Charcot-Marie-Tooth Type 2B: A New Phenotype Associated with a Novel RAB7A Mutation and Inhibited EGFR Degradation
| Autor: | 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 |
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| Přispěvatelé: | 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. |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
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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 |
| Zdroj: | Cells Cells, Vol 9, Iss 1028, p 1028 (2020) Volume 9 Issue 4 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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