A mutational hot spot in the mitochondrial ND6 gene in patients with Leber's hereditary optic neuropathy

Abstract.

Background: Leber's hereditary optic neuropathy (LHON) is a maternally inherited disorder characterized by rapid bilateral loss of central vision. Most patients harbor one of three mutations in the mitochondrial DNA. In order to identify the genetic cause of the disease in one LHON patient without any of the three primary mutations, we sequenced the mitochondrial genome. Methods: Ophthalmological examination was performed in the affected person and his unaffected relatives. The complete mitochondrial protein coding region was sequenced in the patient. Results: Clinical examination of the affected 10-year-old Turkish boy showed typical features of LHON. Peripapillary microangiopathy was also seen in relatives of the maternal line. Sequence analysis revealed a point mutation at position 14482 in the mitochondrial ND6 gene that changes a conserved methionine residue to isoleucine. A mutation at this nucleotide position has been previously suggested to be of pathogenic significance and has not been detected in any controls. Conclusions: We have identified that the mutation at nucleotide position 14482 which is the eight mutation in the ND6 gene that causes LHON, making this gene a hot spot for the disease. All eight identified mutations in the ND6 gene lie within the evolutionarily most conserved region of the ND6 gene in a hydrophobic pocket. This may help in understanding the pathomechanism of LHON.