Centre for Clinical Veterinary Medicine, Faculty of Veterinary Medicine, Ludwig-Maximilians-Universität München (LMU Munich), Veterinärstrasse 13, 80539 Munich, Germany.
Research Programs Unit, Molecular Neurology, University of Helsinki, Haartmaninkatu 8, P.O. Box 63, 00014 Helsinki, Finland; Department of Veterinary Biosciences, University of Helsinki, Agnes Sjöbergin katu 2, 00014 Helsinki, Finland; Folkhälsan Institute of Genetics, Haartmaninkatu 8, 00290 Helsinki, Finland.
Neuromuscul Disord. 2018 Jul;28(7):597-605. doi: 10.1016/j.nmd.2018.05.002. Epub 2018 Jun 19.
An eight week old Labrador Retriever puppy presented with stiff-legged robotic gait. Abnormal gait was most evident after rest and improved with prolonged activity. On occasions, initiation of sudden movements would result in collapse with rigidity of the trunk and stiff extended limbs for several seconds. Other clinical signs were excitement-induced upper airway stridor and oropharyngeal dysphagia. Myotonia congenita was diagnosed based on clinical signs, abundant myotonic discharges on electromyography and exclusion of structural myopathies on histology. Whole exome sequencing revealed a case-specific homozygous variant in CLCN1, c.2275A > T resulting in a premature stop codon, p.R759X. The CLCN1 variant was absent from the genomes of 127 Labrador Retriever controls and 474 control dogs from other breeds. This study expands the spectrum of identified canine CLCN1 mutations and the list of affected breeds in myotonia congenita and highlights the potential value of dogs as translational large animal models of human genetic diseases.
一只 8 周大的拉布拉多猎犬幼犬出现了僵硬腿的机器人步态。异常步态在休息后最为明显，长时间活动后会有所改善。有时，突然开始运动，会导致几秒钟的躯干僵硬和四肢僵硬的瘫痪。其他临床症状为兴奋诱导的上呼吸道喘鸣和口咽吞咽困难。根据临床症状、肌电图上丰富的肌强直性放电以及组织病理学排除结构性肌病，诊断为先天性肌强直。全外显子组测序显示 CLCN1 中一个特定于病例的纯合变体 c.2275A>T，导致提前终止密码子 p.R759X。该 CLCN1 变体不存在于 127 只拉布拉多猎犬对照犬和 474 只其他品种对照犬的基因组中。本研究扩展了先天性肌强直中已鉴定的犬类 CLCN1 突变谱和受影响品种列表，并强调了犬类作为人类遗传性疾病的转化大型动物模型的潜在价值。
