KLHL16 (16q23.2), GAN, GAN1, gigaxoniini (gigantin aksonineuropatian proteiini))

https://www.ncbi.nlm.nih.gov/gene/8139

Also known as

GAN1; KLHL16

Summary

This 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]

Expression axonal nuropathy

Broad expression in skin (RPKM 5.8), esophagus (RPKM 2.0) and 23 other tissues See more

1. KLHL16 Degrades Epidermal Keratins. Büchau F, et al. J Invest Dermatol, 2018 Aug. PMID 29481904
2. Novel homozygous missense mutation in GAN associated with Charcot-Marie-Tooth disease type 2 in a large consanguineous family from Israel. Aharoni S, et al. BMC Med Genet, 2016 Nov 16. PMID 27852232, Free PMC Article
3. A review of gigaxonin mutations in giant axonal neuropathy (GAN) and cancer. Kang JJ, et al. Hum Genet, 2016 Jul. PMID 27023907
4. Giant axonal disease: Report of eight cases. Incecik F, et al. Brain Dev, 2015 Sep. PMID 25533284
5. The instability of the BTB-KELCH protein Gigaxonin causes Giant Axonal Neuropathy and constitutes a new penetrant and specific diagnostic test. Boizot A, et al. Acta Neuropathol Commun, 2014 Apr 24. PMID 24758703, Free PMC Article 

GeneRIFs: Gene References Into Functions

What's a GeneRIF?

1. Study data clearly show that upon overexpression, KLHL16 degrades several keratins including K6, K16, and K17, associated with wound healing, migration, and inflammation, states that are known to require extensive keratin remodeling.
2. Our protocol showed high specificity and sensitivity for homozygosity detection and facilitated the identification of novel mutations in GAN, GBA2, and ZFYVE26 in four families affected by hereditary spastic paraplegia or Charcot-Marie-Tooth disease
3. We believe that molecular and functional investigation of gigaxonin mutations including the exon 8 polymorphism could lead to an improved understanding of the relationship between GAN and cancer
4. A novel sequence alteration in the gene GAN, c.103G > T, was identified as most likely the underlying cause for a sensory-motor axonal neuropathy in a large consanguineous family presenting as Charcot-Marie-Tooth disease type 2.
5. a proteomic screen to identify the normal binding partners of GIG, is reported.
6. The disease is caused by GAN gene mutations on chromosome 16q24.1. To determine clinical and genetic results in Turkish patients with GAN.
7. This study showed that The instability of Gigaxonin causes Giant Axonal Neuropathy.
8. A novel missense mutation in four siblings born to consanguineous parents of Arab origin with clinical and molecular features compatible with giant axonal neuropathy.
9. gigaxonin is a major factor in the degradation of cytoskeletal intermediate filaments Giant axonal neuropathy (GAN) is an early-onset neurological disorder caused by mutations in the GAN gene (encoding for gigaxonin), which is predicted to be an E3 ligase adaptor. In GAN, aggregates of intermediate filaments (IFs) represent the main pathological feature detected in neurons and other cell types, including patients' dermal fibroblasts. The molecular mechanism by which these mutations cause IFs to aggregate is unknown. Using fibroblasts from patients and normal individuals, as well as Gan-/- mice, we demonstrated that gigaxonin was responsible for the degradation of vimentin IFs. Gigaxonin was similarly involved in the degradation of peripherin and neurofilament IF proteins in neurons. Furthermore, proteasome inhibition by MG-132 reversed the clearance of IF proteins in cells overexpressing gigaxonin, demonstrating the involvement of the proteasomal degradation pathway. Together, these findings identify gigaxonin as a major factor in the degradation of cytoskeletal IFs and provide an explanation for IF aggregate accumulation, the subcellular hallmark of this devastating human disease.
10. No GAN variant is identified in DNA obtained from well-characterized cases of human neuronal intermediate filament inclusion disease (frontotemporal dementia).