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

1
Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy
2
Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy
3
Functional Neuromotor Rehabilitation Unit, IRCCS ICS Maugeri Spa-SB, Scientific Institute of Telese Terme, 82037 Telese Terme (Benevento), Italy
4
MRC Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK
5
Department of Neurogenetics, The National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, London WC1N 3BG, UK
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Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy
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Department of Pharmacy, School of Medical and Pharmaceutical Sciences, University of Genova, 16132 Genova, Italy
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Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, 20157 Milan, Italy
9
Unit of Medical Genetics and Neurogenetics, Department of Diagnostics and Technology, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy
*
Authors to whom correspondence should be addressed.
Cells 2020, 9(4), 1028; https://doi.org/10.3390/cells9041028
Received: 24 March 2020 / Revised: 15 April 2020 / Accepted: 16 April 2020 / Published: 21 April 2020
(This article belongs to the Special Issue Neurotrophic Factors in Health and Disease)
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. View Full-Text
Keywords: RAB7A; Charcot–Marie–Tooth disease type 2B; CMT2B; peripheral sensory neuropathy; NGF; RAB7; mutations; axons; lysosomes; autophagy; neurite outgrowth; endocytosis; EGFR RAB7A; Charcot–Marie–Tooth disease type 2B; CMT2B; peripheral sensory neuropathy; NGF; RAB7; mutations; axons; lysosomes; autophagy; neurite outgrowth; endocytosis; EGFR
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Saveri, P.; De Luca, M.; Nisi, V.; Pisciotta, C.; Romano, R.; Piscosquito, G.; Reilly, M.M.; Polke, J.M.; Cavallaro, T.; Fabrizi, G.M.; Fossa, P.; Cichero, E.; Lombardi, R.; Lauria, G.; Magri, S.; Taroni, F.; Pareyson, D.; Bucci, C. Charcot-Marie-Tooth Type 2B: A New Phenotype Associated with a Novel RAB7A Mutation and Inhibited EGFR Degradation. Cells 2020, 9, 1028.

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