EVIDENCE AGAINST AN X-LINKED VISUAL-LOSS SUSCEPTIBILITY LOCUS IN LEBER HEREDITARY OPTIC NEUROPATHY

Pedigree analysis of British families with Leber hereditary optic neur opathy (LHON) closely fits a model in which a pathogenic mtDNA mutatio n interacts with an X-linked visual loss susceptibility locus (VLSL). This model predicts that 60% of affected females will show marked skew ing of X inactivation. Linkage analysis in British and Italian familie s with genetically proven LHON has excluded the presence of such a VLS L over 169 cM of the X chromosome both when all families were analyzed together and when only families with the bp 11778 mutation were studi ed. Further, there was no excess skewing of X inactivation in affected females. There was no evidence for close linkage to three markers in the pseudoautosomal region of the sex chromosomes. The mechanism of in complete penetrance and male predominance in LHON remains unclear.