Novel compound heterozygous mutations in the cytochrome P4501B1 gene (CYP1B1) in a Japanese patient with primary congenital glaucoma

Leber's hereditary optic neuropathy (LHON) is a maternally inherited disorder characterized by a rapid bilateral loss of central vision. The majority of patients have one of three mutations in the mitochondrial DNA. In order to identify the genetic cause of the disease in a family with two affected individuals without any of the three primary LHON mutations, we have sequenced the complete mitochondrial genome. Sequence analysis revealed a point mutation at position 14568 in the mitochondrial ND6 gene that changes a conserved methionine residue to isoleucine. This mutation has been previously suggested to be of pathogenic significance and has not been detected in any controls. This case confirms the pathogenicity of this mutation. It is the seventh mutation in the ND6 gene leading to LHON. All seven identified mutations in the ND6 gene lie within the evolutionarily most conserved region of the ND6 gene in a hydrophobic pocket making it a hot spot for the disease. This clustering of mutations may help to understand the disease mechanism of LHON.