Han Jian, Thompson-Lowrey Angela J, Reiss Alyson, Mayorov Vladimir, Jia Haomiao, Biousse Valerie, Newman Nancy J, Brown Michael D
Department of Basic Medical Sciences, Mercer University School of Medicine, Macon, GA, USA.
Genet Med. 2006 Apr;8(4):217-25. doi: 10.1097/01.gim.0000214299.61930.c0.
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.
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.
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.
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.
常染色体显性遗传性视神经萎缩是一种失明形式，部分原因是影响线粒体靶向的OPA1基因产物的突变。OPA1阳性和OPA1阴性家族均表现出可变表达性和不完全外显率。因此，本研究的目的是确定背景线粒体DNA基因型是否作为该疾病表达的遗传修饰因子。
为了寻找新的致病性OPA1突变，我们对30例患者进行了OPA1基因外显子全测序。为了评估线粒体DNA单倍型作为遗传修饰因子的可能性，我们确定了29例白种人OPA1阳性和OPA1阴性患者的线粒体DNA单倍型。通过统计学方法确定患者组和对照组之间单倍型分布的差异。
发现了7个新的致病性OPA1突变。大多数突变在线粒体靶向的N端或C端的卷曲螺旋结构域中被检测到。线粒体DNA单倍型分析表明，白种人患者和对照组之间的欧洲单倍群分布不同。此外，单倍群J在OPA1阴性患者中出现的频率是对照组的三倍。
总体而言，我们的结果支持单倍剂量不足是OPA1阳性病例中的一种遗传机制，并且还表明线粒体DNA遗传背景可能在一部分病例中影响疾病表达。
