A CADM3 variant causes Charcot-Marie-Tooth disease with marked upper limb involvement

AbstractThe 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 onede novo patient, with axonal Charcot-Marie-Tooth disease (CMT2) sharing the same private variant inCADM3, Tyr172Cys. This variant is absent in 230  000 control chromosomes from gnomAD and predicted to be pathogenic. MostCADM3 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 expressionin 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...
Source: Brain - Category: Neurology Source Type: research