FGD4

Chr 12

FYVE, RhoGEF and PH domain containing 4

Also known as: CMT4H, FRABP, ZFYVE6

NCBI Gene: 121512 ENSG00000139132 UniProt: Q96M96

The protein regulates actin cytoskeleton organization and activates CDC42 through GDP-GTP exchange, forming microspikes that control cell shape and enabling cellular processes including pathogen invasion. Mutations cause Charcot-Marie-Tooth disease type 4H (CMT4H), a peripheral neuropathy inherited in an autosomal recessive pattern. The pathogenic mechanism appears to involve gain-of-function effects that disrupt normal cytoskeletal regulation.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a protein that is involved in the regulation of the actin cytoskeleton and cell shape. This protein contains an actin filament-binding domain, which together with its Dbl homology domain and one of its pleckstrin homology domains, can form microspikes. This protein can activate MAPK8 independently of the actin filament-binding domain, and it is also involved in the activation of CDC42 via the exchange of bound GDP for free GTP. The activation of CDC42 also enables this protein to play a role in mediating the cellular invasion of Cryptosporidium parvum, an intracellular parasite that infects the gastrointestinal tract. Mutations in this gene can cause Charcot-Marie-Tooth disease type 4H (CMT4H), a disorder of the peripheral nervous system. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2015]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtCharcot-Marie-Tooth disease, demyelinating, type 4H

Clinical highlights

Gene-disease validity (ClinGen)

Charcot-Marie-Tooth disease · ARDefinitivesufficient evidence for diagnostic panels

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.46

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — FGD4