NDUFA-1 is not a nuclear modifier gene in Leber hereditary optic neuropathy

Abstract

Over 95% of cases of Leber hereditary optic neuropathy (LHON, OMIM 535000) are primarily due to one of three mitochondrial DNA (mtDNA) point mutations: G3460A, G11778A, or T14484C.1 However, only approximately 50% of men and 10% of women who harbor one of these pathogenic mutations actually develop visual failure. Additional genetic or environmental factors must therefore be modulating the phenotypic expression of LHON. Both the predominance of affected males and segregation analyses suggest the existence of a recessive X-linked visual loss susceptibility gene acting in synergy with the primary mtDNA mutation.2 Attempts to map this susceptibility locus by standard linkage analysis have not been successful.3,4⇓ All pathogenic mtDNA mutations in LHON involve genes encoding complex I subunits of the mitochondrial respiratory chain, but NDUFA-1 is so far the only subunit that has been located on the X-chromosome at Xq24.5 This gene consists of three exons spanning over 5.0 Kb of genomic DNA and three single nucleotide polymorphisms (SNP) have been …