Boso Federica, Taioli Federica, Cabrini Ilaria, Cavallaro Tiziana, Fabrizi Gian Maria
Department of Neurological Sciences, Biomedicine and Movement Sciences, University of Verona, Piazzale L.A. Scuro 10, 37134 Verona, Italy.
Department of Cellular, Computational and Integrative Biology, University of Trento, Via Sommarive 9, 38123 Povo (Trento), Italy.
Brain Sci. 2020 Dec 27;11(1):24. doi: 10.3390/brainsci11010024.
The second most common form of Charcot-Marie-Tooth disease (CMT) follows an X-linked dominant inheritance pattern (CMTX1), referring to mutations in the gap junction protein beta 1 gene () that affect connexin 32 protein (Cx32) and its ability to form gap junctions in the myelin sheath of peripheral nerves. Despite the advances of next-generation sequencing (NGS), attention has only recently also focused on noncoding regions. We describe two unrelated families with a c.-17+1G>T transversion in the 5' untranslated region (UTR) of that cosegregates with typical features of CMTX1. As suggested by in silico analysis, the mutation affects the regulatory sequence that controls the proper splicing of the intron in the corresponding mRNA. The retention of the intron is also associated with reduced levels of the transcript and the loss of immunofluorescent staining for Cx32 in the nerve biopsy, thus supporting the hypothesis of mRNA instability as a pathogenic mechanism in these families. Therefore, our report corroborates the role of 5' UTR of in the pathogenesis of CMTX1 and emphasizes the need to include this region in routine screening, as well as in NGS panels.
夏科-马里-图斯病（CMT）的第二常见形式遵循X连锁显性遗传模式（CMTX1），指的是缝隙连接蛋白β1基因（）发生突变，影响连接蛋白32（Cx32）及其在周围神经髓鞘中形成缝隙连接的能力。尽管下一代测序（NGS）技术取得了进展，但直到最近人们才将注意力集中在非编码区域。我们描述了两个不相关的家族，其缝隙连接蛋白β1基因的5'非翻译区（UTR）存在c.-17+1G>T颠换，该突变与CMTX1的典型特征共分离。计算机分析表明，该突变影响控制相应mRNA中内含子正确剪接的调控序列。内含子的保留还与转录本水平降低以及神经活检中Cx32免疫荧光染色缺失有关，从而支持了mRNA不稳定性作为这些家族致病机制的假说。因此，我们的报告证实了缝隙连接蛋白β1基因5'UTR在CMTX1发病机制中的作用，并强调在常规筛查以及NGS检测板中纳入该区域的必要性。
