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

Cells. 2020 Apr 21;9(4):1028. doi: 10.3390/cells9041028.


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.

Keywords: CMT2B; Charcot–Marie–Tooth disease type 2B; EGFR; NGF; RAB7; RAB7A; autophagy; axons; endocytosis; lysosomes; mutations; neurite outgrowth; peripheral sensory neuropathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Adolescent
  • Adult
  • Animals
  • Base Sequence
  • Biopsy
  • Cell Line
  • Charcot-Marie-Tooth Disease / genetics*
  • ErbB Receptors / genetics
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Humans
  • Laminopathies / genetics*
  • Ligands
  • Male
  • Mice
  • Middle Aged
  • Mutant Proteins / metabolism
  • Mutation / genetics*
  • Neuronal Outgrowth
  • Pedigree
  • Peripherins / metabolism
  • Phenotype
  • Protein Binding
  • Proteolysis*
  • Skin / pathology
  • rab GTP-Binding Proteins / chemistry
  • rab GTP-Binding Proteins / genetics*
  • rab7 GTP-Binding Proteins


  • Adaptor Proteins, Signal Transducing
  • Ligands
  • Mutant Proteins
  • PRPH protein, human
  • Peripherins
  • RILP protein, human
  • rab7 GTP-Binding Proteins
  • rab7 GTP-binding proteins, human
  • rab7 GTP-binding proteins, mouse
  • EGFR protein, human
  • ErbB Receptors
  • rab GTP-Binding Proteins

Supplementary concepts

  • Charcot-Marie-Tooth disease, Type 2B