of Recessively Inherited Simple Optic Atrophy

Abstract

Purpose: : The hereditary optic atrophies comprise a group of neurodegenerative disorders characterized by a gradual loss of retinal ganglion cells. The process affects primarily the macular beam of the optic nerve and may progress to peripheral fibres. Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophies (ADOA) are by far the most frequent optic atrophies. In sharp contrast to LHON and ADOA in which the optic atrophy is usually an isolated event, the autosomal recessive optic atrophy (AROA) are often multisystemic diseases involving the central nervous system and other organs. Compared to syndromic AROA, simple AROA are so uncommon that their very existence has long been debated. Our purpose was to identify the disease gene in families segregating simple AROA.

Methods: : Using a combination of Affymetrics GeneChip mapping 10K arrays and microsatellite markers, we performed homozygosity mapping and candidate genes screening in a large multiplex consanguineous family with simple AROA.

Results: : Genome-wide search pointed a unique region of homozygosity by descent. Through systematic sequence analysis of candidate genes, we identified in affected individuals a homozygous nonsense mutation in a predicted gene of the homozygous region. Additional families were further sequenced allowing identiying mutations in three other families with simple AROA. We overexpressed the wildtype cDNA sequence of this novel gene in cos7 cells and showed that it encodes a mitochondrial protein. Owing to the role of the gene in the mitochondrial function and despite the absence of extraocular dysfunction in patients (age range: 13-37 years), we have asked for complete clinical, metabolic and radiological explorations.

Conclusions: : We report here the identification the first gene responsible for simple optic atrophy transmitted as an autosomal recessive trait. Besides, we further support the view that, hitherto, optic atrophies result from a mitochondrial dysfunction.

Keywords: gene mapping • mitochondria • optic nerve