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FB2026_02
,
released June 18, 2026
This report describes Charcot-Marie-Tooth disease, axonal, type 2KK, which is a subtype of Charcot-Marie-Tooth disease. The human gene implicated is ARHGAP19, which encodes Rho GTPase activating protein 19. There is one high-scoring fly ortholog, Dmel\RhoGAP54D, for which multiple genetic reagents, including classical alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
The human gene WDR45 has not been introduced into flies.
Ubiquitious RNAi knockdown of Dmel\RhoGAP54D results in a decrease in locomotor activity. Cell-type specific RNAi knockdown of Dmel\RhoGAP54D, including in postmitotic neurons, motor neurons, muscle cells, glial cells, or neuroblasts, does not result in significant decrease of locomotor activity. Flies bearing a homozygous null allele of Dmel\RhoGAP54D also exhibit a decrease in locomotor activity.
[updated Mar. 2026 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 2KK; CMT2KK](https://omim.org/entry/621466)
[RHO GTPase-ACTIVATING PROTEIN 19; ARHGAP19](https://omim.org/entry/611587)
Axonal Charcot-Marie-Tooth disease type 2KK (CMT2KK) is a slowly progressive autosomal recessive peripheral neuropathy with onset of symptoms usually in the first or second decades. The disorder predominantly affects motor nerves in the lower limbs, leading to gait difficulties with foot drop, increased falls, muscle atrophy of the lower limbs, and areflexia. Some patients may have upper limb involvement. Just over half of patients also have distal sensory impairment. Electrophysiologic studies indicate a neuropathic origin, and most have normal or mildly decreased nerve conduction velocities, consistent with type 2 axonal CMT, but some show decreased or intermediate nerve conduction velocity (NCV), suggesting a demyelinating process (Dominik et al., 2025, pubmed:41086021). [from MIM:621466; 2026.03.05]
Axonal Charcot-Marie-Tooth disease type 2KK (CMT2KK) is caused by homozygous mutation in the ARHGAP19 gene on chromosome 10q24. [from MIM:621466; 2026.03.05]
Members of the ARHGAP family, such as ARHGAP19, encode negative regulators of Rho GTPases, which are involved in cell migration, proliferation, and differentiation, actin remodeling, and G1 cell cycle progression (Lv et al., 2007, pubmed:17454002). [from MIM:611587; 2026.03.05]
One to one (1 human to 1 Drosophila); ARHGAP19 has one high-scoring Drosophila ortholog, RhoGAP54D.
High-scoring ortholog of human ARHGAP19 (1 Drosophila to 1 human).