Neurology/Neurosurgery Service, Centre for Small Animal Studies, Animal Health Trust, Kentford, Newmarket, Suffolk, United Kingdom.
Department of Pathology, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
PLoS One. 2018 Feb 23;13(2):e0193372. doi: 10.1371/journal.pone.0193372. eCollection 2018.
Four full-sibling intact male Miniature Poodles were evaluated at 4-19 months of age. One was clinically normal and three were affected. All affected dogs were reluctant to exercise and had generalised muscle atrophy, a stiff gait and a markedly elevated serum creatine kinase activity. Two affected dogs also showed poor development, learning difficulties and episodes of abnormal behaviour. In these two dogs, investigations into forebrain structural and metabolic diseases were unremarkable; electromyography demonstrated fibrillation potentials and complex repetitive discharges in the infraspinatus, supraspinatus and epaxial muscles. Histopathological, immunohistochemical and immunoblotting analyses of muscle biopsies were consistent with dystrophin-deficient muscular dystrophy. DNA samples were obtained from all four full-sibling male Poodles, a healthy female littermate and the dam, which was clinically normal. Whole genome sequencing of one affected dog revealed a >5 Mb deletion on the X chromosome, encompassing the entire DMD gene. The exact deletion breakpoints could not be experimentally ascertained, but we confirmed that this region was deleted in all affected males, but not in the unaffected dogs. Quantitative polymerase chain reaction confirmed all three affected males were hemizygous for the mutant X chromosome, while the wildtype chromosome was observed in the unaffected male littermate. The female littermate and the dam were both heterozygous for the mutant chromosome. Forty-four Miniature Poodles from the general population were screened for the mutation and were homozygous for the wildtype chromosome. The finding represents a naturally-occurring mutation causing dystrophin-deficient muscular dystrophy in the dog.
四只同窝全雄性迷你贵宾犬在 4-19 月龄时接受评估。其中一只临床正常，三只发病。所有发病犬均不愿运动，且出现全身性肌肉萎缩、僵硬步态和明显升高的血清肌酸激酶活性。两只发病犬还表现出发育不良、学习困难和异常行为发作。在这两只犬中，对大脑前脑结构和代谢疾病的调查无明显异常；肌电图显示三角肌、冈上肌和竖脊肌出现纤颤电位和复杂重复放电。肌肉活检的组织病理学、免疫组织化学和免疫印迹分析与肌营养不良症一致。从四只同窝全雄性贵宾犬、一只健康的雌性同窝犬和临床正常的母犬中获取 DNA 样本。一只发病犬的全基因组测序显示 X 染色体上存在 >5 Mb 的缺失，包含整个 DMD 基因。确切的缺失断点无法通过实验确定，但我们证实该区域在所有发病雄性犬中缺失，但在未受影响的犬中未缺失。定量聚合酶链反应证实所有三只发病雄性犬均为突变 X 染色体的半合子，而未受影响的雄性同窝犬观察到野生型染色体。同窝的雌性犬和母犬均为突变染色体的杂合子。从普通人群中筛选了 44 只迷你贵宾犬，发现它们均为野生型染色体的纯合子。该发现代表了一种在犬中引起肌营养不良症的自然发生突变。
