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FB2026_01
,
released March 12, 2026
This report describes Charcot-Marie-Tooth disease, RAB40B-related, a subtype of Charcot-Marie-Tooth disease type 2. Based on the pedigree of one family, this disease exhibits autosomal dominant inheritance. The human gene implicated is RAB40B, which encodes one of several members of an atypical subgroup of RAB proteins. There is one high-scoring fly ortholog, Dmel\Rab40, for which multiple genetic reagents, including amorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis, have been generated.
Multiple UAS constructs of the human Hsap\RAB40B gene, including wild-type Hsap\RAB40B and a gene carrying a nonsense variant associated with human disease, have been introduced into flies. See the 'Disease-Implicated Variants' table below.
Ubiquitous overexpression of either wild-type or variant Hsap\RAB40B is semi-lethal at larval or pupal stages. A majority of flies survive through adulthood, but have a reduced lifespan. Larval development is delayed; a similar delay is observed subsequent to RNAi-mediated knockdown of Dmel\Rab40.
Pan-glial expression of variant Hsap\RAB40B protein results in a progressive decline in locomotor ability. This decline is not observed with pan-neuronal, sensory neuron, or motor neuron-specific expression of variant Hsap\RAB40B (FBrf0258518).
[updated Mar. 2024 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]
Two individuals in a single family were affected with axonal peripheral neuropathy consistent with Charcot-Marie-Tooth disease type 2. (Son, et al., 2024, pubmed:8196136; FBrf0258518).
Charcot-Marie-Tooth disease, RAB40B-related shows an autosomal dominant inheritance pattern, and has been shown to be caused by a nonsense mutation in the RAB40B gene that results in a truncated protein (Son, et al., 2024, pubmed:8196136; FBrf0258518).
RAB40 proteins, consisting of four paralog members including RAB40B in humans, are an atypical subgroup of RAB proteins with unique structural and functional features. Besides the GTPase domain of the RAB family, RAB40 proteins are distinguished by an unusual domain of suppressor of cytokine signaling (SOCS) box in the C terminal part (Son, et al., 2024, and references therein; pubmed:8196136; FBrf0258518).
Many to one (many human to 1 Drosophila); RAB40B has one high-scoring Drosophila ortholog, Rab40.
High-scoring ortholog of human RAB40C and RAB40B; moderate-scoring ortholog of RAB40AL, RAB40A.