Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
Research Platform AgroVet-Strickhof, Vetsuisse Faculty, University of Zurich, Lindau, Switzerland.
Anim Genet. 2024 Dec;55(6):849-853. doi: 10.1111/age.13475. Epub 2024 Sep 22.
Muscular dystrophies represent a group of disorders characterized by progressive muscle degeneration and weakness. An important subgroup are the dystrophin-related muscular dystrophies caused by variants in the DMD gene. They can be divided into the more severe Duchenne muscular dystrophy and the milder Becker muscular dystrophy. Here, we characterize the clinical, histopathological and molecular genetic aspects of two male Entlebucher Mountain Dogs with clinical signs of muscular dystrophy. The two dogs presented with marked dysphagia starting at the age of several weeks and in the later course recognizable exercise intolerance with highly increased serum creatine kinase levels. Histopathological signs of a dystrophic myopathy represented by degeneration of muscle fibers and signs of regeneration were present. Whole genome sequencing of one affected dog identified an intragenic 8.6 kb duplication in the X-chromosomal DMD gene, c.7528-4048_7645 + 4450dup. No other protein-changing variants in candidate genes for muscular dystrophy were identified. The duplication includes exon 52 of DMD and is predicted to lead to a frameshift and truncation of 30% of the wild-type open reading frame. Genotyping of the whole family confirmed the presence of the mutant allele in both affected dogs and the unaffected dam. The correct co-segregation of the mutant allele in the affected family as well as knowledge from humans and other species suggest the identified DMD variant as the most likely candidate variant for the muscular dystrophy phenotype in the two investigated dogs.
肌肉萎缩症是一组以进行性肌肉退化和无力为特征的疾病。一个重要的亚组是由 DMD 基因突变引起的与 dystrophin 相关的肌肉萎缩症。它们可以分为更严重的杜氏肌营养不良症和较轻的贝克肌营养不良症。在这里，我们描述了两只具有肌肉萎缩症临床症状的雄性恩特雷布赫山地犬的临床、组织病理学和分子遗传学特征。这两只狗在几周大时开始出现明显的吞咽困难，在后期可识别出运动不耐受，血清肌酸激酶水平显著升高。存在肌纤维变性和再生迹象的肌营养不良症的组织病理学特征。对一只受影响的狗进行全基因组测序发现，X 染色体 DMD 基因内存在一个 8.6kb 的基因内重复，c.7528-4048_7645+4450dup。未在肌肉萎缩症候选基因中发现其他导致蛋白质改变的变异。该重复包括 DMD 的外显子 52，预计会导致野生型开放阅读框的 30%发生移码和截断。对整个家族的基因分型证实，两只受影响的狗和未受影响的母犬都携带突变等位基因。受影响家族中突变等位基因的正确共分离以及来自人类和其他物种的知识表明，所鉴定的 DMD 变体是这两只被研究犬肌肉萎缩表型的最可能候选变体。
