Identification of the variants in PARL, the nuclear modifier gene, responsible for the expression of LHON patients in Thailand.

The present study explored variation in the PARL gene as one of the potential nuclear modifiers in the pathogenesis of Leber hereditary optic neuropathy (LHON). Ten exons, their franking introns and 3' UTR of the PARL gene were analysed. Seventeen SNPs detected were investigated in 83 affected and 53 unaffected individuals from 47 independent Thai LHON pedigrees using MQLS statistics in order to minimize the influence of the family background. Three intronic SNPs (rs953419, rs3749446 and rs1402000) showed statistically significant results. Joint haplotypes were constructed based on the genotypes at 3 SNPs and 7 possible haplotypes were observed in the 136 subjects. Our findings that the frequency of the haplotype AAC, and AAT were significantly higher in the unaffected cases and the frequencies of haplotype GGT were significantly higher in LHON cases, indicate that it might have a role in the penetrance of this mitochondrial disease.

Mitochondrial haplogroup background may influence Southeast Asian G11778A Leber hereditary optic neuropathy.

PURPOSE: To investigate the role of mitochondrial DNA (mt DNA) background on the expression of Leber hereditary optic neuropathy (LHON) in Southeast Asian carriers of the G11778A mutation. METHODS: Complete mtDNA sequences were analyzed from 53 unrelated Southeast Asian G11778A LHON pedigrees in Thailand and 105 normal Thai controls, and mtDNA haplogroups were determined. Clinical phenotypes were tested for association with mtDNA haplogroup, with adjustment for potential confounders such as sex and age at onset. RESULTS: mtDNA subhaplogroup B was significantly associated with LHON. Follow-up analysis narrowed the association down to subhaplogroup B5a1 (P = 0.008). Survival analyses with Cox's proportional hazards modeling on 469 samples (91 affected and 378 unaffected), adjusted for sex and heteroplasmy, revealed that haplogroup B5a1 tended to increase the risk of visual loss, but the trend was not statistically significant. Conversely, haplogroup F, the second most common haplogroup in the control population, was the least frequent haplogroup in LHON. This negative association was narrowed down to subhaplogroup F1 (P = 0.00043), suggesting that haplogroup F1 confers a protective effect. The distributions of sex, age at onset and heteroplasmy were not significantly different among haplogroups. CONCLUSIONS: The specific mtDNA background B5a1 was significantly associated with Southeast Asian G11778A LHON and appeared to modify the risk of visual loss.

Genome-wide linkage scan and association study of PARL to the expression of LHON families in Thailand.

Leber hereditary optic neuropathy (LHON) is the most common mitochondrially inherited disease causing blindness, preferentially in young adult males. Most of the patients carry the G11778A mitochondrial DNA (mtDNA) mutation. However, the marked incomplete penetrance and the gender bias indicate some additional genetic and/or environmental factors to disease expression. Herein, we first conducted a genome-wide linkage scan with 400 microsatellite markers in 9 large Thai LHON G11778A pedigrees. Using an affecteds-only nonparametric linkage analysis, 4 regions on chromosomes 3, 12, 13 and 18 showed Zlr scores greater than 2 (P < 0.025), which is consistently significant across several linkage statistics. The most suggestive marker D3S1565 (Zlr > 2 in 10 of 16 allele sharing models tested) was then expanded to include the region 3q26.2-3q28 covering SLC7A14 (3q26.2), MFN1 (3q26.32), MRPL47 (3q26.33), MCCC1 (3q27.1), PARL (3q27.1) and OPA1 (3q28-q29). All of these candidate genes were selected from the Maestro database and had known to be localized in mitochondria. Sixty tag SNPs were genotyped in 86 cases, 211 of their relatives and 32 unrelated Thai controls, by multiplex-PCR-based Invader assay. Analyses using a powerful association testing tool that adjusts for relatedness (the M(QLS) statistic) showed the most evidence of association between two SNPs, rs3749446 and rs1402000 (located in PARL presenilins-associated rhomboid-like) and LHON expression (both P = 8.8 x 10(-5)). The mitochondrial PARL protease has been recently known to play a role with a dynamin-related OPA1 protein in preventing apoptotic events by slowing down the release of cytochrome c out of mitochondrial cristae junctions. Moreover, PARL is required to activate the intramembranous proteolyses resulting in the degradation of an accumulated pro-apoptotic protein in the outer mitochondrial membrane. Under these circumstances, variants of PARL are suggested to influence cell death by apoptosis which has long been believed to intrigue the neurodegeneration of LHON.

Transmission of heteroplasmic G11778A in extensive pedigrees of Thai Leber hereditary optic neuropathy.

Leber hereditary optic neuropathy (LHON) is characterized by the acute or subacute bilateral painless loss of central vision, predominantly in young males. G11778A is the most common mitochondrial DNA mutation responsible for the disease. Thirty-seven percent of our LHON pedigrees (which is a much higher prevalence than that generally found) carried heteroplasmic G11778A. Analyses of four large Thai LHON pedigrees spanning four to six generations strongly suggested that the transmission of the heteroplasmic G11778A mutation is under selective pressure in favour of the mutated allele and that heteroplasmy influences the disease expression.