This report describes Charcot-Marie-Tooth disease, type 2B (CMT2B), which is a subtype of Charcot-Marie-Tooth disease; CMT2B exhibits autosomal dominant inheritance. The human gene implicated in this disease is RAB7A, a member of the RAB family of RAS-related GTP-binding proteins and a regulator of endosomal-lysosomal trafficking. There is a single fly ortholog, Rab7, for which an amorphic allele gene has been created by targeted replacement of the CDS; RNAi-targeting constructs and alleles caused by insertional mutagenesis have also been generated.
Multiple different UAS constructs of the human Hsap\RAB7A gene have been introduced into flies, including wild-type RAB7A and genes carrying mutational lesions implicated in CMT2B. UAS-mutant alleles of Hsap\RAB7A produce locomotor-defective and other behavior-defective phenotypes. Heterologous rescue (functional complementation) has been demonstrated.
Variant(s) implicated in human disease tested (as transgenic human gene, RAB7A): the K157N and L129F variant forms of the human gene have been introduced into flies. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): K157N in the fly Rab7 gene (corresponds to K157N in the human RAB7A gene); L129F in the fly Rab7 gene (corresponds to L129F in the human RAB7A gene); N161T in the fly Rab7 gene (corresponds to N161T in the human RAB7A gene); V162M in the fly Rab7 gene (corresponds to V162M in the human RAB7A gene). [Seriously conserved gene...]
An amorphic allele of the fly Rab7 gene is a recessive lethal; heterozygous animals exhibit neuroanatomy-defective phenotypes. Rescue experiments using CMT2B-implicated variants (using variants in transgenic fly genes or transgenic human genes) are not consistent with a gain-of-function mechanism. Expression of CMT2B mutants at levels between 0.5 and 10-fold their endogenous levels fully rescue the Rab7 null mutant; this has implications for therapeutic approaches. Phenotypic assays using the fly gene have allowed characterization of genetic interactions. Physical interactions of the Dmel\Rab7 protein product have been described; see below and in the FlyBase gene report for Rab7.
[updated Apr. 2017 by FlyBase; FBrf0222196]
Charcot-Marie-Tooth disease (CMT) constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory peripheral neuropathies. CMT is divided into several major types: Type 1 is characterized by demyelination and by a significantly slowed motor median nerve conduction velocity (NCV). Type 2 is characterized by axonal abnormalities and a normal or slightly reduced NCV. "Intermediate" types describe CMT families with nerve conduction velocities, in different affected individuals, that overlap the division between Type 1 and Type 2. Additional types are defined on the basis inheritance patterns. [from MIM:609260 and MIM:606482; 2015.12.15]
Symptoms typically include progressive distal muscle weakness and atrophy, often associated with mild to moderate sensory loss, depressed tendon reflexes, and high-arched feet. [from Gene Reviews, http://www.ncbi.nlm.nih.gov/books/NBK1358 2015.12.15]
[CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B; CMT2B](https://omim.org/entry/600882)
[RAS-ASSOCIATED PROTEIN RAB7; RAB7](https://omim.org/entry/602298)
CMT2B is clinically characterized by severe symmetric distal sensory loss, reduced tendon reflexes at ankles, weakness in the lower limbs and muscle atrophy. Onset is typically in in adolescence or young adulthood (Bucci and De Luca, 2012; pubmed:23176482).
See description of different CMT classification types, above.
Four missense mutations in the RAB7A gene have been associated with CMT2B (Bucci and De Luca, 2012; pubmed:23176482).
CMT2B exhibits an autosomal dominant pattern of transmission; it has been shown to be caused by mutations in the RAB7A gene ("RAB7" in OMIM). [from MIM:600882, 2015.12.15]
RAB7A is a regulator of endosomal-lysosomal trafficking. It regulates early-to-late endosomal maturation, endosomal migration and positioning, and endosome-lysosome transport through different protein-protein interaction cascades. [from UniProt:P51149, 2015.12.15]
RAB7A is member of the RAB family of RAS-related GTP-binding proteins, which are regulators of vesicular transport; RAB7A has been localized to endosomes. [from MIM:602298, 2015.12.15]
One to one: 1 human to 1 Drosophila.
Ortholog of human RAB7A (1 Drosophila to 1 human). Dmel\Rab7 shares 76% identity and 88% similarity with human RAB7A; the two proteins are identical in length (207aa).
