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首页> 外文期刊>Human mutation >Mutation spectrum in the large GTPase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy.
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Mutation spectrum in the large GTPase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy.

机译：大的GTPase dynamin 2中的突变谱和常染色体显性遗传性中心核肌病的基因型-表型相关性。

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摘要

Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype-phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot-Marie-Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT.
机译：中心核肌病（CNM）是一种遗传异质性疾病，与一般骨骼肌无力，I型纤维优势和萎缩以及异常集中的核相关。常染色体显性CNM是由于大型GTPase dynamin 2（DNM2）中的突变所致，DNG2是一种调节细胞骨架和细胞膜运输的机械化学酶。迄今为止，已经描述了40个具有CNM相关DNM2突变的家庭，在这里我们报告了另外60个家庭，涵盖了广泛的基因型和表型谱。总共在100个家庭中报告了18种不同的突变，我们的队列包含9个已知突变和4个新突变，包括第一个剪接位点突变。基因型与表型的相关假设来自已发表的数据和新数据，并为分子诊断提供了有效的筛选策略。除了CNM，异种DNM2突变还与Charcot-Marie-Tooth（CMT）周围神经病变（CMTD1B和CMT2M）相关，提示该突变具有组织特异性。在这项研究中，我们讨论了基于Dynamin 2的已知功能及其蛋白结构，CNM和CMT在临床上可能重叠，以及各个突变的生物学意义。由DNM2突变引起的膜运输缺陷可能代表了CNM和CMT中的常见病理机制。

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