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

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

Brain : a journal of neurology (2021-04-24)
Adriana P Rebelo, Andrea Cortese, Amit Abraham, Yael Eshed-Eisenbach, Gal Shner, Anna Vainshtein, Elena Buglo, Vladimir Camarena, Gabriel Gaidosh, Ramin Shiekhattar, Lisa Abreu, Steve Courel, Dennis K Burns, Yunhong Bai, Chelsea Bacon, Shawna M E Feely, Diana Castro, Elior Peles, Mary M Reilly, Michael E Shy, Stephan Zuchner
摘要

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.

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Millipore
蛋白酶抑制剂混合物套装III,无EDTA, Protease inhibitor cocktail III, EDTA-free for inhibiting aspartic, cysteine, and serine proteases as well as aminopeptidases in mammalian cells and tissues.
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Anti-GAPDH,克隆6C5, clone 6C5, Chemicon®, from mouse
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Anti-Mouse IgG (whole molecule)−Agarose antibody produced in goat, affinity isolated antibody, suspension