Shelton G Diane, Rider Branden E, Child Georgina, Tzannes Sophia, Guo Ling T, Moghadaszadeh Behzad, Troiano Emily C, Haase Bianca, Wade Claire M, Beggs Alan H
Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA USA.
Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave., Boston, MA 02115 USA.
Skelet Muscle. 2015 Jan 27;5(1):1. doi: 10.1186/s13395-014-0025-3. eCollection 2015.
Congenital and inherited myopathies in dogs are faithful models of human muscle diseases and are being recognized with increasing frequency. In fact, canine models of dystrophin deficient muscular dystrophy and X-linked myotubular myopathy are of tremendous value in the translation of new and promising therapies for the treatment of these diseases. We have recently identified a family of Australian Rottweilers in which male puppies were clinically affected with severe muscle weakness and atrophy that resulted in early euthanasia or death. X-linked myotubular myopathy was suspected based on the early and severe clinical presentation and histopathological changes within muscle biopsies. The aim of this study was to determine the genetic basis for myopathy in these dogs and compare and contrast the clinical presentation, histopathology, ultrastructure, and mutation in this family of Rottweiler dogs with the previously described myotubular myopathy in Labrador retrievers.
Histopathology, histochemistry, and ultrastructural examination of muscle biopsies from affected Rottweiler puppies were consistent with an X-linked myotubular myopathy. An unusual finding that differed from the previously reported Labradors and similar human cases was the presence of excessive autophagy and prominent autophagic vacuoles. Molecular investigations confirmed a missense mutation in exon 11 of MTM1 that was predicted to result in a non-functional phosphatase activity. Although the clinical presentations and histopathology were similar, the MTM1 p.(Q384P) mutation is different from the p.(N155K) mutation in exon 7 affecting Labrador retrievers with X-linked myotubular myopathy.
Here we describe a second pathogenic mutation in MTM1 causing X-linked myotubular myopathy in dogs. Our findings suggest a variety of MTM1 mutations in dogs as seen in human patients. The number of MTM1 mutations resulting in similar severe and progressive clinical myopathy and histopathological changes are likely to increase as canine myopathies are further characterized.
犬类先天性和遗传性肌病是人类肌肉疾病的可靠模型，且其被识别的频率越来越高。事实上，抗肌萎缩蛋白缺乏型肌营养不良症和X连锁肌管性肌病的犬类模型对于这些疾病新的、有前景的治疗方法的转化具有巨大价值。我们最近鉴定出一个澳大利亚罗威纳犬家族，其中雄性幼犬临床上表现为严重的肌肉无力和萎缩，导致早期实施安乐死或死亡。基于早期严重的临床表现以及肌肉活检的组织病理学变化，怀疑为X连锁肌管性肌病。本研究的目的是确定这些犬类肌病的遗传基础，并将该罗威纳犬家族的临床表现、组织病理学、超微结构及突变与先前描述的拉布拉多犬的肌管性肌病进行比较和对比。
对受影响的罗威纳幼犬的肌肉活检进行组织病理学、组织化学和超微结构检查，结果与X连锁肌管性肌病一致。与先前报道的拉布拉多犬及类似人类病例不同的一个异常发现是存在过度自噬和明显的自噬空泡。分子研究证实MTM1基因第11外显子存在一个错义突变，预计该突变会导致磷酸酶活性丧失功能。尽管临床表现和组织病理学相似，但MTM1基因的p.(Q384P)突变与影响拉布拉多犬X连锁肌管性肌病的第7外显子p.(N155K)突变不同。
在此我们描述了MTM1基因中导致犬类X连锁肌管性肌病的第二个致病突变。我们的研究结果表明，犬类中存在多种MTM1突变，如同在人类患者中所见。随着犬类肌病的进一步特征化，导致类似严重进行性临床肌病和组织病理学变化的MTM1突变数量可能会增加。
