Phowthongkum P, Sun A
Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA; Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA, USA.
Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA.
Neuromuscul Disord. 2017 Jul;27(7):616-618. doi: 10.1016/j.nmd.2017.03.013. Epub 2017 Apr 6.
DNA2 encodes a protein with nuclease, ATPase, and helicase domains, and serves to maintain mitochondrial DNA integrity. Mutations in DNA2 cause autosomal dominant progressive ophthalmoplegia with mitochondrial DNA deletions. This disorder was first reported in four patients with heterozygous, missense mutations in DNA2. Clinical symptoms include limb-girdle and lower extremity weakness, myalgia, and ophthalmoplegia. All had a slowly progressive disease course and did not present for clinical evaluation until the fifth or sixth decade. We report a case of congenital-onset myopathy and ptosis in a child who was found to have a novel DNA2 variant resulting in a premature termination codon (p.Asn568Ilefs*4). Only one other case of a truncating mutation in DNA2 has been reported, and that patient also had early-onset, severe disease. We hypothesize that haploinsufficiency for the DNA2 protein due to truncating mutations results in mitochondrial genome instability and clinical symptoms of early-onset myopathy. Missense mutations that allow for residual protein function lead to a milder clinical phenotype.
DNA2编码一种具有核酸酶、ATP酶和解旋酶结构域的蛋白质，用于维持线粒体DNA的完整性。DNA2突变会导致伴有线粒体DNA缺失的常染色体显性进行性眼肌麻痹。这种疾病最初在4名DNA2基因杂合错义突变患者中被报道。临床症状包括肩胛带和下肢无力、肌痛和眼肌麻痹。所有患者病情进展缓慢，直到第五或第六个十年才进行临床评估。我们报告了一例先天性起病的儿童肌病和上睑下垂病例，该儿童被发现有一种新的DNA2变异，导致提前终止密码子（p.Asn568Ilefs*4）。仅报道过另一例DNA2截短突变病例，该患者也患有早发性严重疾病。我们推测，由于截短突变导致DNA2蛋白单倍剂量不足会导致线粒体基因组不稳定和早发性肌病的临床症状。允许残留蛋白质功能的错义突变会导致较轻的临床表型。
