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Abstract：
Duchenne muscular dystrophy is caused by mutations in the dystrophin-encoding DMD gene. While Duchenne is most commonly caused by large intragenic deletions that cause frameshift and complete loss of dystrophin expression, in-frame deletions in DMD can result in the expression of internally truncated dystrophin proteins and may be associated with a milder phenotype. In this study, we describe two individuals with large in-frame 5\' deletions (exon 3-23 and exon 3-28) that remove the majority of the N-terminal region, including part of the actin binding and central rod domains. Both patients had progressive muscle weakness during childhood but are observed to have a relatively mild disease course compared to typical Duchenne. We show that in muscle biopsies from both patients, truncated dystrophin is expressed at the sarcolemma. We have additionally developed a patient-specific fibroblast-derived cell model, which can be inducibly reprogrammed to form myotubes that largely recapitulate biopsy findings for the patient with the exon 3-23 deletion, providing a culture model for future investigation of this unusual case. We discuss these mutations in the context of previously reported 5\' in-frame DMD deletions and relevant animal models, and review the spectrum of phenotypes associated with these deletions.
摘要：
Duchenne肌营养不良是由编码肌营养不良蛋白的DMD基因突变引起的。虽然Duchenne最常见的原因是基因内的大量缺失，导致肌萎缩蛋白表达的移码和完全丧失，DMD中的框内缺失可导致内部截短的肌营养不良蛋白的表达，并且可能与较温和的表型有关。在这项研究中,我们描述了两个具有大的框内5'缺失（外显子3-23和外显子3-28）的个体，这些缺失删除了大部分N末端区域，包括部分肌动蛋白结合和中央杆域。两名患者在儿童期都有进行性肌无力，但与典型的Duchenne相比，病程相对较轻。我们表明，在两名患者的肌肉活检中，截短的肌营养不良蛋白在肌膜上表达。我们还开发了一种患者特异性成纤维细胞来源的细胞模型，它可以被诱导地重新编程以形成肌管，这在很大程度上重现了外显子3-23缺失患者的活检结果，为未来对这一不寻常案件的调查提供了一种文化模式。我们在先前报道的5'框内DMD缺失和相关动物模型的背景下讨论这些突变，并回顾与这些缺失相关的表型谱。
