GAN

Inheritance Pattern: AR

Disease ID:MONDO:0009749

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009749

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0009749

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009749

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009749

Submitter: ClinGen

The GAN locus was first located to chromosome 16q24.1 by homozygosity mapping in three unrelated consanguineous Tunisian families with Giant axonal neuropathy in 1997 (PMID: 10732815, 1997). The locus was later refined to a smaller interval in 2000 (PMID: 10909853). Within the same year, Bomont and colleagues were able to identify the GAN gene (PMID: 11062483). GAN contains 11 exons and encodes a 597 aa protein that they named gigaxonin. Gigaxonin is a subunit of the E3 ubiquitin ligase, containing a BTB domain at its N-terminal and a Kelch domain at its C-terminal. It plays key roles in sustaining neuron survival and cytoskeleton architecture. Gigaxonin is a low abundance protein, ubiquitously expressed in human and murine tissues, although found to be enriched in the nervous system and during murine prenatal stages (PMID: 19168853, PMID: 11062483, PMID: 21486449). Giant axonal neuropathy (GAN) is a rare autosomal recessive neurodegenerative disease affecting both peripheral and central nervous system, first described in 1972 (PMID: 4339350, PMID: 21356581). A prominent pathological feature of GAN is the presence of giant axons densely packed with aberrant intermediate filaments (IFs) (PMID: 33192535). Classical form of GAN presents as severe peripheral motor and sensory neuropathy during infancy and evolves into central nervous system impairment including seizures, cerebellar signs, and cognitive impairment. Nerve conduction studies show normal to moderately reduced nerve conduction velocity (NCV), and severely reduced compound motor action potentials. Patients become wheel chair bound during the second decade with death by early adulthood. Milder forms with later onset and minor alterations of the CNS were also reported (PMID: 11062483). A total of 14 pathogenic homozygous and compound heterozygous variants were identified in 12 out of the 15 initial families tested (PMID: 11062483). To date, more than 80 variants distributed throughout the coding sequence, including missense, splice, truncating and structural variants, have been reported in patients with GAN (PMID: 33192535, PMID: 19231187, PMID: 21356581, PMID: 15897506, PMID: 12668605, PMID: 17578852). Some of these variants are enriched in particular populations, with possible founder effect in Turkey (c.1502+G>T) and Algeria (p.R477X). Inter- and intra-familial clinical heterogeneity reported in patients carrying the same variant (PMID: 19231187). More genetic evidence supporting this gene-disease relationship including case-level data and segregation data is available in the literature, but the maximum score (12 pts.) has been reached. There are three different GAN knockout mouse models generated to date (PMID: 21486449, PMID: 18680552, PMID: 16565160). They all have mild phenotype although the absence of gigaxonin had a striking impact on cytoskeletal architecture. Accumulation of intermediate filaments was also evidenced in a number of cellular models, including dorsal root ganglion (DRG) neurons from GAN KO mice (PMID: 27000625), GAN-deficient neuroblastoma cell lines (PMID: 31944090), patient induced pluripotent stem cells (iPSCs)-derived motor neurons (PMID: 25398950), among others. Furthermore, neurons from GAN KO mice exhibited inhibition of autophagosome synthesis, unveiling a fundamental role of gigaxonin in controlling the autophagy pathway. As KO mice do not mimic the axonal defects that are hallmarks of human GAN, recently generated zebrafish KO model stand out as the first robust animal model for GAN, reproducing both neuronal loss and loss of motility, as in GAN patients. Morphological, behavioral and cellular deficits were rescued by human gigaxonin (PMID: 31503551). In summary, GAN gene is DEFINITELY associated with autosomal recessive Giant axonal neuropathy (GAN). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.