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

Abstract

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.

Profiling the Mitochondrial Proteome of Leber’s Hereditary Optic Neuropathy (LHON) in Thailand: Down-Regulation of Bioenergetics and Mitochondrial Protein Quality Control Pathways in Fibroblasts with the 11778G>A Mutation

“…The numbers of affected LHON patients recruited from pedigrees F1, F9 and F66 were two, two and three respectively. All affected individuals have been diagnosed by an ophthalmologist (WC) and have been confirmed as bearing homoplasmic mtDNA 11778G>A [9], [13], [27]. The characteristics of each patient are summarized in Table 1.…”

No association between the SNPs (rs3749446 and rs1402000) in the PARL gene and LHON in Chinese patients with m.11778G>A

“…However, the frequency of genotype CT of rs953419 (this SNP was not significant after multiple testing correction in Phasukkijwatana et al (2010)) was higher (P = 0.038) in LHON patients (55.9%) than in the control population (45.7%; Table 1), but the P value changed to 0.114 after the Bonferroni correction. Five haplotypes were constructed based on the three SNPs (rs3749446-rs953419-rs1402000).…”

“…However, no nuclear gene or SNP has been identified to explain the riddle of LHON. Recently, by using a genome-wide linkage scan and association study, Phasukkijwatana et al (2010) first reported that two SNPs (rs3749446 and rs1402000) in the PARL gene were associated with the expression of LHON in patients from Thailand. Because of potential limits in that study, these authors called for more studies to confirm their observation (Phasukkijwatana et al 2010).…”

“…Recently, based on a genome-wide linkage scan and association study of families with m.11778G[A in Thailand, Phasukkijwatana et al (2010) reported an association between two PARL gene SNPs (rs3749446 and rs1402000) and Leber hereditary optic neuropathy (LHON) in Thailand families with m.11778G[A. We genotyped three SNPs of the PARL gene (rs3749446, rs953419, and rs1402000) in 179 Chinese LHON patients with m.11778G[A, 170 samples with suspected LHON, and 58 normal individuals to confirm the association of the PARL gene SNPs with LHON in Chinese patients.…”

Mitochondrial disorders and the eye

“…62 Single nucleotide polymorphisms of PARL have been associated with glaucoma, LHON, and mutations causing Parkinson's disease. 59,63,64 Altering the fission-fusion balance has profound effects on mitochondrial function and structure. With pharmaceutical or genetic inhibition of fusion, there is a collapse of mitochondrial energy production as mitochondria consume ATP 65 which alters mitochondrial distribution toward fission, 54,66 promoting apoptosis.…”