Genome-wide linkage scan and association study of PARL to the expression of LHON families in Thailand |
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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 |
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Affiliation: | 1. Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand 2. Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia 3. Menzies Research Institute, University of Tasmania, Hobart, TAS, 7000, Australia 4. Department of Ophthalmology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand 5. Siriraj Neurogenetics Network, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand 6. Department of Biostatistics, University of Washington, Washington, 98195-7232, USA 7. Laboratory for Pharmacogenetics, RIKEN Center for Genomic Medicine, Yokohama, 230-0045, Japan 8. Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan 9. Medical Genetic Section, National Institute of Health, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, 11000, Thailand 10. Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand 11. Department of Medicine, Faculty of Medicine Ramathibodhi Hospital, Mahidol University, Bangkok, 10400, Thailand
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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 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. |
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