Objective To analyze the clinical and genetic features of a five-generation Chinese Han LHON family and detect the pathogenic mutations in mitochondrial DNA (mtDNA). To study whether there was a linkage between X-chromosome and mtDNA mutations in this LHON family.Methods The clinical data of a five-generation Chinese Han family diagnosed as LHON in clinic were reviewed and their genetic features were analyzed. The three primary mutations of LHON in this family were determined by PCR-sequencing. Complete sequence analysis of the proband mitochondrial DNA in this pedigree was performed to identify the pathogenic mutations. Sequence variation was scored according to the revised Cambridge Reference Sequence (rCRS). Haplogroup of mtDNA of proband was classified according to the East Asian mtDNA phylogenetic tree. The information of mtDNA mutations were reviewed in detail and all the mtDNA mutations were assayed in the control group. Fluorescence-based Genescan with the microsatellite markers covering the whole X chromosome was carried out by parametric and non-parametric linkage analysis combined with haplotype analysis.Results The patients in this family presented with maternal inheritance. In this family there were only 6 of 30 matrilineal relatives who were affected and they were exclusively males, exhibiting a low penetrance of 20% and male predominance. The results of complete sequence analysis of the proband mtDNA revealed 31 homoplasmic variants in all, including a reported LHON-associated ND1 G3635A mutation, an unreported nonsense mutation ND4 T11809C, a novel missense mutation ND5 A12340G and the remaining 28 reported polymorphisms belonging to the Asian haplogroup F1. Both the G3635A and novel A12340G mutations were absent in non-maternal members and 107 unrelated Chinese controls, but they coexisted in all of the maternal members. The maximum two point parametric LOD score was 1.46(θ=0.0)for marker DXS1060, located at Xp22.3, all the p-values were >0.05 in the two-point and multipoint non-parametric linkage analysis.Conclusion This family is confirmed as LHON pedigree haboring both the G3635A and A12340G mutations; there is no evidence for an X-linked modifiers locus in this family. |