Gene Summary
RefSeq / NCBIThis gene encodes a member of the cytoskeletal BTB/kelch (Broad-Complex, Tramtrack and Bric a brac) repeat family. The encoded protein plays a role in neurofilament architecture and is involved in mediating the ubiquitination and degradation of some proteins. Defects in this gene are a cause of giant axonal neuropathy (GAN). [provided by RefSeq, Oct 2008]
Clinical Phenotype
Giant axonal neuropathy (GAN): childhood-onset progressive mixed sensorimotor neuropathy with distinctive tightly-curled hair, often with central nervous system involvement (cerebellar, pyramidal, cognitive). Rare but genetically homogeneous.
Molecular Mechanism
Gigaxonin is an E3 ubiquitin ligase adaptor that targets intermediate filament proteins for degradation. Loss leads to accumulation of neurofilament and vimentin aggregates in axons, forming the giant axon expansions (axons packed with neurofilaments) that define the disease.
Clinical Hallmarks & Key Evidence
Tightly-curled, kinky hair is the pathognomonic clinical sign in GAN — present in nearly all patients regardless of ancestry, reflecting intermediate filament dysregulation in hair follicle cells.
Berg BO et al. Pediatrics. 1972;49(6):894-99.
Nerve biopsy shows focally enlarged axons stuffed with densely packed neurofilaments — the 'giant axon' — with preferential loss of large myelinated fibers.
Donaghy M et al. Brain. 1988;111(Pt 5):1187-1200.
An intrathecal AAV9 gene therapy trial (NCT02362438) showed preliminary evidence of slowing CNS progression in GAN — one of the first CNS-targeted gene therapies for a peripheral neuropathy.
Bharucha-Goebel DX et al. J Neuromuscul Dis. 2021;8(6):891-910.
External Resources
Gene data compiled from the Washington University Neuromuscular Disease Center, NCBI Gene, and OMIM. For clinical use, always refer to primary sources.