Mitochondrial DNA mutation in Leber's hereditary optic neuropathy.

Leber's hereditary optic neuropathy (LHON) causes acute or subacute central visual loss in healthy young males. Recently, it has been thought to be caused by a single nucleotide change in the ND4 gene in the mitochondrial genome. Mitochondrial DNA (mtDNA) of leukocytes and hair follicle cells from five patients in four families with LHON and nine relatives were analyzed by Sfa NI and Mae III enzyme digestion and DNA sequencing. Loss of Sfa NI site was found in all patients and maternal lineages but not in nonmaternal lineages and normal controls. Mae III digested all the mtDNAs that lost the Sfa NI site. The restriction fragment pattern of polymerase chain reaction (PCR) products exhibited mtDNA heteroplasmy in the hair follicle cells but not in blood cells of the proband in one family. Direct sequencing of PCR-amplified mtDNA fragments encompassing the ND4 gene of the patients disclosed a transition from guanine to adenine at nucleotide position 11778. These results confirm previous reports that a G to A point mutation is associated with LHON and that tissue variability and heteroplasmy of mtDNA exist in some, but not all, LHON patients.