Leber hereditary optic neuropathy and a new MT‐ND1 pathologic mutation

• Published in: Acta ophthalmologica (Oxford, England) Vol. 92; no. s253
• Main Authors: ESTEBAN, O, MARTINEZ‐ROMERO, I, HERRERO‐MARTIN, MD, LLOBET, L, EMPERADOR, S, MARTIN‐NAVARRO, A, NARBERHAUS, B, ASCASO, FJ, LOPEZ‐GALLARDO, E, MONTOYA, J, RUIZ‐PESINI, E
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-09-2014; Wiley Subscription Services, Inc
• Subjects: Mitochondrial DNA; Mutation; Ophthalmology
• ISSN: 1755-375X; 1755-3768
• DOI: 10.1111/j.1755-3768.2014.T114.x

Purpose Over 90% of Leber hereditary optic neuropathy (LHON) is caused by one of three mitochondrial DNA (mtDNA) mutations (m.11778A>G, m.3460G>A, m.14484T>C) in genes for respiratory complex I (CI) subunits. These mutations are homoplasmic and characterized by incomplete penetrance, and a large percentage of patients harboring these mutations have no family history of disease. However, the pathogenicity of these mutations has not been confirmed. We report a patient who exhibited typical clinical features of LHON and presented a new mutation in the MT‐ND1 gene and lacked all three of the most common mtDNA mutations.
Methods The diagnosis of LHON in our patient was based on clinical studies. The mtDNA was completely sequenced and the candidate mutation was analyzed in more than 18,000 individuals around the world, its conservation index was estimated in more than 3,100 species from protists to mammals, its position was modeled in the crystal structure of a bacteria ortholog subunit and its functional consequences were studied in a cybrid model.
Results Genetic analysis revealed an m.3472T>C transition in the MT‐ND1 gene that changes a phenylalanine to leucine at position 56. Bioinformatics, molecular‐genetic analysis and functional studies suggest that this transition is the etiologic factor for the disorder.
Conclusion The evidence presented strongly suggest that this new mutation expands the spectrum of deleterious changes in mtDNA‐encoded complex I polypeptides associated with this pathology and highlights the difficulties in assigning pathogenicity to new homoplasmic mutations that show incomplete penetrance in sporadic LHON patients.