Canine models of Duchenne muscular dystrophy (DMD) are a valuable tool to evaluate potential therapies because they faithfully reproduce the human disease. Several cases of dystrophinopathies have been described in canines, but the Golden Retriever muscular dystrophy (GRMD) model remains the most used in preclinical studies. Here, we report a new spontaneous dystrophinopathy in a Labrador Retriever strain, named Labrador Retriever muscular dystrophy (LRMD). A colony of LRMD dogs was established from spontaneous cases. Fourteen LRMD dogs were followed-up and compared to the GRMD standard using several functional tests. The disease causing mutation was studied by several molecular techniques and identified using RNA-sequencing. The main clinical features of the GRMD disease were found in LRMD dogs; the functional tests provided data roughly overlapping with those measured in GRMD dogs, with similar inter-individual heterogeneity. The LRMD causal mutation was shown to be a 2.2-Mb inversion disrupting the DMD gene within intron 20 and involving the TMEM47 gene. In skeletal muscle, the Dp71 isoform was ectopically expressed, probably as a consequence of the mutation. We found no evidence of polymorphism in either of the two described modifier genes LTBP4 and Jagged1. No differences were found in Pitpna mRNA expression levels that would explain the inter-individual variability. This study provides a full comparative description of a new spontaneous canine model of dystrophinopathy, found to be phenotypically equivalent to the GRMD model. We report a novel large DNA mutation within the DMD gene and provide evidence that LRMD is a relevant model to pinpoint additional DMD modifier genes.

中文翻译：

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拉布拉多猎犬品系中的 X 连锁肌营养不良症：表型和分子特征。

Duchenne 肌营养不良症 (DMD) 的犬模型是评估潜在疗法的宝贵工具，因为它们忠实地再现了人类疾病。在犬科动物中已经描述了几例肌营养不良症，但金毛猎犬肌营养不良症 (GRMD) 模型仍然是临床前研究中最常用的模型。在这里，我们报告了拉布拉多猎犬品系中一种新的自发性肌营养不良症，称为拉布拉多猎犬肌营养不良症 (LRMD)。从自发病例中建立了 LRMD 犬群。对 14 只 LRMD 犬进行了随访，并使用多项功能测试与 GRMD 标准进行了比较。通过几种分子技术研究了引起突变的疾病，并使用 RNA 测序进行了鉴定。GRMD病的主要临床特征见于LRMD犬；功能测试提供的数据与 GRMD 犬的测量数据大致重叠，具有相似的个体间异质性。LRMD 因果突变被证明是一个 2.2-Mb 的倒位，它破坏了内含子 20 内的 DMD 基因并涉及 TMEM47 基因。在骨骼肌中，Dp71 亚型异位表达，可能是突变的结果。我们在两个描述的修饰基因 LTBP4 和 Jagged1 中都没有发现多态性的证据。Pitpna mRNA 表达水平没有发现可以解释个体间差异的差异。本研究提供了一种新的自发性肌营养不良症犬模型的完整比较描述，发现其表型等同于 GRMD 模型。