Mitochondrial DNA Haplogroups M7b1′2 and M8a Affect Clinical Expression of Leber Hereditary Optic Neuropathy in Chinese Families with the m.11778G→A Mutation

Abstract

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 M7b1'2 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 M7b1'2 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.

Leber's Hereditary Optic Neuropathy–Specific Mutation m.11778G>A Exists on Diverse Mitochondrial Haplogroups in India

“…1 Interestingly, not all individuals who inherit these primary mtDNA mutations develop optic neuropathy and loss of vision, consistent with variable penetrance among different pedigrees. 8,9 Furthermore, only approximately 50% of the males and approximately 10% of the females carrying these mutations manifest visual symptoms. 10 These observations suggest additional factors contribute toward disease expression, [11][12][13] including mtDNA haplogroup and heteroplasmy, nuclear background, and environment factors, such as smoking and alcohol consumption.…”

Mitochondrial DNA SNPs associated with Schizophrenia exhibit Highly Variable Inter-allelic Haplogroup Affiliation and Nuclear Genogeographic Affinity: Bi-Genomic Linkage Disequilibrium raises Major Concerns for Link to Disease

“…http://dx.doi.org/10.1101/149070 doi: bioRxiv preprint first posted online Jun. 12, 2017; associations between mtDNA SNPs and a particular phenotype, when restricted to persons of a specific mtDNA hg 25 , may however be due to population stratification at the sub-hg level.…”

Mitochondrial DNA haplogroups and somatic mutations are associated with lung cancer in patients from Southwest China

“…They have also been associated with bioenergetic or mitochondrial dysfunction (Mishmar et al, 2003;Ruiz-Pesini et al, 2004;Wallace, 2005), with previous studies demonstrating associations between mutations of haplogroup N9a and type 2 diabetes in Asians (Fuku et al, 2007) and between haplogroups M7b1'2 and M8 with the expression of Leber hereditary optic neuropathy in Chinese families with the m11778G/A mutation (Ji et al, 2008). mtDNA is highly susceptible to mutation because of its continuous exposure to high levels of reactive oxygen species generated during oxidative phosphorylation (Wallace et al, 1999), leading to a higher mutation rate of mtDNA than of nuclear DNA (Yakes and Van Houten, 1997).…”