Nafisinia Michael, Riley Lisa G, Gold Wendy A, Bhattacharya Kaustuv, Broderick Carolyn R, Thorburn David R, Simons Cas, Christodoulou John
Genetic Metabolic Disorders Research Unit, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
Discipline of Child & Adolescent Health, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
PLoS One. 2017 Jun 8;12(6):e0178125. doi: 10.1371/journal.pone.0178125. eCollection 2017.
Glycyl-tRNA synthetase (GARS; OMIM 600287) is one of thirty-seven tRNA-synthetase genes that catalyses the synthesis of glycyl-tRNA, which is required to insert glycine into proteins within the cytosol and mitochondria. To date, eighteen mutations in GARS have been reported in patients with autosomal-dominant Charcot-Marie-Tooth disease type 2D (CMT2D; OMIM 601472), and/or distal spinal muscular atrophy type V (dSMA-V; OMIM 600794). In this study, we report a patient with clinical and biochemical features suggestive of a mitochondrial respiratory chain (MRC) disorder including mild left ventricular posterior wall hypertrophy, exercise intolerance, and lactic acidosis. Using whole exome sequencing we identified compound heterozygous novel variants, c.803C>T; p.(Thr268Ile) and c.1234C>T; p.(Arg412Cys), in GARS in the proband. Spectrophotometric evaluation of the MRC complexes showed reduced activity of Complex I, III and IV in patient skeletal muscle and reduced Complex I and IV activity in the patient liver, with Complex IV being the most severely affected in both tissues. Immunoblot analysis of GARS protein and subunits of the MRC enzyme complexes in patient fibroblast extracts showed significant reduction in GARS protein levels and Complex IV. Together these studies provide evidence that the identified compound heterozygous GARS variants may be the cause of the mitochondrial dysfunction in our patient.
甘氨酰 - tRNA合成酶（GARS；OMIM 600287）是37种tRNA合成酶基因之一，它催化甘氨酰 - tRNA的合成，而甘氨酰 - tRNA是将甘氨酸插入胞质溶胶和线粒体中的蛋白质所必需的。迄今为止，已在常染色体显性遗传的2D型夏科 - 马里 - 图斯病（CMT2D；OMIM 601472）和/或V型远端脊髓性肌萎缩症（dSMA - V；OMIM 600794）患者中报道了18种GARS突变。在本研究中，我们报告了一名具有线粒体呼吸链（MRC）障碍临床和生化特征的患者，包括轻度左心室后壁肥厚、运动不耐受和乳酸性酸中毒。通过全外显子组测序，我们在先证者的GARS基因中鉴定出复合杂合新变体，即c.803C>T；p.（Thr268Ile）和c.1234C>T；p.（Arg412Cys）。对MRC复合物的分光光度评估显示，患者骨骼肌中复合物I、III和IV的活性降低，患者肝脏中复合物I和IV的活性降低，其中复合物IV在两种组织中受影响最严重。对患者成纤维细胞提取物中GARS蛋白和MRC酶复合物亚基的免疫印迹分析显示，GARS蛋白水平和复合物IV显著降低。这些研究共同提供了证据，表明所鉴定的复合杂合GARS变体可能是我们患者线粒体功能障碍的原因。
