title: 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.
authors.affiliation: Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.
authors.forename: Nopasak
authors.initials: N
authors.lastname: Phasukkijwatana
authors.forename: Bussaraporn
authors.initials: B
authors.lastname: Kunhapan
authors.forename: Jim
authors.initials: J
authors.lastname: Stankovich
authors.forename: Wanicha L
authors.initials: WL
authors.lastname: Chuenkongkaew
authors.forename: Russell
authors.initials: R
authors.lastname: Thomson
authors.forename: Timothy
authors.initials: T
authors.lastname: Thornton
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
authors.forename: Taisei
authors.initials: T
authors.lastname: Mushiroda
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Surakameth
authors.initials: S
authors.lastname: Mahasirimongkol
authors.forename: Aung Win
authors.initials: AW
authors.lastname: Tun
authors.forename: Chatchawan
authors.initials: C
authors.lastname: Srisawat
authors.forename: Chanin
authors.initials: C
authors.lastname: Limwongse
authors.forename: Chayanon
authors.initials: C
authors.lastname: Peerapittayamongkol
authors.forename: Thanyachai
authors.initials: T
authors.lastname: Sura
authors.forename: Wichit
authors.initials: W
authors.lastname: Suthammarak
authors.forename: Patcharee
authors.initials: P
authors.lastname: Lertrit
mesh_terms: D000328:Adult; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D045726:Metalloproteases / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics*; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013785:Thailand
chemical_list: D024101:Mitochondrial Proteins; D045726:Metalloproteases; C485223:PARL protein, human
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