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.

中文翻译：

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与轻度杜氏肌营养不良相关的 DMD 中大的框内 5' 缺失：两个病例报告和文献综述


杜氏肌营养不良症是由编码肌营养不良蛋白的 DMD 基因突变引起的。虽然 Duchenne 最常见的原因是大的基因内缺失，导致移码和肌营养不良蛋白表达完全丧失，但 DMD 中的框内缺失可导致内部截短的肌营养不良蛋白表达，并可能与较温和的表型相关。在这项研究中，我们描述了两个具有大框内 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结构域。两名患者在儿童时期都患有进行性肌无力，但与典型的杜氏病相比，观察到其病程相对较轻。我们发现，在两名患者的肌肉活检中，截短的肌营养不良蛋白在肌膜处表达。我们还开发了一种患者特异性成纤维细胞衍生细胞模型，该模型可以诱导重编程形成肌管，很大程度上重现了外显子 3-23 缺失患者的活检结果，为未来研究这一不寻常病例提供了培养模型。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。