2. Academic Validation
  3. 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. 2021 May 7;144(4):1197-1213. doi: 10.1093/brain/awab019.
Adriana P Rebelo 1,  Andrea Cortese 2 3,  Amit Abraham 4,  Yael Eshed-Eisenbach 4,  Gal Shner 4,  Anna Vainshtein 4,  Elena Buglo 1,  Vladimir Camarena 1,  Gabriel Gaidosh 1 5,  Ramin Shiekhattar 1 5,  Lisa Abreu 1,  Steve Courel 1,  Dennis K Burns 6,  Yunhong Bai 7,  Chelsea Bacon 7,  Shawna M E Feely 7,  Diana Castro 8,  Elior Peles 4,  Mary M Reilly 2,  Michael E Shy 7,  Stephan Zuchner 1
Affiliations

Affiliations

  • 1 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.
  • 2 MRC Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
  • 3 Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
  • 4 Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
  • 5 Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, USA.
  • 6 Department of Pathology, UT Southwestern Medical Center, Dallas, Texas, USA.
  • 7 Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, USA.
  • 8 Departments of Pediatrics, Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, USA.
PMID: 33889941 DOI: 10.1093/brain/awab019
Abstract

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.

Keywords

CADM3; CMT; Charcot-Marie-Tooth disease; cell-adhesion molecule.

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