Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USA.
MRC Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
Brain. 2021 May 7;144(4):1197-1213. doi: 10.1093/brain/awab019.
The CADM family of proteins consists of four neuronal specific adhesion molecules (CADM1, CADM2, CADM3 and CADM4) that mediate the direct contact and interaction between axons and glia. In the peripheral nerve, axon-Schwann cell interaction is essential for the structural organization of myelinated fibres and is primarily mediated by the binding of CADM3, expressed in axons, to CADM4, expressed by myelinating Schwann cells. We have identified-by whole exome sequencing-three unrelated families, including one de novo patient, with axonal Charcot-Marie-Tooth disease (CMT2) sharing the same private variant in CADM3, Tyr172Cys. This variant is absent in 230 000 control chromosomes from gnomAD and predicted to be pathogenic. Most CADM3 patients share a similar phenotype consisting of autosomal dominant CMT2 with marked upper limb involvement. High resolution mass spectrometry analysis detected a newly created disulphide bond in the mutant CADM3 potentially modifying the native protein conformation. Our data support a retention of the mutant protein in the endoplasmic reticulum and reduced cell surface expression in vitro. Stochastic optical reconstruction microscopy imaging revealed decreased co-localization of the mutant with CADM4 at intercellular contact sites. Mice carrying the corresponding human mutation (Cadm3Y170C) showed reduced expression of the mutant protein in axons. Cadm3Y170C mice showed normal nerve conduction and myelin morphology, but exhibited abnormal axonal organization, including abnormal distribution of Kv1.2 channels and Caspr along myelinated axons. Our findings indicate the involvement of abnormal axon-glia interaction as a disease-causing mechanism in CMT patients with CADM3 mutations.
CADM 蛋白家族由四个神经元特异性粘附分子（CADM1、CADM2、CADM3 和 CADM4）组成，它们介导轴突和神经胶质之间的直接接触和相互作用。在周围神经中，轴突-施万细胞相互作用对于髓鞘纤维的结构组织至关重要，主要是通过轴突中表达的 CADM3 与施万细胞中表达的 CADM4 结合来介导的。我们通过全外显子组测序鉴定了三个不相关的家族，包括一个从头发生的患者，他们患有轴索型夏科-马里-图什病（CMT2），在 CADM3 中存在相同的私有变异，Tyr172Cys。该变体在 gnomAD 的 230000 个对照染色体中缺失，预测为致病性的。大多数 CADM3 患者具有相似的表型，包括常染色体显性遗传的 CMT2，上肢受累明显。高分辨率质谱分析检测到突变 CADM3 中存在新形成的二硫键，可能修饰了天然蛋白构象。我们的数据支持突变蛋白在内质网中的保留，并在体外减少细胞表面表达。随机光学重建显微镜成像显示，突变与 CADM4 在细胞间接触部位的共定位减少。携带相应人类突变（Cadm3Y170C）的小鼠在轴突中表现出突变蛋白表达减少。Cadm3Y170C 小鼠表现出正常的神经传导和髓鞘形态，但表现出异常的轴突组织，包括异常分布的 Kv1.2 通道和 Caspr 沿髓鞘轴突。我们的研究结果表明，CADM3 突变患者的异常轴突-神经胶质相互作用可能是一种致病机制。
