Genetic variants of TP53 and EPHX1 in Leber’s hereditary optic neuropathy and their relationship to age at onset

Ishikawa, Kenzo; Funayama, Tomoyo; Ohde, Hisao; Inagaki, Yoko; Mashima, Yukihiko

doi:10.1007/s10384-004-0166-8

Cited by 17 publications

(4 citation statements)

References 34 publications

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“…Many factors, such as mtDNA background, heteroplasmy of mtDNA mutation, nuclear gene(s), and environmental factors, have been shown to play active roles in the phenotypic expression of LHON. 1,4,[9][10][11][12][13][14][15][16][17][18][19][20] Most recently, Hudson et al 7 provided clear evidence that the expression of LHON primary mutations was influenced by the mtDNA haplogroup background in European fami-lies. The risk of visual failure is higher when m.11778G/ A or m.14484T/C mutations are present in haplogroup J and when m.3460G/A is present in haplogroup K, whereas haplogroup H reduces the disease manifestation in families with m.11778G/A.…”

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confidence: 99%

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

Zhang

Jia

et al. 2008

The American Journal of Human Genetics

121

125

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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.

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confidence: 99%

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

Zhang

Jia

et al. 2008

The American Journal of Human Genetics

121

125

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“…There have been many other studies investigating LHON susceptibility nuclear genes such as NDUFA-1, EPHX1…etc. [ 30 , 31 ] by using conventional genetic approaches. However, no conclusive evidence supports the pathogenic role of these genetic candidates.…”

Section: Introductionmentioning

confidence: 99%

Candidate Modifier Genes for the Penetrance of Leber’s Hereditary Optic Neuropathy

Cheng

Chi

Liang

et al. 2022

IJMS

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Leber’s hereditary optic neuropathy (LHON) is a maternally transmitted disease caused by mitochondria DNA (mtDNA) mutation. It is characterized by acute and subacute visual loss predominantly affecting young men. The mtDNA mutation is transmitted to all maternal lineages. However, only approximately 50% of men and 10% of women harboring a pathogenic mtDNA mutation develop optic neuropathy, reflecting both the incomplete penetrance and its unexplained male prevalence, where over 80% of patients are male. Nuclear modifier genes have been presumed to affect the penetrance of LHON. With conventional genetic methods, prior studies have failed to solve the underlying pathogenesis. Whole exome sequencing (WES) is a new molecular technique for sequencing the protein-coding region of all genes in a whole genome. We performed WES from five families with 17 members. These samples were divided into the proband group (probands with acute onset of LHON, n = 7) and control group (carriers including mother and relative carriers with mtDNSA 11778 mutation, without clinical manifestation of LHON, n = 10). Through whole exome analysis, we found that many mitochondria related (MT-related) nuclear genes have high percentage of variants in either the proband group or control group. The MT genes with a difference over 0.3 of mutation percentage between the proband and control groups include AK4, NSUN4, RDH13, COQ3, and FAHD1. In addition, the pathway analysis revealed that these genes were associated with cofactor metabolism pathways. Family-based analysis showed that several candidate MT genes including METAP1D (c.41G > T), ACACB (c.1029del), ME3 (c.972G > C), NIPSNAP3B (c.280G > C, c.476C > G), and NSUN4 (c.4A > G) were involved in the penetrance of LHON. A GWAS (genome wide association study) was performed, which found that ADGRG5 (Chr16:575620A:G), POLE4 (Chr2:7495872T:G), ERMAP (Chr1:4283044A:G), PIGR (Chr1:2069357C:T;2069358G:A), CDC42BPB (Chr14:102949A:G), PROK1 (Chr1:1104562A:G), BCAN (Chr 1:1566582C:T), and NES (Chr1:1566698A:G,1566705T:C, 1566707T:C) may be involved. The incomplete penetrance and male prevalence are still the major unexplained issues in LHON. Through whole exome analysis, we found several MT genes with a high percentage of variants were involved in a family-based analysis. Pathway analysis suggested a difference in the mutation burden of MT genes underlining the biosynthesis and metabolism pathways. In addition, the GWAS analysis also revealed several candidate nuclear modifier genes. The new technology of WES contributes to provide a highly efficient candidate gene screening function in molecular genetics.

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“…Two amino acid polymorphisms have been identified in the coding region of exon three (EPHX*3), the tyrosine 113 histidine (Y113H) exchange, resulting in a low activity form of the enzyme (Hassett et al 1994), which may influence epoxide deactivation in the cell. Patients with Leber's Hereditary Optic Neuropathy, who were homozygous for histidine 113 developed the disease earlier than those without this genotype (Ishikawa et al 2005). The polymorphism in exon four, histidine 139 arginine (H139R, rs2234922), has been suggested as a high‐activity isoform of mEPHX (Smith and Harrison 1997; Benhamou et al 1998).…”

Section: Introductionmentioning

confidence: 99%

“…The GSTT1 gene is situated on chromosome 22. For both GSTT1 and GSTM1, the null genotype has been associated with an increased risk of optic neuropathies (Abu‐Amero et al 2009) and adverse events to drugs, including cognitive impairment after therapy in patients with medulloblastoma (Barahmani et al 2009), but not to Leber's Hereditary Optic Neuropathy (Ishikawa et al 2005) or neuropathy in patients receiving oxaliplatin‐based chemotherapy (Lecomte et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms of GSTT1, GSTM1, and EPHX genotypes in patients with cryptogenic polyneuropathy: a case–control study

et al. 2011

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The aim of this study was to analyze whether polymorphisms for the null alleles of Glutathione S-Transferase Mu-1 (GSTM1), Glutathione S-Transferase Theta-1 (GSTT1), and a low-activity genetic variation of epoxide hydrolase exon three (EPHX*3) affect the risk of developing polyneuropathy. The enzymes of these genes are important in the metabolism of toxic compounds. Seventy-nine patients with cryptogenic polyneuropathy (equivalent to chronic idiopathic axonal neuropathy) and 398 controls were tested for the genetic polymorphism. Medical records were reviewed to collect data regarding clinical findings at diagnosis, and exposure data was collected via questionnaires. The odds ratios (ORs) for the null forms of GSTM1 and GSTT1 and the normal activity YY form of EPHX*3 were close to one except GSTT1, which reached 1.86. The highest risk of polyneuropathy was found in smokers with GSTT1 null, who had a 3.7 times increased risk. Interactions between genes were analyzed and confirmed the increased OR for GSTT1, which was strongest if the patients had the low-activity HH form of EPHX*3 (OR 2.37). Our hypothesis is that the GSTT1 null polymorphism may be related to an impaired metabolism of toxic substances that could lead to nerve damage in the peripheral nervous system.

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Genetic variants of TP53 and EPHX1 in Leber’s hereditary optic neuropathy and their relationship to age at onset

Abstract: Nuclear genetic polymorphisms related to oxidative stress or apoptosis may modify the age at onset of LHON.

Cited by 17 publications

References 34 publications

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

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

Candidate Modifier Genes for the Penetrance of Leber’s Hereditary Optic Neuropathy

Polymorphisms of GSTT1, GSTM1, and EPHX genotypes in patients with cryptogenic polyneuropathy: a case–control study

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