Journal article
A CADM3 variant causes Charcot-Marie-Tooth disease with marked upper limb involvement
Brain (London, England : 1878), Vol.144(4), pp.1197-1213
04/23/2021
DOI: 10.1093/brain/awab019
PMID: 33889941
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, as previously shown in mice. 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.
Details
- Title: Subtitle
- A CADM3 variant causes Charcot-Marie-Tooth disease with marked upper limb involvement
- Creators
- Adriana P Rebelo - Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USAAndrea Cortese - Department of Brain and Behavioral Sciences, University of Pavia, Pavia, ItalyAmit Abraham - Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, IsraelYael Eshed-Eisenbach - Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, IsraelGal Shner - Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, IsraelAnna Vainshtein - Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, IsraelElena Buglo - Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USAVladimir Camarena - Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USAGabriel Gaidosh - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, USARamin Shiekhattar - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, USALisa Abreu - Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USASteve Courel - Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USADennis K Burns - Department of Pathology, UT Southwestern Medical Center, Dallas, Texas, USAYunhong Bai - Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, IsraelChelsea Bacon - Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, USAShawna M E Feely - Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, USADiana Castro - Departments of Pediatrics, Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, USAElior Peles - Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, IsraelMary M Reilly - MRC Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UKMichael E Shy - Department of Pathology, UT Southwestern Medical Center, Dallas, Texas, USAStephan Zuchner - 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
- Resource Type
- Journal article
- Publication Details
- Brain (London, England : 1878), Vol.144(4), pp.1197-1213
- DOI
- 10.1093/brain/awab019
- PMID
- 33889941
- NLM abbreviation
- Brain
- eISSN
- 1460-2156
- Publisher
- England
- Grant note
- DOI: 10.13039/100000065, name: NINDS, award: U54NS065712, R01NS105755; name: NCATS-ORD; DOI: 10.13039/100004952, name: MDA; name: CMT-Association; name: Hereditary Neuropathy Foundation; name: The Genesis Project foundation; DOI: 10.13039/501100003977, name: Israel Science Foundation; name: Dr Miriam and Sheldon G. Adelson Medical Research Foundation; name: Hanna Hertz Professorial Chair for Multiple Sclerosis and Neuroscience; DOI: 10.13039/501100000265, name: Medical Research Council, award: MR/T001712/1; DOI: 10.13039/501100002803, name: Fondazione CARIPLO, award: 2019-1836; name: Italian Ministry of Health - Ricerca Corrente
- Language
- English
- Date published
- 04/23/2021
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Psychiatry; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9984072090702771
Metrics
38 Record Views