Corrado L, Magri S, Bagarotti A, Carecchio M, Piscosquito G, Pareyson D, Varrasi C, Vecchio D, Zonta A, Cantello R, Taroni F, D'Alfonso S
Human Genetics Laboratory, Department of Health Sciences, Amedeo Avogadro University, Via Solaroli 17, 28100 Novara, Italy; Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Amedeo Avogadro University, Novara, Italy.
Unit of Genetics of Neurodegenerative and Metabolic Disease, Fondazione IRCCS Istituto Neurologico Carlo Besta, via Celoria 11, 20133 Milano, Italy.
Neuromuscul Disord. 2016 Aug;26(8):516-20. doi: 10.1016/j.nmd.2016.05.011. Epub 2016 May 24.
Charcot-Marie-Tooth disease (CMT) is an inherited peripheral neuropathy with a heterogeneous genetic background. Here, we describe two CMT1B families with a mild sensory-motor neuropathy and a novel synonymous variant (c.309G > T, p.G103G) in exon 3 of the MPZ gene. Next generation sequencing analysis on a 94 CMT gene panel showed no mutations in other disease genes. In vitro splicing assay and mRNA expression analysis indicated that the c.309T variant enhances a cryptic donor splice site at position c.304 resulting in the markedly increased expression of the r.304_448del alternative transcript in patients' cells. This transcript is predicted to encode a truncated P0 protein (p.V102Cfs11*) lacking the transmembrane domain, thus suggesting a possible haploinsufficiency mechanism for this mutation. This is the third reported synonymous MPZ variant associated with CMT1 and affecting splicing. These data confirm the functional impact of synonymous variants on MPZ splicing and their possible role as disease-causing mutations rather than silent polymorphisms.
夏科-马里-图斯病（CMT）是一种具有异质性遗传背景的遗传性周围神经病。在此，我们描述了两个患有轻度感觉运动神经病的CMT1B家系，以及MPZ基因第3外显子中的一个新的同义变异（c.309G＞T，p.G103G）。对一个包含94个CMT基因的基因panel进行的二代测序分析显示，其他疾病基因中无突变。体外剪接试验和mRNA表达分析表明，c.309T变异增强了c.304位置的一个隐蔽供体剪接位点，导致患者细胞中r.304_448del替代转录本的表达显著增加。该转录本预计编码一种缺少跨膜结构域的截短型P0蛋白（p.V102Cfs11*），因此提示该突变可能存在单倍剂量不足机制。这是第三个报道的与CMT1相关且影响剪接的同义MPZ变异。这些数据证实了同义变异对MPZ剪接的功能影响及其作为致病突变而非沉默多态性的可能作用。
