Department of Neurological Sciences, University of Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy.
Hum Mol Genet. 2011 May 15;20(10):1893-905. doi: 10.1093/hmg/ddr071. Epub 2011 Feb 24.
Dominant optic atrophy (DOA) is genetically heterogeneous and pathogenic mutations have been identified in the OPA1 and OPA3 genes, both encoding for mitochondrial proteins. We characterized clinical and laboratory features in a large OPA1-negative family with complicated DOA. Search for mitochondrial dysfunction was performed by studying muscle biopsies, fibroblasts, platelets and magnetic resonance (MR) spectroscopy. Genetic investigations included mitochondrial DNA (mtDNA) analysis, linkage analysis, copy number variation (CNV) analysis and candidate gene screening. Optic neuropathy was undistinguishable from that in OPA1-DOA and frequently associated with late-onset sensorineural hearing loss, increases of central conduction times at somato-sensory evoked potentials and various cardiac abnormalities. Serum lactic acid after exercise, platelet respiratory complex activities, adenosine triphosphate (ATP) content in fibroblasts and muscle phosphorus MR spectroscopy all failed to reveal a mitochondrial dysfunction. However, muscle biopsies and their mtDNA analysis showed increased mitochondrial biogenesis. Furthermore, patient's fibroblasts grown in the galactose medium were unable to increase ATP content compared with controls, and exhibited abnormally high rate of fusion activity. Genome-wide linkage revealed a locus on chromosome 16q21-q22 with a maximum two-point LOD score of 8.84 for the marker D16S752 and a non-recombinant interval of ∼ 6.96 cM. Genomic screening of 45 genes in this interval including several likely candidate genes (CALB2, CYB5B, TK2, DHODH, PLEKHG4) revealed no mutation. Moreover, we excluded the presence of CNVs using array-based comparative genome hybridization. The identification of a new OPA locus (OPA8) in this pedigree demonstrates further genetic heterogeneity in DOA, and our results indicate that the pathogenesis may still involve mitochondria.
原发性视神经萎缩（OPA）是一种遗传异质性疾病，OPA1 和 OPA3 基因突变与该疾病相关，这两个基因均编码线粒体蛋白。我们对一个大的 OPA1 阴性伴有复杂视神经萎缩的家族进行了临床和实验室特征分析。通过研究肌肉活检、成纤维细胞、血小板和磁共振（MR）波谱检查，我们对线粒体功能障碍进行了研究。遗传研究包括线粒体 DNA（mtDNA）分析、连锁分析、拷贝数变异（CNV）分析和候选基因筛查。该视神经病变与 OPA1-DOA 无法区分，常伴有迟发性感觉神经性听力损失、体感诱发电位中枢传导时间延长以及各种心脏异常。运动后血清乳酸、血小板呼吸复合物活性、成纤维细胞三磷酸腺苷（ATP）含量和肌肉磷磁共振波谱均未能显示线粒体功能障碍。然而，肌肉活检及其 mtDNA 分析显示线粒体生物发生增加。此外，与对照组相比，患者的成纤维细胞在半乳糖培养基中无法增加 ATP 含量，并且融合活性异常高。全基因组连锁分析显示 16q21-q22 染色体上存在一个位点，以标记 D16S752 为标记的两点最大 LOD 得分为 8.84，非重组间隔约为 6.96 cM。对该区间内包括几个可能候选基因（CALB2、CYB5B、TK2、DHODH、PLEKHG4）在内的 45 个基因进行基因组筛查，未发现突变。此外，我们还使用基于阵列的比较基因组杂交排除了 CNV 的存在。在这个家族中鉴定了一个新的 OPA 基因座（OPA8），进一步证明了 OPA 的遗传异质性，我们的结果表明，其发病机制可能仍与线粒体有关。
