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V. Carelli, K. Wang, M.L. Valentino, S.P. Shankar, S.S. Salomao, R. Belford, A.A. Sadun, E.M. Stone; Segregation Analysis of a Large Lhon Pedigree Is Consistent With the Existence of a Nuclear Modifying Gene . Invest. Ophthalmol. Vis. Sci. 2003;44(13):937.
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Purpose: To investigate the possibility that an unknown nuclear gene may interact as a modifier of the mtDNA pathogenic mutations associated with Leber hereditary optic neuropathy (LHON). In LHON the primary pathogenic event is an mtDNA mutation, in most cases homoplasmic, predisposing to optic neuropathy. This is reflected by the maternal inheritance of LHON. However, the penetrance may be very variable even in the same family suggesting that other factors are necessary to trigger the disease. Moreover, the mtDNA mutation cannot explain the gender bias towards males. Various environmental factors have been implicated, but a major role could be played by a nuclear modifier gene. We have tested the compatibility of disease segregation with the existence of a nuclear modifier gene in a large Brazilian family of Italian ancestry carrying the 11778 homoplasmic mutation and haplogroup J. Methods: 128 maternally related individuals over 8 generations, 33 of which affected, were disaggregated into single nuclear families and penetrance was evaluated comparing offspring of affected females with unaffected females. Furthermore, compatibility of disease segregation with a nuclear gene was modeled testing both an X-linked recessive and an autosomal recessive hypothesis. Results: Penetrance amongst offspring of affected females was 47.7% (66.7% in males, 30% in females), at variance with offspring of unaffected females where penetrance was 16.6% (19.04% in males, 0% in females). The segregation analysis was compatible with both an X-linked recessive and an autosomal recessive gene, the likelihood for the X-linked hypothesis being higher. Conclusions: Our results indicate that segregation of LHON in this large pedigree is compatible with the existence of a nuclear modifier gene, most probably X-linked or autosomal recessive. The three-fold higher penetrance in offspring of affected females compared with unaffected females is also suggestive of the co-occurrence of a nuclear gene. This is the most robust data-set to date indicating the presence of a nuclear modifier that we hypothesize could be a functional polymorphism widely distributed within the population, not ethnically restricted, and most likely not able to induce any pathology by itself.
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