Genome-wide linkage scan and association study of PARL to the expression of LHON families in Thailand
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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.
KeywordsG11778A Mutation Well Linear Unbiased Estimate Autosomal Dominant Optic Atrophy Facioscapulohumeral Muscular Dystrophy Invader Assay
The genome-wide linkage scan was performed with the assistance of Dr. Kelly Ewen-White in Australian Genome Research Facility (AGRF), Victoria, Australia. SNPs genotyping and all facilities to perform multiplex-PCR-based Invader assay were supported by Laboratory for Pharmacogenetics, RIKEN Center for Genomic Medicine, Yokohama, Japan, through the genotyping services supports and fellowships to Thai researchers and institutes executed on DMSc-RIKEN’s Center for Genomics Medicine (CGM) Collaboration. We acknowledge Sukanya Wattanapokayakit (DMSc, Thailand) for her assistance on collaboration process and SNPs genotyping at RIKEN. Also we sincerely thank Dr. Briony Patterson for the guidance on bioinformatics analyses and discussions. We are especially grateful to Dr. Komon Luangtrakool, Pattamon Tharaphan, Sarinee Pingsutthiwong, Thitima Sunpachudayan, Benjamas Intharabut, Treenud Suntisiri, Yutthana Joyjinda, Dr. Patchara Nantasri and the ophthalmologists for their great assistance in the field trip, DNA extraction and data manipulation. Finally, we thank all of the patients and families for their wonderful cooperation. This work was supported by the Thailand Research Fund (TRF) grant number BRG4580018 to P. Lertrit and PHD/0031/2546 through the Royal Golden Jubilee Ph.D. Program to N. Phasukkijwatana and P. Lertrit, and by Siriraj Research and Development Fund, Faculty of Medicine Siriraj Hospital, Mahidol University (Grant No. 014(II)/49). The SNPs genotyping and statistical genetics analyses were supported by grants from the Faculty of Medicine Siriraj Hospital, Mahidol University and from the National Center for Genetic Engineering and Biotechnology (BIOTEC), Thailand.
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