Luberichs J., Leo-Kottler B., Besch D., Fauser S.

Universitäts-Augenklinik Abt. II, Röntgenweg 11, D-72076 Tübingen

Objective: Leber's hereditary optic neuropathy (LHON) is a maternally inherited disorder characterized by rapid bilateral loss of central vision. Most patients harbour 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 mutation, we have sequenced the mitochondrial genome.
Methods: Ophthalmological examination was performed in the affected person and his unaffected relatives. The complete mitochondrial DNA protein coding region was sequenced in the patient.
Results: Clinical examination of the affected 10-year-old male patient showed typical features of LHON. Peripapillary microangiopathy was also seen in relatives of the maternal line. Sequence analysis revealed a point mutation at position14482 in the mitochondrial ND6 gene that changes a conserved methionine residue to isoleucine. This mutation had been previously suggested to be of pathogenic significance and had not been detected in any controls.
Conclusion: We have confirmed that the mutation at nucleotide position 14482 is the seventh mutation in the ND6 gene that causes LHON, making this gene a hot spot for the disease. All seven identified mutations in the ND6 gene lie within the evolutionarily most conserved region of the ND6 gene in a hydrophobic pocket. This may help to understand the pathomechansim of LHON.

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