PURPOSE: Autosomal dominant optic atrophy is a form of blindness, due in part to mutations affecting the mitochondrial-targeted OPA1 gene product. Both OPA1-positive and OPA1-negative families exhibit variable expressivity and incomplete penetrance. The purpose of this study was therefore to determine if the background mtDNA genotype acts as a genetic modifier for the expression of this disease. METHODS: To find novel pathogenic OPA1 mutations, we performed complete OPA1 gene exon sequencing in 30 patients. To assess the possibility that mitochondrial DNA haplotype acts as a genetic modifier, we determined the mitochondrial DNA haplotype in 29 Caucasian OPA1-positive and OPA1-negative patients. Deviations in haplotype distribution between patient and control groups were determined by statistical means. RESULTS: Seven new pathogenic OPA1 mutations were found. Most were detected in the mitochondrial targeting N-terminus or in the coiled-coil domain at the C-terminus. Mitochondrial DNA haplotype analysis indicated that the European haplogroup distribution was different between Caucasian patients and controls. Further, haplogroup J was three-fold over-represented in OPA1-negative patients. CONCLUSIONS: Overall, our results support haploinsufficiency as a genetic mechanism in OPA1-positive cases and also suggest that mtDNA genetic background may influence disease expression in a subset of cases.
PURPOSE: Autosomal dominant optic atrophy is a form of blindness, due in part to mutations affecting the mitochondrial-targeted OPA1 gene product. Both OPA1-positive and OPA1-negative families exhibit variable expressivity and incomplete penetrance. The purpose of this study was therefore to determine if the background mtDNA genotype acts as a genetic modifier for the expression of this disease. METHODS: To find novel pathogenic OPA1 mutations, we performed complete OPA1 gene exon sequencing in 30 patients. To assess the possibility that mitochondrial DNA haplotype acts as a genetic modifier, we determined the mitochondrial DNA haplotype in 29 Caucasian OPA1-positive and OPA1-negative patients. Deviations in haplotype distribution between patient and control groups were determined by statistical means. RESULTS: Seven new pathogenic OPA1 mutations were found. Most were detected in the mitochondrial targeting N-terminus or in the coiled-coil domain at the C-terminus. Mitochondrial DNA haplotype analysis indicated that the European haplogroup distribution was different between Caucasian patients and controls. Further, haplogroup J was three-fold over-represented in OPA1-negative patients. CONCLUSIONS: Overall, our results support haploinsufficiency as a genetic mechanism in OPA1-positive cases and also suggest that mtDNA genetic background may influence disease expression in a subset of cases.
Authors: Tomokazu Souma; Stuart W Tompson; Benjamin R Thomson; Owen M Siggs; Krishnakumar Kizhatil; Shinji Yamaguchi; Liang Feng; Vachiranee Limviphuvadh; Kristina N Whisenhunt; Sebastian Maurer-Stroh; Tammy L Yanovitch; Luba Kalaydjieva; Dimitar N Azmanov; Simone Finzi; Lucia Mauri; Shahrbanou Javadiyan; Emmanuelle Souzeau; Tiger Zhou; Alex W Hewitt; Bethany Kloss; Kathryn P Burdon; David A Mackey; Keri F Allen; Jonathan B Ruddle; Sing-Hui Lim; Steve Rozen; Khanh-Nhat Tran-Viet; Xiaorong Liu; Simon John; Janey L Wiggs; Francesca Pasutto; Jamie E Craig; Jing Jin; Susan E Quaggin; Terri L Young Journal: J Clin Invest Date: 2016-06-06 Impact factor: 14.808
Authors: Eric D Gaier; Katherine Boudreault; Isao Nakata; Maria Janessian; Philip Skidd; Elizabeth DelBono; Keri F Allen; Louis R Pasquale; Emily Place; Dean M Cestari; Rebecca C Stacy; Joseph F Rizzo; Janey L Wiggs Journal: Mol Vis Date: 2017-08-10 Impact factor: 2.367
Authors: Vladimir I Mayorov; Angela J Lowrey; Valerie Biousse; Nancy J Newman; Susan D Cline; Michael D Brown Journal: BMC Biochem Date: 2008-09-10 Impact factor: 4.059