1. Charcot-Marie-Tooth Type 2B: A New Phenotype Associated with a Novel RAB7A Mutation and Inhibited EGFR Degradation
- Author
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Veronica Nisi, Franco Taroni, Cecilia Bucci, Tiziana Cavallaro, Maria De Luca, Giuseppe Lauria, Stefania Magri, James M. Polke, Roberta Romano, Davide Pareyson, Raffaella Lombardi, Giuseppe Piscosquito, Mary M. Reilly, Paola Fossa, Chiara Pisciotta, Elena Cichero, Gian Maria Fabrizi, Paola Saveri, 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., and Bucci, C.
- Subjects
Proband ,Male ,Biopsy ,Charcot Marie Tooth disease type 2B ,Mutant ,Peripherins ,medicine.disease_cause ,Ligands ,Mice ,CMT2B ,Mutant protein ,Charcot-Marie-Tooth Disease ,RAB7 ,lcsh:QH301-705.5 ,Skin ,axon ,NGF ,Mutation ,Chronic axonal neuropathy ,medicine.diagnostic_test ,RAB7A ,Charcot–Marie–Tooth disease type 2B ,EGFR ,autophagy ,axons ,endocytosis ,lysosomes ,mutations ,neurite outgrowth ,peripheral sensory neuropathy ,Peripherin ,General Medicine ,Middle Aged ,Pedigree ,ErbB Receptors ,endocytosi ,Phenotype ,RAB7A, Charcot Marie Tooth disease type 2B, CMT2B, peripheral sensory neuropathy, NGF, RAB7, mutations, axons, lysosomes, autophagy, neurite outgrowth, endocytosis, EGFR ,lysosome ,Female ,Protein Binding ,Adult ,Adolescent ,Neuronal Outgrowth ,Biology ,Article ,Cell Line ,medicine ,Animals ,Humans ,Adaptor Proteins, Signal Transducing ,Nerve biopsy ,Base Sequence ,Laminopathies ,rab7 GTP-Binding Proteins ,Fibroblasts ,lcsh:Biology (General) ,rab GTP-Binding Proteins ,Proteolysis ,Cancer research ,Mutant Proteins ,mutation - 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.
- Published
- 2020