Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, 77843-4458, USA.
Department of Neurology and Neurosurgery, Pieper Memorial Veterinary Center, Middletown, CT, 06457, USA.
Skelet Muscle. 2018 May 29;8(1):16. doi: 10.1186/s13395-018-0162-1.
Boys with Duchenne muscular dystrophy (DMD) have DMD gene mutations, with associated loss of the dystrophin protein and progressive muscle degeneration and weakness. Corticosteroids and palliative support are currently the best treatment options. The long-term benefits of recently approved compounds such as eteplirsen and ataluren remain to be seen. Dogs with naturally occurring dystrophinopathies show progressive disease akin to that of DMD. Accordingly, canine DMD models are useful for studies of pathogenesis and preclinical therapy development. A dystrophin-deficient, male border collie dog was evaluated at the age of 5 months for progressive muscle weakness and dysphagia.
Dramatically increased serum creatine kinase levels (41,520 U/L; normal range 59-895 U/L) were seen on a biochemistry panel. Histopathologic changes characteristic of dystrophinopathy were seen. Dystrophin was absent in the skeletal muscle on immunofluorescence microscopy and western blot. Whole genome sequencing, polymerase chain reaction, and Sanger sequencing revealed a frameshift, single nucleotide deletion in canine DMD exon 20, position 27,626,466 (c.2841delT mRNA), resulting in a stop codon six nucleotides downstream. Semen was archived for future line perpetuation.
This spontaneous canine dystrophinopathy occurred due to a novel mutation in the minor DMD mutation hotspot (between exons 2 through 20). Perpetuating this line could allow for preclinical testing of genetic therapies targeted to this area of the DMD gene.
患有杜氏肌营养不良症（DMD）的男孩存在 DMD 基因突变，导致抗肌萎缩蛋白缺失，以及进行性肌肉退化和无力。目前，皮质类固醇和姑息性支持是最佳治疗选择。最近批准的化合物，如依特司群和阿替洛尔，其长期疗效仍有待观察。患有天然发生的抗肌萎缩蛋白病的狗表现出类似于 DMD 的进行性疾病。因此，犬 DMD 模型对于发病机制和临床前治疗开发的研究很有用。一只缺乏抗肌萎缩蛋白的雄性边境牧羊犬，在 5 个月大时因进行性肌肉无力和吞咽困难而接受评估。
生化小组检测到血清肌酸激酶水平显著升高（41520U/L；正常范围 59-895U/L）。组织病理学变化具有抗肌萎缩蛋白病的特征。免疫荧光显微镜和 Western blot 显示骨骼肌中缺乏抗肌萎缩蛋白。全基因组测序、聚合酶链反应和 Sanger 测序显示，犬 DMD 外显子 20 位置 27626466 （c.2841delTmRNA）发生单核苷酸缺失，导致 6 个核苷酸下游出现终止密码子，这是一个移码突变。保存了精液以备将来进行系谱维持。
这种自发性犬抗肌萎缩蛋白病是由于 minor DMD 突变热点（外显子 2 到 20 之间）的一个新突变引起的。延续这个系谱可以允许针对 DMD 基因这一区域的基因治疗进行临床前测试。
Zotero 插件
