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Title: Genome-wide linkage scan and association study of PARL to the expression of LHON families in Thailand
Authors: Nopasak Phasukkijwatana
Bussaraporn Kunhapan
Jim Stankovich
Wanicha L. Chuenkongkaew
Russell Thomson
Timothy Thornton
Melanie Bahlo
Taisei Mushiroda
Yusuke Nakamura
Surakameth Mahasirimongkol
Aung Win Tun
Chatchawan Srisawat
Chanin Limwongse
Chayanon Peerapittayamongkol
Thanyachai Sura
Wichit Suthammarak
Patcharee Lertrit
Mahidol University
Walter and Eliza Hall Institute of Medical Research
University of Tasmania
Faculty of Medicine, Siriraj Hospital, Mahidol University
University of Washington, Seattle
Institute of Medical Science The University of Tokyo
National Institutes of Health, Bethesda
Keywords: Biochemistry, Genetics and Molecular Biology;Medicine
Issue Date: 1-Jul-2010
Citation: Human Genetics. Vol.128, No.1 (2010), 39-49
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 MQLS 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 = 8.8×10-5). 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 proapoptotic 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. © 2010 Springer-Verlag.
ISSN: 14321203
Appears in Collections:Scopus 2006-2010

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