Purpose: Leber hereditary optic neuropathy (LHON) is a common cause of genetically determined blindness in young adults. LHON preferentially affects males and is primarily due to a mutation affecting complex I genes of mitochondrial DNA (mtDNA). While LHON primarily affects men, a number of women are affected. Segregation analysis has implicated an interacting recessive X-chromosomal locus, with skewed X-inactivation as an explanation for visual failure in affected women. Small studies have failed to detect dramatic skewed X-inactivation in women transmitting LHON mutations. However, segregation analyses predicted skewing only in a proportion of women, which would not have been detected in these studies.
Methods: The aim of the present study was to determine whether affected or unaffected women with LHON have subtle skewed X-inactivation patterns as a whole, or whether extreme skewing was more common in affected women than in unaffected women.
Results: We studied X-inactivation by measuring methylation status of the androgen receptor (AR)-(CAG)(n) repeat in 192 women homoplasmic for established LHON mtDNA mutations and 96 healthy female controls.
Conclusions: We found no evidence of subtle skewed X-inactivation or an excess of skewed inactivation in affected or unaffected women with LHON mtDNA mutations. The frequency of AR homozygotes was greater in affected LHON females than unaffected women or healthy controls, implicating the androgen receptor in the pathophysiology of LHON either directly, or through linkage disequilibrium with a different visual loss susceptibility gene.