Alternative titles; symbols
HGNC Approved Gene Symbol: GAN
Cytogenetic location: 16q23.2 Genomic coordinates (GRCh38) : 16:81,314,962-81,390,809 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q23.2 | Giant axonal neuropathy-1 | 256850 | Autosomal recessive | 3 |
GAN is an E3 ubiquitin ligase that positively controls SHH (600725) induction by controlling degradation of SHH-bound PTCH (PTCH1; 601309) (Arribat et al., 2019).
Using a positional cloning approach in the critical region defined for giant axonal neuropathy (GAN; 256850) on chromosome 16q24, Bomont et al. (2000) isolated a novel, ubiquitously expressed gene (GAN) encoding a protein that they named gigaxonin. Gigaxonin contains an N-terminal BTB (broad-complex, tramtrack, and bric-a-brac) domain followed by 6 kelch repeats, which were predicted to adopt a beta-propeller shape. Distantly related proteins sharing a similar domain organization have various functions associated with the cytoskeleton, predicting that gigaxonin is a novel and distinct cytoskeletal protein.
Arribat et al. (2019) cloned zebrafish gan, which encodes a 609-amino acid protein with an N-terminal BTB domain and a C-terminal 6-Kelch repeat domain. Zebrafish gan shares 78% amino acid identity with its human ortholog. In situ hybridization and RT-PCR analyses showed ubiquitous and constant expression of zebrafish gan from early embryogenesis through juvenile/adult stages, with enrichment in eye, notochord, muscle, and heart.
Gross (2014) mapped the GAN gene to chromosome 16q23.2 based on an alignment of the GAN sequence (GenBank BC044840) with the genomic sequence (GRCh37).
Bomont and Koenig (2003) showed that vimentin (VIM; 193060) aggregation in primary fibroblasts from patients with giant axonal neuropathy demonstrated great variation on prolonged culture at confluence and in low serum conditions. While neither the microfilament nor the microtubule networks were perturbed by vimentin destabilization, the aggregates were in close proximity to the microtubule organizing centers. Microtubule depolymerization induced a total vimentin aggregation in GAN fibroblasts. Bomont and Koenig (2003) proposed that gigaxonin may play an important role in the crosstalk between the cytoplasmic intermediate filament and microtubule networks.
Allen et al. (2005) showed that gigaxonin controls protein degradation and is essential for neuronal function and survival. They presented evidence that gigaxonin binds to the ubiquitin-activating enzyme E1 (314370) through its amino-terminal BTB domain, while the carboxy-terminal kelch repeat domain interacts directly with the light chain (LC) of microtubule-associated protein-1B (MAP1B; 157129). Overexpression of gigaxonin leads to enhanced degradation of MAP1B-LC, which could be antagonized by proteasome inhibitors. Ablation of gigaxonin caused a substantial accumulation of MAP1B-LC in GAN-null neurons. Moreover, Allen et al. (2005) showed that overexpression of MAP1B in wildtype cortical neurons led to cell death characteristic of GAN-null neurons, whereas reducing MAP1B levels significantly improved the survival rate of null neurons. Allen et al. (2005) concluded that their results identified gigaxonin as a ubiquitin scaffolding protein that controls MAP1B-light chain degradation and provided insight into the molecular mechanisms underlying human neurodegenerative disorders.
Giant axonal neuropathy, a severe autosomal recessive sensorineural neuropathy affecting both the peripheral nerves and the central nervous system, is characterized by neurofilament accumulation, leading to segmental distention of axons. The neuropathy is part of a generalized disorganization of the cytoskeletal intermediate filaments (IFs), to which neurofilaments belong, as abnormal aggregation of multiple tissue-specific IFs has been reported in this disorder. In patients with giant axonal neuropathy, Bomont et al. (2000) identified missense, nonsense, and frameshift mutations in the GAN gene (see, e.g., 605379.0001-605379.0003). Bomont et al. (2000) suggested that GAN may represent a general pathologic target for other neurodegenerative disorders with alterations in the neurofilament network.
Arribat et al. (2019) found that gan controlled differentiation of secondary motor neurons and axonal pathfinding of primary motor neurons in spinal cord and promoted muscle innervation and somitogenesis in zebrafish. Similar to shh repression, gan depletion in zebrafish caused severe morphologic abnormalities with impaired motility, and gan deletion recapitulated this phenotype. Shh activation restored both neuronal and muscle development deficits in gan-depleted zebrafish. In human, mouse, and zebrafish systems, SHH signaling failed to activate properly in the absence of GAN, demonstrating that GAN functions as a positive regulator of the SHH pathway. Further analysis in mouse cells demonstrated that Gan acted positively on the Shh pathway through interaction with Ptch and targeting Ptch for degradation in an Shh-dependent manner.
Bomont et al. (2000) found a glu486-to-lys (E486K) mutation of the GAN gene associated with giant axonal neuropathy (GAN1; 256850) in a Tunisian and a northern French family. They concluded that these corresponded to distinct mutational events because the mutation affected a CpG dinucleotide (CG to CA) and the associated haplotypes were different.
Bomont et al. (2000) found that affected members of a family with giant axonal neuropathy (GAN1; 256850) were homozygous for a nonsense mutation (gln483 to ter; Q483X) in the GAN gene.
Bomont et al. (2000) found that affected members of a family with giant axonal neuropathy (GAN1; 256850) were homozygous for a frameshift (18insA) mutation in the GAN gene.
In a young patient with giant axonal neuropathy (GAN1; 256850) diagnosed clinically by characteristic features of peripheral and central nervous system abnormalities and hair findings, Kuhlenbaumer et al. (2002) identified compound heterozygosity for mutations in the GAN gene: a 601C-T mutation resulting in an arg201-to-ter (R201X) substitution and a 1238C-T mutation in exon 8 resulting in an ile423-to-thr (I423T; 605379.0005) substitution. The patient's asymptomatic father was heterozygous for the R201X mutation, and his asymptomatic mother was heterozygous for the I423T mutation.
For discussion of the ile423-to-thr (I423T) mutation in the GAN gene that was found in compound heterozygous state in a patient with giant axonal neuropathy (GAN1; 256850) by Kuhlenbaumer et al. (2002), see 605379.0004.
In affected members of a consanguineous Algerian family with giant axonal neuropathy (GAN1; 256850) described by Zemmouri et al. (2000), Bomont et al. (2000) identified a homozygous 413G-A transition in exon 3 of the GAN gene, resulting in an arg138-to-his (R138H) substitution. None of the patients had hair abnormalities.
In affected members of a consanguineous Tunisian family with giant axonal neuropathy (GAN1; 256850) described by Ben Hamida et al. (1990), Bomont et al. (2000) identified a homozygous 43C-A transversion in exon 1 of the GAN gene, resulting in an arg15-to-ser (R15S) substitution in the BTB domain of the protein. The clinical presentation in this family was slightly unusual in that there were no hair abnormalities and the proband had a severe sensorimotor neuropathy.
In affected members of 4 unrelated consanguineous Algerian families with giant axonal neuropathy (GAN1; 256850), Tazir et al. (2009) identified a homozygous 1429C-T transition in exon 9 of the GAN gene, resulting in an arg477-to-ter (R477X) substitution in the C terminus in 1 of the Kelch domains. The phenotype was variable. Patients from 2 families had the classic phenotype with kinky red hair, cerebellar ataxia, and peripheral motor and sensory neuropathy. A patient from another family had frizzy hair, spastic paraparesis with Babinski sign, facial diplegia, and minor clinical signs of neuropathy and cerebellar ataxia. The patient from the fourth family had a congenital neuropathy with mental retardation and a rapid and severe progression, but without abnormal hair.
In a boy, born of consanguineous Algerian parents, with giant axonal neuropathy (GAN1; 256850), Tazir et al. (2009) identified a homozygous 505G-A transition in exon 3 of the GAN gene, resulting in a glu169-to-lys (E169K) substitution in an interdomain region between the BTB and Kelch domains. The boy had onset at age 3 years of weakness of the face and distal and proximal limbs. He also had short stature, foot and hand deformities, scoliosis, and sensory impairment. Mental retardation, spasticity, and kinky hair were not observed.
Allen, E., Ding, J., Wang, W., Pramanik, S., Chou, J., Yau, V., Yang, Y. Gigaxonin-controlled degradation of MAP1B light chain is critical to neuronal survival. Nature 438: 224-228, 2005. [PubMed: 16227972] [Full Text: https://doi.org/10.1038/nature04256]
Arribat, Y., Mysiak, K. S., Lescouzeres, L., Boizot, A., Ruiz, M., Rossel, M., Bomont, P. Sonic Hedgehog repression underlies gigaxonin mutation-induced motor deficits in giant axonal neuropathy. J. Clin. Invest. 129: 5312-5326, 2019. [PubMed: 31503551] [Full Text: https://doi.org/10.1172/JCI129788]
Ben Hamida, M., Hentati, F., Ben Hamida, C. Giant axonal neuropathy with inherited multisystem degeneration in a Tunisian kindred. Neurology 40: 245-250, 1990. [PubMed: 2153943] [Full Text: https://doi.org/10.1212/wnl.40.2.245]
Bomont, P., Cavalier, L., Blondeau, F., Ben Hamida, C., Belal, S., Tazir, M., Demir, E., Topaloglu, H., Korinthenberg, R., Tuysuz, B., Landrieu, P., Hentati, F., Koenig, M. The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy. Nature Genet. 26: 370-374, 2000. [PubMed: 11062483] [Full Text: https://doi.org/10.1038/81701]
Bomont, P., Koenig, M. Intermediate filament aggregation in fibroblasts of giant axonal neuropathy patients is aggravated in non dividing cells and by microtubule destabilization. Hum. Molec. Genet. 12: 813-822, 2003. [PubMed: 12668605] [Full Text: https://doi.org/10.1093/hmg/ddg092]
Gross, M. B. Personal Communication. Baltimore, Md. 6/6/2014.
Kuhlenbaumer, G., Young, P., Oberwittler, C., Hunermund, G., Schirmacher, A., Domschke, K., Ringelstein, B., Stogbauer, F. Giant axonal neuropathy (GAN): case report and two novel mutations in the gigaxonin gene. Neurology 58: 1273-1276, 2002. Note: Erratum: Neurology 58: 1444, 2002. [PubMed: 11971098] [Full Text: https://doi.org/10.1212/wnl.58.8.1273]
Tazir, M., Nouioua, S., Magy, L., Huehne, K., Assami, S., Urtizberea, A., Grid, D., Hamadouche, T., Rautenstrauss, B., Vallat, J.-M. Phenotypic variability in giant axonal neuropathy. Neuromusc. Disord. 19: 270-274, 2009. [PubMed: 19231187] [Full Text: https://doi.org/10.1016/j.nmd.2009.01.011]
Zemmouri, R., Azzedine, H., Assami, S., Kitouni, N., Vallat, J. M., Maisonobe, T., Hamadouche, T., Kessaci, M., Mansouri, B., Le Guern, E., Grid, D., Tazir, M. Charcot-Marie-Tooth 2-like presentation of an Algerian family with giant axonal neuropathy. Neuromusc. Disord. 10: 592-598, 2000. [PubMed: 11053687] [Full Text: https://doi.org/10.1016/s0960-8966(00)00141-3]