{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nGigaxonin, the protein product of the GAN gene, functions as a key adaptor for E3 ubiquitin ligase complexes that mediate the selective ubiquitination and subsequent proteasomal degradation of cytoskeletal proteins. In multiple studies, gigaxonin has been shown to bind via its Kelch domain to intermediate filament subunits—including vimentin, neurofilaments, and peripherin—as well as to microtubule‐associated proteins (for example, tubulin folding cofactor B), thereby ensuring proper turnover and dynamic organization of the cytoskeletal network. This regulated proteostasis is central to maintaining neuronal integrity, and loss‐of‐function mutations in gigaxonin lead to aberrant accumulation of these proteins, a hallmark of giant axonal neuropathy."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in proteostasis, gigaxonin is essential for proper intracellular transport and for modulating developmental signaling. Deficiency of gigaxonin has been linked to impaired kinesin‐1–mediated transport of intermediate filament assemblies along microtubules, which may further exacerbate cytoskeletal disorganization. Moreover, gigaxonin has been implicated in the regulation of the Sonic Hedgehog pathway through its control of Patched receptor degradation—a process critical for motor neuron specification, somitogenesis, neuromuscular junction formation, and ultimately coordinated locomotion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nComplementary genetic and clinical investigations reinforce the multifaceted role of gigaxonin in neural maintenance. Advanced genomic approaches—including exome sequencing, homozygosity mapping, and copy number variation screening—have revealed a broad spectrum of mutations in the GAN gene that correlate with the pathological accumulation of intermediate filaments and progressive neurodegeneration. Additional studies examining global gene expression further underscore the complexity of gigaxonin’s functions, while analyses in diverse patient cohorts and even in contexts where GAN variants are absent help to delineate the genotype–phenotype correlations underlying giant axonal neuropathy and related disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Wei Wang, Jianqing Ding, Elizabeth Allen, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Giant axonal neuropathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Mol Life Sci (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00018-007-6396-4"}], "href": "https://doi.org/10.1007/s00018-007-6396-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17256086"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17256086"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Henry Houlden, Mike Groves, Zosia Miedzybrodzka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "New mutations, genotype phenotype studies and manifesting carriers in giant axonal neuropathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurol Neurosurg Psychiatry (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/jnnp.2007.118968"}], "href": "https://doi.org/10.1136/jnnp.2007.118968"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17578852"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17578852"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Olga Koop, Anja Schirmacher, Eva Nelis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genotype-phenotype analysis in patients with giant axonal neuropathy (GAN)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuromuscul Disord (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.nmd.2007.03.012"}], "href": "https://doi.org/10.1016/j.nmd.2007.03.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17587580"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17587580"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "A Nalini, N Gayathri, T C Yasha, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clinical, pathological and molecular findings in two siblings with giant axonal neuropathy (GAN): report from India."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Med Genet (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ejmg.2008.05.006"}], "href": "https://doi.org/10.1016/j.ejmg.2008.05.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18595793"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18595793"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Don W Cleveland, Koji Yamanaka, Pascale Bomont "}, {"type": "b", "children": [{"type": "t", "text": "Gigaxonin controls vimentin organization through a tubulin chaperone-independent pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddp044"}], "href": "https://doi.org/10.1093/hmg/ddp044"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19168853"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19168853"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Saleemulla Mahammad, S N Prasanna Murthy, Alessandro Didonna, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Giant axonal neuropathy-associated gigaxonin mutations impair intermediate filament protein degradation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI66387"}], "href": "https://doi.org/10.1172/JCI66387"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23585478"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23585478"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Alexia Boizot, Yasmina Talmat-Amar, Deborah Morrogh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The instability of the BTB-KELCH protein Gigaxonin causes Giant Axonal Neuropathy and constitutes a new penetrant and specific diagnostic test."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Neuropathol Commun (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/2051-5960-2-47"}], "href": "https://doi.org/10.1186/2051-5960-2-47"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24758703"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24758703"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Bethany L Johnson-Kerner, Alejandro Garcia Diaz, Sean Ekins, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Kelch Domain of Gigaxonin Interacts with Intermediate Filament Proteins Affected in Giant Axonal Neuropathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0140157"}], "href": "https://doi.org/10.1371/journal.pone.0140157"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26460568"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26460568"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Bhuvanasundar Renganathan, James P Zewe, Yuan Cheng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gigaxonin is required for intermediate filament transport."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FASEB J (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1096/fj.202202119R"}], "href": "https://doi.org/10.1096/fj.202202119R"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37043392"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37043392"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "James J Kang, Isabelle Y Liu, Marilene B Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A review of gigaxonin mutations in giant axonal neuropathy (GAN) and cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Genet (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00439-016-1659-5"}], "href": "https://doi.org/10.1007/s00439-016-1659-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27023907"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27023907"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Yoan Arribat, Karolina S Mysiak, Léa Lescouzères, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sonic Hedgehog repression underlies gigaxonin mutation-induced motor deficits in giant axonal neuropathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI129788"}], "href": "https://doi.org/10.1172/JCI129788"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31503551"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31503551"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Conrad L Leung, Yinghua Pang, Chang Shu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Alterations in lipid metabolism gene expression and abnormal lipid accumulation in fibroblast explants from giant axonal neuropathy patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Genet (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2156-8-6"}], "href": "https://doi.org/10.1186/1471-2156-8-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17331252"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17331252"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Florence Dequen, Nigel J Cairns, Eileen H Bigio, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gigaxonin mutation analysis in patients with NIFID."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurobiol Aging (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neurobiolaging.2009.08.018"}], "href": "https://doi.org/10.1016/j.neurobiolaging.2009.08.018"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19782434"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19782434"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "M Abu-Rashid, M Mahajnah, L Jaber, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A novel mutation in the GAN gene causes an intermediate form of giant axonal neuropathy in an Arab-Israeli family."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Paediatr Neurol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ejpn.2012.10.012"}], "href": "https://doi.org/10.1016/j.ejpn.2012.10.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23332420"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23332420"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Faruk Incecik, Ozlem M Herguner, Serdar Ceylaner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Giant axonal disease: Report of eight cases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain Dev (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.braindev.2014.12.002"}], "href": "https://doi.org/10.1016/j.braindev.2014.12.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25533284"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25533284"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Daliya Kancheva, Derek Atkinson, Peter De Rijk, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Novel mutations in genes causing hereditary spastic paraplegia and Charcot-Marie-Tooth neuropathy identified by an optimized protocol for homozygosity mapping based on whole-exome sequencing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genet Med (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/gim.2015.139"}], "href": "https://doi.org/10.1038/gim.2015.139"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26492578"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26492578"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Sharon Aharoni, Katy E S Barwick, Rachel Straussberg, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Novel homozygous missense mutation in GAN associated with Charcot-Marie-Tooth disease type 2 in a large consanguineous family from Israel."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Med Genet (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12881-016-0343-x"}], "href": "https://doi.org/10.1186/s12881-016-0343-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27852232"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27852232"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Andoni Echaniz-Laguna, Jean-Marie Cuisset, Lucie Guyant-Marechal, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Giant axonal neuropathy: a multicenter retrospective study with genotypic spectrum expansion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurogenetics (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10048-019-00596-z"}], "href": "https://doi.org/10.1007/s10048-019-00596-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31655922"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31655922"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "J Mortreux, J Bacquet, A Boyer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of novel pathogenic copy number variations in Charcot-Marie-Tooth disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Hum Genet (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s10038-019-0710-5"}], "href": "https://doi.org/10.1038/s10038-019-0710-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31852984"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31852984"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Yaser Rafiq Mir, Xue Zeng, Atul K Taneja, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Giant axonal neuropathy with novel GAN pathogenic variant in a patient of consanguineous origin from Poonch Jammu and Kashmir-India."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Rep (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11033-021-06166-7"}], "href": "https://doi.org/10.1007/s11033-021-06166-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33528728"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33528728"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Xinying Zhang, Ya Guo, Wenxiu Sun "}, {"type": "b", "children": [{"type": "t", "text": "Two novel pathogenic mutations of GAN gene identified in a chinese family with giant axonal neuropathy: a case report."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Rep (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11033-022-07716-3"}], "href": "https://doi.org/10.1007/s11033-022-07716-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35764747"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35764747"}]}]}]}