The MT-ND1 and MT-ND5 genes are mutational hotspots for Chinese families with clinical features of LHON but lacking the three primary mutations.
LHON is one of the most common and primary causes of acute blindness in young male adults. Over 95% of LHON cases are caused by one of the three primary mutations (m.11778G>A, m.14484T>C, and m.3460G>A). In contrast to these genetically diagnosed LHON patients, there are many patients with clinical features of LHON but without the three primary mutations, and these patients have been insufficiently analyzed. We reported 10 suspected Chinese LHON families without the three primary mutations. The overall penetrance (53.4%) in these families is significantly higher than in those families with m.11778G>A (33.3%) or m.3460G>A (25.6%). Complete mtDNA genome sequencing of the 10 families showed that they belonged to different haplogroups and all identified variants (excluding m.12332A>G in mt-tRNA(Leu)) were previously reported. Eight of 12 private non-synonymous variants in the probands are located in the MT-ND1 and MT-ND5 genes, which is substantially higher than that of individuals from general Chinese populations. Comparison of the private variants in the 10 families and in 10 randomly selected mtDNAs from general Chinese populations using resampling simulation strategy further confirmed this pattern. Our results suggest that the MT-ND1 and MT-ND5 genes are mutational hotspots for Chinese families with suspected LHON lacking the common primary mutations. Variants m.3736G>A (p.V144I) in family Le1235 and m.10680G>A (p.A71T) in Le1107 can be the pathogenic mutations for LHON.
Zou
Yang
Y
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China.
Jia
Xiaoyun
X
Zhang
A-Mei
AM
Wang
Wen-Zhi
WZ
Li
Shiqiang
S
Guo
Xiangming
X
Kong
Qing-Peng
QP
Zhang
Qingjiong
Q
Yao
Yong-Gang
YG
D044466:Asian People / Q000235:genetics; D002681:China / Q000453:epidemiology; D004272:DNA, Mitochondrial / Q000235:genetics; D042967:Electron Transport Complex I / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation; D009245:NADH Dehydrogenase / Q000235:genetics*; D029242:Optic Atrophy, Hereditary, Leber / Q000453:epidemiology / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D055815:Young Adult
D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; C481838:MT-ND5 protein, human; D009245:NADH Dehydrogenase; C515075:NADH dehydrogenase subunit 1, human; D042967:Electron Transport Complex I