Nuclear Modifier Genes Research Articles

The coexistence of mitochondrial ND6 T14484C and 12S rRNA A1555G mutations in a Chinese family with Leber’s hereditary optic neuropathy and hearing loss

We report here the clinical, genetic and molecular characterization of one three-generation Han Chinese family with Leber’s hereditary optic neuropathy (LHON) and hearing loss. Four of 14 matrilineal relatives exhibited the moderate central vision loss at the average age of 12.5 years. Of these, one subject exhibited both LHON and mild hearing impairment. Sequence analysis of the complete mitochondrial genomes in the pedigree showed the presence of homoplasmic LHON-associated ND6 T14484C mutation, deafness-associated 12S rRNA A1555 mutation and 47 other variants belonging to Eastern Asian haplogroup H2. None of other mitochondrial variants was evolutionarily conserved and functional significance. Therefore, the coexistence of the A1555G mutation and T14484C mutations in this Chinese family indicate that the A1555G mutation may play a synergistic role in the phenotypic manifestation of LHON associated ND6 T14484C mutation. However, the incomplete penetrance of vision and hearing loss suggests the involvement of nuclear modifier genes and environmental factors in the phenotypic expression of these mtDNA mutations.

A novel recurrent mitochondrial DNA mutation in ND3 gene is associated with isolated complex I deficiency causing Leigh syndrome and dystonia

Defects in NADH:ubiquinone oxidoreductase (complex I), the largest complex of the mitochondrial respiratory chain, account for most cases of respiratory chain deficiency in human. Complex I contains at least 45 subunits, 7 of which are encoded by mitochondrial DNA (mtDNA). Here we report a novel 10197G>A mutation of the ND3 gene in three unrelated families with Leigh syndrome (LS) or dystonia. Variable degrees of heteroplasmy were found in all tissues tested and a high percentage of mutant mtDNA was observed in muscle. The 10197G>A mutation modifies a hydrophobic alanine residue into a hydrophilic threonine (A47T) in a highly conserved domain of ND3 subunit. Furthermore, this defect could be transferred along with the mutant mtDNAs to rho degrees lymphoblastoid cells in cybrid experiments. However, nuclear modifier genes may also play a role in the phenotypic expression and severity of the 10197G>A mutation. The association of the 10197G>A ND3 mutation with an isolated biochemical defect involving complex I and the discovery of the 10197G>A mutation with a similar phenotype in three unrelated families establish its pathogenicity and demonstrate that the amino acid position A47 is important for the function of complex I. These results show that the 10197G>A mutation in the mitochondrial ND3 gene should be considered as a common mtDNA mutation responsible for LS and dystonia.

Mutation in TRMU Related to Transfer RNA Modification Modulates the Phenotypic Expression of the Deafness-Associated Mitochondrial 12S Ribosomal RNA Mutations

The human mitochondrial 12S ribosomal RNA (rRNA) A1555G mutation has been associated with aminoglycoside-induced and nonsyndromic deafness in many families worldwide. Our previous investigation revealed that the A1555G mutation is a primary factor underlying the development of deafness but is not sufficient to produce a deafness phenotype. However, it has been proposed that nuclear-modifier genes modulate the phenotypic manifestation of the A1555G mutation. Here, we identified the nuclear-modifier gene TRMU, which encodes a highly conserved mitochondrial protein related to transfer RNA (tRNA) modification. Genotyping analysis of TRMU in 613 subjects from 1 Arab-Israeli kindred, 210 European (Italian pedigrees and Spanish pedigrees) families, and 31 Chinese pedigrees carrying the A1555G or the C1494T mutation revealed a missense mutation (G28T) altering an invariant amino acid residue (A10S) in the evolutionarily conserved N-terminal region of the TRMU protein. Interestingly, all 18 Arab-Israeli/Italian-Spanish matrilineal relatives carrying both the TRMU A10S and 12S rRNA A1555G mutations exhibited prelingual profound deafness. Functional analysis showed that this mutation did not affect importation of TRMU precursors into mitochondria. However, the homozygous A10S mutation leads to a marked failure in mitochondrial tRNA metabolisms, specifically reducing the steady-state levels of mitochondrial tRNA. As a consequence, these defects contribute to the impairment of mitochondrial-protein synthesis. Resultant biochemical defects aggravate the mitochondrial dysfunction associated with the A1555G mutation, exceeding the threshold for expressing the deafness phenotype. These findings indicate that the mutated TRMU, acting as a modifier factor, modulates the phenotypic manifestation of the deafness-associated 12S rRNA mutations.

Leber’s hereditary optic neuropathy is associated with the mitochondrial ND6 T14484C mutation in three Chinese families

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.

Mitochondrial 12S rRNA A827G mutation is involved in the genetic susceptibility to aminoglycoside ototoxicity

We have analyzed the clinical and molecular characterization of a Chinese family with aminoglycoside-induced and non-syndromic hearing impairment. Clinical evaluations revealed that only those family members who had a history of exposure to aminoglycoside antibiotics subsequently developed hearing loss, suggesting mitochondrial genome involvement. Sequence analysis of the mitochondrial 12S rRNA and tRNA Ser(UCN) genes led to the identification of a homoplasmic A827G mutation in all maternal relatives, a mutation that was identified previously in a few sporadic patients and in another Chinese family with non-syndromic deafness. The pathogenicity of the A827G mutation is strongly supported by the occurrence of the same mutation in two independent families and several genetically unrelated subjects. The A827G mutation is located at the A-site of the mitochondrial 12S rRNA gene which is highly conserved in mammals. It is possible that the alteration of the tertiary or quaternary structure of this rRNA by the A827G mutation may lead to mitochondrial dysfunction, thereby playing a role in the pathogenesis of hearing loss and aminoglycoside hypersensitivity. However, incomplete penetrance of hearing impairment indicates that the A827G mutation itself is not sufficient to produce clinical phenotype but requires the involvement of modifier factors for the phenotypic expression. Indeed, aminoglycosides may contribute to the phenotypic manifestation of the A827G mutation in this family. In contrast with the congenital or early-onset hearing impairment in another Chinese family carrying the A827G mutation, three patients in this pedigree developed hearing loss only after use of aminoglycosides. This discrepancy likely reflects the difference of genetic backgrounds, either mitochondrial haplotypes or nuclear modifier genes, between two families.

Human TRMU encoding the mitochondrial 5-methylaminomethyl-2-thiouridylate-methyltransferase is a putative nuclear modifier gene for the phenotypic expression of the deafness-associated 12S rRNA mutations

Nuclear modifier genes have been proposed to modulate the phenotypic manifestation of human mitochondrial 12S rRNA A1491G mutation associated with deafness in many families world-wide. Here we identified and characterized the putative nuclear modifier gene TRMU encoding a highly conserved mitochondrial protein related to tRNA modification. A 1937 bp TRMU cDNA has been isolated and the genomic organization of TRMU has been elucidated. The human TRMU gene containing 11 exons encodes a 421 residue protein with a strong homology to the TRMU-like proteins of bacteria and other homologs. TRMU is ubiquitously expressed in various tissues, but abundantly in tissues with high metabolic rates including heart, liver, kidney, and brain. Immunofluorescence analysis of human 143B cells expressing TRMU-GFP fusion protein demonstrated that the human Trmu localizes and functions in mitochondrion. Furthermore, we show that in families with the deafness-associated 12S rRNA A1491G mutation there is highly suggestive linkage and linkage disequilibrium between microsatellite markers adjacent to TRMU and the presence of deafness. These observations suggest that human TRMU may modulate the phenotypic manifestation of the deafness-associated mitochondrial 12S rRNA mutations.

Aminoglycoside-induced and non-syndromic hearing loss is associated with the G7444A mutation in the mitochondrial COI/tRNA Ser(UCN) genes in two Chinese families

We report here the clinical, genetic, and molecular characterization of two Chinese families with aminoglycoside induced and non-syndromic hearing impairment. Clinical and genetic evaluations revealed the variable severity and age-of-onset in hearing impairment in these families. Strikingly, there were extremely low penetrances of hearing impairment in these Chinese families. Sequence analysis of the complete mitochondrial genomes in these pedigrees showed the distinct sets of mtDNA polymorphism, in addition to the identical G7444A mutation associated with hearing loss. Indeed, the G7444A mutation in the CO1 gene and the precursor of tRNA Ser(UCN) gene is present in homoplasmy only in the maternal lineage of those pedigrees but not other members of these families and 164 Chinese controls. Their mitochondrial genomes belong to the Eastern Asian haplogroups C5a and D4a, respectively. In fact, the occurrence of the G7444A mutation in these several genetically unrelated subjects affected by hearing impairment strongly indicates that this mutation is involved in the pathogenesis of hearing impairment. However, there was the absence of other functionally significant mtDNA mutations in two Chinese pedigrees carrying the G7444A mutation. Therefore, nuclear modifier gene(s) or aminoglycoside(s) may play a role in the phenotypic expression of the deafness-associated G7444A mutation in these Chinese pedigrees.

Leber’s hereditary optic neuropathy is associated with the mitochondrial ND4 G11696A mutation in five Chinese families

We report here the clinical, genetic, and molecular characterization of five Chinese families with Leber’s hereditary optic neuropathy (LHON). Clinical and genetic evaluations revealed the variable severity and age-of-onset in visual impairment in these families. Strikingly, there were extremely low penetrances of visual impairment in these Chinese families. Sequence analysis of the complete mitochondrial genomes in these pedigrees showed the distinct sets of mtDNA polymorphism, in addition to the identical ND4 G11696A mutation associated with LHON. Indeed, this mutation is present in homoplasmy only in the maternal lineage of those pedigrees but not other members of these families. In fact, the occurrence of the G11696A mutation in these several genetically unrelated subjects affected by visual impairment strongly indicates that this mutation is involved in the pathogenesis of visual impairment. Furthermore, the N405D in the ND5 and G5820A in the tRNA Cys, showing high evolutional conservation, may contribute to the phenotypic expression of G11696A mutation in the WZ10 pedigree. However, there was the absence of functionally significant mtDNA mutations in other four Chinese pedigrees carrying the G11696A mutation. Therefore, nuclear modifier gene(s) or environmental factor(s) may play a role in the phenotypic expression of the LHON-associated G11696A mutation in these Chinese pedigrees.

Mutations in MTO2 Related to tRNA Modification Impair Mitochondrial Gene Expression and Protein Synthesis in the Presence of a Paromomycin Resistance Mutation in Mitochondrial 15 S rRNA

Nuclear gene(s) have been shown to modulate the phenotypic expression of mitochondrial DNA mutations. We report here the identification and characterization of the yeast nuclear gene MTO2 encoding an evolutionarily conserved protein involved in mitochondrial tRNA modification. Interestingly, mto2 null mutants expressed a respiratory-deficient phenotype when coexisting with the C1409G mutation of mitochondrial 15 S rRNA at the very conservative site for human deafness-associated 12 S rRNA A1491G and C1409T mutations. Furthermore, the overall rate of mitochondrial translation was markedly reduced in a yeast mto2 strain in the wild type mitochondrial background, whereas mitochondrial protein synthesis was almost abolished in a yeast mto2 strain carrying the C1409G allele. The other interesting feature of mto2 mutants is the defective expression of mitochondrial genes, especially CYTB and COX1, but only when coexisting with the C1409G allele. These data strongly indicate that a product of MTO2 functionally interacts with the decoding region of 15 S rRNA, particularly at the site of the C1409G or A1491G mutation. In addition, we showed that yeast and human Mto2p localize in mitochondria. The isolated human MTO2 cDNA can partially restore the respiratory-deficient phenotype of yeast mto2 cells carrying the C1409G mutation. These functional conservations imply that human MTO2 may act as a modifier gene, modulating the phenotypic expression of the deafness-associated A1491G or C1409T mutation in mitochondrial 12 S rRNA.

Clinical evaluation and mitochondrial DNA sequence analysis in three Chinese families with Leber’s hereditary optic neuropathy

We report here the clinical, genetic, and molecular characterization of three Chinese families (WZ4, WZ5, and WZ6) with Leber’s hereditary optic neuropathy (LHON). Clinical and genetic evaluations revealed the variable severity and age-of-onset in visual impairment in these families. Penetrances of visual impairment in these Chinese families were 33.3%, 35.7%, and 35.5%, respectively, with an average 34.8%. Furthermore, the average age-at-onset in those Chinese families was 17, 20, and 18 years. In addition, the ratios between affected male and female matrilineal relatives in these Chinese families were 3:0, 1:1, and 1.2:1, respectively. Sequence analysis of the complete mitochondrial genomes in these pedigrees showed the distinct sets of mtDNA polymorphism, in addition to the identical G11778A mutation associated with LHON in many families. The fact that mtDNA of those pedigrees belonged to different haplogroups F1, D4, and M10 suggested that the G11778A mutation occurred sporadically and multiplied through evolution of the mtDNA in China. However, there was the absence of functionally significant mutations in tRNA and rRNAs or secondary LHON mutations in these Chinese families. The I187T mutation in the ND1, the S99A mutation in the A6, the V254I in CO3, and I58V in ND6 mutation, showing high evolutional conservation, may contribute to the phenotypic expression of the G11778A mutation in the WZ6 pedigree. By contrast, none of mtDNA variants are evolutionarily conserved and implicated to have significantly functional consequence in WZ4 and WZ5 pedigrees. Apparently, these variants do not have a potential modifying role in the development of visual impairment associated with G11778A mutation in those two families. Thus, nuclear modifier gene(s) or environmental factor(s) seem to account for the penetrance and expressivity of LHON in these three Chinese families carrying the G11778A mutation.

Audiological Features and Mitochondrial DNA Sequence in a Large Family Carrying Mitochondrial A1555G Mutation without Use of Aminoglycoside

To elucidate the pathophysiological and genetic mechanisms of hearing loss associated with the homoplasmic mitochondrial A1555G mutation in the absence of aminoglycoside exposure, we conducted audiological and genetic analyses on 67 maternally related members of a large Japanese family carrying this mutation. A consistent pattern was evident in the audiograms, with features of sensory presbycusis, cochlear origin at all levels of hearing loss, and a high degree of vulnerability of outer hair cells. That the degree of hearing loss was similar in affected subjects within the same sibling group but differed between sibling groups suggests the involvement of nuclear modifier genes. Total mitochondrial DNA sequences were completely identical among subjects with various levels of hearing loss, and lacked additional pathogenic mutations. For the diagnosis of sensorineural hearing loss, the mitochondrial A1555G mutation should be considered when these features are present even in the absence of aminoglycoside exposure.

Only male matrilineal relatives with Leber’s hereditary optic neuropathy in a large Chinese family carrying the mitochondrial DNA G11778A mutation

We report here the characterization of a five-generation large Chinese family with Leber’s hereditary optic neuropathy (LHON). Very strikingly, six affected individuals of 38 matrilineal relatives (17 females/21 males) are exclusively males in this Chinese family. These matrilineal relatives in this family exhibited late-onset/progressive visual impairment with a wide range of severity, ranging from blindness to normal vision. The age of onset in visual impairment varies from 17 to 30 years. Sequence analysis of the complete mitochondrial genome in this pedigree revealed the presence of the G11778A mutation in ND4 gene and 29 other variants. This mitochondrial genome belongs to the Southern Chinese haplogroup B5b. We showed that the G11778A mutation is present at near homoplasmy in matrilineal relatives of this Chinese family but not in 164 Chinese controls. Incomplete penetrance of LHON in this family indicates the involvement of modulatory factors in the phenotypic expression of visual dysfunction associated with the G11778A mutation. However, none of other mtDNA variants are evolutionarily conserved and implicated to have significantly functional consequence. Thus, nuclear modifier gene(s) or environmental factor(s) seem to account for the penetrance and phenotypic variability of LHON in this Chinese family carrying the G11778A mutation.

Phenotype of non-syndromic deafness associated with the mitochondrial A1555G mutation is modulated by mitochondrial RNA modifying enzymes MTO1 and GTPBP3

Phenotypic expression of the deafness-associated mitochondrial A1555G mutation in the 12S rRNA gene is influenced by aminoglycosides and complex inheritance of nuclear-encoded modifier genes. The position of a major nuclear modifier gene has been localized to chromosome 8p23.1, but the identification of this gene has remained elusive. Recently, we identified a second modifier gene, mitochondrial transcription factor B1 ( TFB1M), involved in mitochondrial rRNA modification. In the present study, we tested three genes involved in mitochondrial tRNA or rRNA modification, and two genes associated with non-syndromic deafness, for linkage and linkage disequilibrium (LD) in 214 DNA samples from Spanish, Italian, and Arab–Israeli families with maternally inherited non-syndromic hearing loss. The multipoint non-parametric linkage analysis and transmission disequilibrium test testing were done using all families combined as well as divided based on linkage to the chromosome 8 locus and ethnicity. Two genes, MTO1 and GTPBP3, showed strongly suggestive linkage and significant LD results. Since both genes, as well as TFB1M, are involved in the process of mitochondrial RNA modification, it appears that the modification of mitochondrial RNA is an important regulatory pathway in the phenotypic expression of the deafness-associated mitochondrial A1555G mutation. This conclusion was supported by comparing linkage results of simulated genotypes with actual results for the four genes involved in mitochondrial RNA modification.

Molecular Pathogenetic Mechanism of Maternally Inherited Deafness

Abstract: Mutations in the mitochondrial DNA (mtDNA) have been shown to be one important cause of deafness. In particular, mutations in the mtDNA have been associated with both syndromic and nonsyndromic forms of sensori‐neural hearing loss. The deafness‐linked mutations often occur in the mitochondrial 12S rRNA gene and in tRNA genes. Mutations in the 12S rRNA gene account for most of the cases of aminoglycoside ototoxicity. The other hot spot for mutations associated with hearing impairment is the tRNASer(UCN) gene, as five deafness‐linked mutations have been identified in this gene. Nonsyndromic deafness‐linked mtDNA mutations are often homoplasmic or at high levels of heteroplasmy, indicating a high threshold for pathogenicity. Phenotypic expression of these mtDNA mutations requires the contribution of other factors such as nuclear modifier gene(s), environmental factor(s), or mitochondrial haplotype(s).

Molecular pathogenetic mechanism of maternally inherited deafness.

Mutations in the mitochondrial DNA (mtDNA) have been shown to be one important cause of deafness. In particular, mutations in the mtDNA have been associated with both syndromic and nonsyndromic forms of sensori-neural hearing loss. The deafness-linked mutations often occur in the mitochondrial 12S rRNA gene and in tRNA genes. Mutations in the 12S rRNA gene account for most of the cases of aminoglycoside ototoxicity. The other hot spot for mutations associated with hearing impairment is the tRNA(Ser(UCN)) gene, as five deafness-linked mutations have been identified in this gene. Nonsyndromic deafness-linked mtDNA mutations are often homoplasmic or at high levels of heteroplasmy, indicating a high threshold for pathogenicity. Phenotypic expression of these mtDNA mutations requires the contribution of other factors such as nuclear modifier gene(s), environmental factor(s), or mitochondrial haplotype(s).

A human mitochondrial GTP binding protein related to tRNA modification may modulate phenotypic expression of the deafness-associated mitochondrial 12S rRNA mutation.

Human mitochondrial 12S rRNA A1555G mutation has been found to be associated with deafness. However, putative nuclear modifier gene(s) has been proposed to regulate the phenotypic expression of this mutation. In yeast cells, mutant alleles of MSS1, encoding a mitochondrial GTP-binding protein, manifest a respiratory-deficient phenotype only when coupled with mitochondrial 15S rRNA P(R)(454) mutation corresponding to human A1555G mutation. This suggests that an MSS1-like modifier gene may influence the phenotypic expression of the A1555G mutation. We report here the identification and characterization of human MSS1 homolog, GTPBP3, the first identified vertebrate gene related to mitochondrial tRNA modification. The Gtpbp3 is the mitochondrial GTPase evolutionarily conserved from bacteria to mammals. Functional conservation of this protein is supported by the observation that isolated human GTPBP3 cDNA can complement the respiratory-deficient phenotype of yeast mss1 cells carrying P(R)(454) mutation. GTPBP3 is ubiquitously expressed in various tissues as multiple transcripts, but with a markedly elevated expression in tissues of high metabolic rates. We showed that Gtpbp3 localizes in mitochondrion. These observations suggest that the human GTPBP3 is a structural and functional homolog of yeast MSS1. Thus, allelic variants in GTPBP3 could, if they exist, modulate the phenotypic manifestation of human mitochondrial A1555G mutation.

Isolation and Characterization of the Putative Nuclear Modifier Gene MTO1 Involved in the Pathogenesis of Deafness-associated Mitochondrial 12 S rRNA A1555G Mutation

The human mitochondrial 12 S rRNA A1555G mutation has been found to be associated with aminoglycoside-induced and non-syndromic deafness. However, putative nuclear modifier gene(s) have been proposed to regulate the phenotypic expression of this mutation. In yeast, the mutant alleles of MTO1, encoding a mitochondrial protein, manifest respiratory-deficient phenotype only when coupled with the mitochondrial 15 S rRNA P(R)454 mutation corresponding to human A1555G mutation. This suggests that the MTO1-like modifier gene may influence the phenotypic expression of human A1555G mutation. Here we report the identification of full-length cDNA and elucidation of genomic organization of the human MTO1 homolog. Human Mto1 is an evolutionarily conserved protein that implicates a role in the mitochondrial tRNA modification. Functional conservation of this protein is supported by the observation that isolated human MTO1 cDNA can complement the respiratory deficient phenotype of yeast mto1 cells carrying P(R)454 mutation. MTO1 is ubiquitously expressed in various tissues, but with a markedly elevated expression in tissues of high metabolic rates including cochlea. These observations suggest that human MTO1 is a structural and functional homolog of yeast MTO1. Thus, it may play an important role in the pathogenesis of deafness-associated A1555G mutation in 12 S rRNA gene or mutations in tRNA genes.

Modifier locus for mitochondrial DNA disease: Linkage and linkage disequilibrium mapping of a nuclear modifier gene for maternally inherited deafness

Purpose: To examine the role of the nuclear genome in affecting the phenotypic expression of the simplest model of a mitochondrial DNA disease, maternally transmitted deafness.Methods: Linkage analysis in families with maternally inherited deafness associated with the homoplasmic A1555G mutation.Results: Significant linkage and linkage disequilibrium on chromosome 8 was identified.Conclusions: This finding represents the first identification of a modifier locus for a human mitochondrial DNA disease and supports the concept of mitochondrial DNA diseases having complex genetic inheritance. The eventual identification of this modifier gene will provide insights into the pathophysiological pathways determining the clinical expression of mitochondrial DNA diseases, an important step toward diagnostic and therapeutic interventions.

Candidate Locus for a Nuclear Modifier Gene for Maternally Inherited Deafness

Maternally inherited deafness associated with the A1555G mutation in the mitochondrial 12S ribosomal RNA (rRNA) gene appears to require additional environmental or genetic changes for phenotypic expression. Aminoglycosides have been identified as one such environmental factor. In one large Arab-Israeli pedigree with congenital hearing loss in some of the family members with the A1555G mutation and with no exposure to aminoglycosides, biochemical evidence has suggested the role of nuclear modifier gene(s), but a genomewide search has indicated the absence of a single major locus having such an effect. Thus it has been concluded that the penetrance of the mitochondrial mutation appears to depend on additive effects of several nuclear genes. We have now investigated 10 multiplex Spanish and Italian families with 35 members with the A1555G mutation and sensorineural deafness. Parametric analysis of a genomewide screen again failed to identify significant evidence for linkage to a single autosomal locus. However, nonparametric analysis supported the role of the chromosomal region around marker D8S277. The combined maximized allele-sharing LOD score of 3.1 in Arab-Israeli/Spanish/Italian families represents a highly suggestive linkage result. We suggest that this region should be considered a candidate for containing the first human nuclear modifier gene for a mitochondrial DNA disorder. The locus operates in Arab-Israeli, Spanish, and Italian families, resulting in the deafness phenotype on a background of the mitochondrial A1555G mutation. No obvious candidate genes are located in this region.

Meiotic breakpoint mapping of a proposed X linked visual loss susceptibility locus in Leber's hereditary optic neuropathy.

Leber's hereditary optic neuropathy (LHON) is a maternally inherited degenerative disorder characterised by an acute or subacute optic nerve degeneration resulting in visual failure. Mitochondrial DNA mutations have been reported...