title: Strikingly different penetrance of LHON in two Chinese families with primary mutation G11778A is independent of mtDNA haplogroup background and secondary mutation G13708A.
abstract: The penetrance of Leber's hereditary optic neuropathy (LHON) in families with primary mitochondrial DNA (mtDNA) mutations is very complex. Matrilineal and nuclear genetic background, as well as environmental factors, have been reported to be involved in different affected pedigrees. Here we describe two large Chinese families that show a striking difference in the penetrance of LHON, in which 53.3% and 15.0% of members were affected (P<0.02), respectively. Analysis of the complete mtDNA genome of the two families revealed the presence of the primary mutation G11778A and several other variants suggesting the same haplogroup status G2a. The family with higher penetrance contained a previously described secondary mutation G13708A, which presents a polymorphism in normal Chinese samples and does not affect in vivo mitochondrial oxidative metabolism as described in a previous study. Evolutionary analysis failed to indicate any putatively pathogenic mutation that cosegregated with G11778A in these two pedigrees. Our results suggest that the variable penetrance of LHON in the two Chinese families is independent of both their mtDNA haplotype background and a secondary mutation G13708A. As a result, it is likely that unknown nuclear gene involvement and/or other factors contribute to the strikingly different penetrance of LHON.
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
authors.forename: Hua-Wei
authors.initials: HW
authors.lastname: Wang
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Jia
authors.forename: Yanli
authors.initials: Y
authors.lastname: Ji
authors.forename: Qing-Peng
authors.initials: QP
authors.lastname: Kong
authors.forename: Qingjiong
authors.initials: Q
authors.lastname: Zhang
authors.forename: Yong-Gang
authors.initials: YG
authors.lastname: Yao
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Zhang
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics; D002648:Child; D002681:China; D004272:DNA, Mitochondrial / Q000235:genetics*; D019143:Evolution, Molecular; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D029242:Optic Atrophy, Hereditary, Leber / Q000208:ethnology / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D017386:Sequence Homology, Amino Acid
chemical_list: D004272:DNA, Mitochondrial