Molecular characterization of six Chinese families with m.3460G>A and Leber hereditary optic neuropathy (original) (raw)
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Journal of Translational Medicine, 2012
Background: Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder with gender biased and incomplete penetrance. The majority of LHON patients are caused by one of the three primary mutations (m.3460G > A, m.11778G > A and m.14484T > C). Rare pathogenic mutations have been occasionally reported in LHON patients. Methods: We screened mutation m.10680G > A in the MT-ND4L gene in 774 Chinese patients with clinical features of LHON but lacked the three primary mutations by using allele specific PCR (AS-PCR). Patients with m.10680G > A were further determined entire mtDNA genome sequence. Results: The optimal AS-PCR could detect as low as 10% heteroplasmy of mutation m.10680G > A. Two patients (Le1263 and Le1330) were identified to harbor m.10680G > A. Analysis of the complete mtDNA sequences of the probands suggested that they belonged to haplogroups B4a1 and D6a1. There was no other potentially pathogenic mutation, except for a few private yet reported variants in the MT-ND1 and MT-ND5 genes, in the two lineages. A search in reported mtDNA genome data set (n = 9277; excluding Chinese LHON patients) identified no individual with m.10680G > A. Frequency of m.10680G > A in Chinese LHON patients analyzed in this study and our previous studies (3/784) was significantly higher than that of the general populations (0/9277) (P = 0.0005). Conclusion: Taken together, we speculated that m.10680G > A may be a rare pathogenic mutation for LHON in Chinese. This mutation should be included in future clinical diagnosis.
Journal of Translational Medicine, 2012
Background: Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder with gender biased and incomplete penetrance. The majority of LHON patients are caused by one of the three primary mutations (m.3460G > A, m.11778G > A and m.14484T > C). Rare pathogenic mutations have been occasionally reported in LHON patients. Methods: We screened mutation m.10680G > A in the MT-ND4L gene in 774 Chinese patients with clinical features of LHON but lacked the three primary mutations by using allele specific PCR (AS-PCR). Patients with m.10680G > A were further determined entire mtDNA genome sequence. Results: The optimal AS-PCR could detect as low as 10% heteroplasmy of mutation m.10680G > A. Two patients (Le1263 and Le1330) were identified to harbor m.10680G > A. Analysis of the complete mtDNA sequences of the probands suggested that they belonged to haplogroups B4a1 and D6a1. There was no other potentially pathogenic mutation, except for a few private yet reported variants in the MT-ND1 and MT-ND5 genes, in the two lineages. A search in reported mtDNA genome data set (n = 9277; excluding Chinese LHON patients) identified no individual with m.10680G > A. Frequency of m.10680G > A in Chinese LHON patients analyzed in this study and our previous studies (3/784) was significantly higher than that of the general populations (0/9277) (P = 0.0005). Conclusion: Taken together, we speculated that m.10680G > A may be a rare pathogenic mutation for LHON in Chinese. This mutation should be included in future clinical diagnosis.
Biochemical and Biophysical Research Communications, 2010
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.
Journal of Human Genetics, 2002
We studied 19 patients of Southeast Asian (SEA) ethnic ancestry with Leber's hereditary optic neuropathy (LHON) to investigate the mtDNA haplotypes associated with the primary mutation(s). Eighteen patients carried a mitochondrial DNA (mtDNA) G11778A mutation (Arg340His in the respiratory complex I ND4 subunit), while one had a T14484C mutation (Met64Val in the ND6 subunit). One patient had a class II LHON mtDNA mutation, G3316A. Sequencing data of the ND genes showed many single-nucleotide polymorphisms (62 SNPs in 17 individuals; 10 LHON patients and 7 normal controls) not previously reported in Europeans or Japanese. The SEA G11778A LHON mutation was associated mostly with two mtDNA haplogroups, M (47%) and a novel lineage, characterized by the gain of a 10394 DdeI site but absence of the 10397 AluI site, designated BM (37%). A significant association was observed between one SNP, A10398G, resulting in a Thr114Ala substitution in the ND3 subunit, and the primary LHON mutation. This SNP also characterizes haplogroup J, with which the European LHON 11778 and 14484 mutations show preferential association. The combination of A10398G and other SNPs, specific for the haplogroups J, M, or BM, might act synergistically to increase the penetrance of the LHON mutations, thus allowing their detection.
The American Journal of Human Genetics, 2008
Leber hereditary optic neuropathy (LHON) is the most extensively studied mitochondrial disease, with the majority of the cases being caused by one of three primary mitochondrial DNA (mtDNA) mutations. Incomplete disease penetrance and gender bias are two features of LHON and indicate involvement of additional genetic or environmental factors in the pathogenesis of the disorder. Haplogroups J, K, and H have been shown to influence the clinical expression of LHON in subjects harboring primary mutations in European families. However, whether mtDNA haplogroups would affect the penetrance of LHON in East Asian families has not been evaluated yet. By studying the penetrance of LHON in 1859 individuals from 182 Chinese families (including one from Cambodia) with the m.11778G/A mutation, we found that haplogroup M7b1 0 2 significantly increases the risk of visual loss, whereas M8a has a protective effect. Analyses of the complete mtDNA sequences from LHON families with m.11778G/A narrow the association of disease expression to m.12811T/C (Y159H) in the NADH dehydrogenase 5 gene (MT-ND5) in haplogroup M7b1 0 2 and suggest that the specific combination of amino acid changes (A20T-T53I) in the ATP synthase 6 protein (MT-ATP6) caused by m.8584G/A and m.8684C/T might account for the beneficial background effect of M8a. Protein secondary-structure prediction for the MT-ATP6 with the two M8a-specific amino acid changes further supported our inferences. These findings will assist in further understanding the pathogenesis of LHON and guide future genetic counseling in East Asian patients with m.11778G/A.
Biochemical and Biophysical Research Communications, 2006
We report here the clinical, genetic, and molecular characterization of three Chinese families with maternally transmitted Leber's hereditary optic neuropathy (LHON). Clinical and genetic evaluations revealed the variable severity and age-of-onset in visual impairment in these families. In the affected matrilineal relatives, the loss of central vision is bilateral, the fellow eye becoming affected either simultaneously (45%) or sequentially (55%). The penetrances of vision loss in these pedigrees were 27%, 50%, and 60%, respectively. The age-at-onset of vision loss in these families was 14, 19, and 24 years, respectively. Furthermore, the ratios between affected male and female matrilineal relatives were 1:1, 1:1.2, and 1:2, respectively. Mutational analysis of mitochondrial DNA revealed the presence of homoplasmic ND6 T14484C mutation, which has been associated with LHON. The incomplete penetrance and phenotypic variability implicate the involvement of nuclear modifier gene(s), environmental factor(s) or mitochondrial haplotype(s) in the phenotypic expression of the LHON-associated T14484C mutation in these Chinese pedigrees.