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Charcot-Marie-Tooth Type 2B: A New Phenotype Associated with a Novel RAB7A Mutation and Inhibited EGFR Degradation

Authors :
Paola Saveri
Maria De Luca
Veronica Nisi
Chiara Pisciotta
Roberta Romano
Giuseppe Piscosquito
Mary M. Reilly
James M. Polke
Tiziana Cavallaro
Gian Maria Fabrizi
Paola Fossa
Elena Cichero
Raffaella Lombardi
Giuseppe Lauria
Stefania Magri
Franco Taroni
Davide Pareyson
Cecilia Bucci
Source :
Cells, Vol 9, Iss 4, p 1028 (2020)
Publication Year :
2020
Publisher :
MDPI AG, 2020.

Abstract

The rare autosomal dominant Charcot-Marie-Tooth type 2B (CMT2B) is associated with mutations in the RAB7A gene, involved in the late endocytic pathway. CMT2B is characterized by predominant sensory loss, ulceromutilating features, with lesser-to-absent motor deficits. We characterized clinically and genetically a family harboring a novel pathogenic RAB7A variant and performed structural and functional analysis of the mutant protein. A 39-year-old woman presented with early-onset walking difficulties, progressive distal muscle wasting and weakness in lower limbs and only mild sensory signs. Electrophysiology demonstrated an axonal sensorimotor neuropathy. Nerve biopsy showed a chronic axonal neuropathy with moderate loss of all caliber myelinated fibers. Next-generation sequencing (NGS) technology revealed in the proband and in her similarly affected father the novel c.377A>G (p.K126R) heterozygous variant predicted to be deleterious. The mutation affects the biochemical properties of RAB7 GTPase, causes altered interaction with peripherin, and inhibition of neurite outgrowth, as for previously reported CMT2B mutants. However, it also shows differences, particularly in the epidermal growth factor receptor degradation process. Altogether, our findings indicate that this RAB7A variant is pathogenic and widens the phenotypic spectrum of CMT2B to include predominantly motor CMT2. Alteration of the receptor degradation process might explain the different clinical presentations in this family.

Details

Language :
English
ISSN :
20734409
Volume :
9
Issue :
4
Database :
Directory of Open Access Journals
Journal :
Cells
Publication Type :
Academic Journal
Accession number :
edsdoj.40e8ec09c7a4d0ba4d9b2060ea96573
Document Type :
article
Full Text :
https://doi.org/10.3390/cells9041028