Abstract
Disorganization of the neurofilament network is a prominent feature of several neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), infantile spinal muscular atrophy and axonal Charcot-Marie-Tooth disease1,2,3,4. Giant axonal neuropathy (GAN, MIM 256850), a severe, autosomal recessive sensorimotor neuropathy affecting both the peripheral nerves and the central nervous system, is characterized by neurofilament accumulation, leading to segmental distension of the axons5,6. GAN corresponds to a generalized disorganization of the cytoskeletal intermediate filaments (IFs), to which neurofilaments belong, as abnormal aggregation of multiple tissue-specific IFs has been reported: vimentin in endothelial cells, Schwann cells and cultured skin fibroblasts, and glial fibrillary acidic protein (GFAP) in astrocytes7,8,9,10,11. Keratin IFs also seem to be alterated, as most patients present characteristic curly or kinky hairs12. We report here identification of the gene GAN, which encodes a novel, ubiquitously expressed protein we have named gigaxonin. We found one frameshift, four nonsense and nine missense mutations in GAN of GAN patients. Gigaxonin is composed of an amino-terminal BTB (for Broad-Complex, Tramtrack and Bric a brac) domain followed by a six kelch repeats, which are predicted to adopt a β-propeller shape13. 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 that may represent a general pathological target for other neurodegenerative disorders with alterations in the neurofilament network.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Rouleau, G.A. et al. SOD1 mutation is associated with accumulation of neurofilaments in amyotrophic lateral sclerosis. Ann. Neurol. 39, 128–131 (1996).
Xu, Z., Cork, L.C., Griffin, J.W. & Cleveland, D.W. Involvement of neurofilaments in motor neuron disease. J. Cell Sci. Suppl. 17, 101–108 (1993).
Lupski, J.R. Axonal charcot-marie-tooth disease and the neurofilament light gene (NF-L) . Am. J. Hum. Genet. 67, 8– 10 (2000).
Mersiyanova, I.V. et al. A new variant of charcot-marie-tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene. Am. J. Hum. Genet. 67, 37–46 ( 2000).
Asbury, A.K., Gale, M.K., Cox, S.C., Baringer, J.R. & Berg, B.O. Giant axonal neuropathy: a unique case with segmental neurofilamentous masses. Acta Neuropathol. 20, 237–247 (1972).
Ben Hamida, M., Hentati, F. & Ben Hamida, C. Giant axonal neuropathy with inherited multisystem degeneration in a Tunisian kindred. Neurology 40, 245–250 (1990).
Prineas, J.W., Ouvrier, R.A., Wright, R.G., Walsh, J.C. & McLeod, J.G. Giant axonal neuropathy: a generalized disorder of cytoplasmic microfilament formation. J. Neuropathol. Exp. Neurol. 35, 458–470 (1976).
Pena, S.D. Giant axonal neuropathy: an inborn error of organization of intermediate filaments . Muscle Nerve 5, 166–172 (1982).
Kretzschmar, H.A., Berg, B.O. & Davis, R.L. Giant axonal neuropathy. A neuropathological study. Acta Neuropathol. 73, 138– 144 (1987).
Buissonniere, R.F., Routon, M.C., Robain, O., Ponsot, G. & Arthuis, M. Giant axonal neuropathy: intermediate filament disease with involvement of the peripheral and central nervous system . Rev. Neurol. 145, 355– 361 (1989).
Bousquet, O. et al. Aggregation of a subpopulation of vimentin filaments in cultured human skin fibroblasts derived from patients with giant axonal neuropathy . Cell. Motil. Cytoskeleton 33, 115– 129 (1996).
Treiber-Held, S. et al. Giant axonal neuropathy: a generalized disorder of intermediate filaments with longitudinal grooves in the hair. Neuropediatrics 25, 89–93 ( 1994).
Ito, N., Phillips, S.E., Yadav, K.D. & Knowles, P.F. Crystal structure of a free radical enzyme, galactose oxidase. J. Mol. Biol. 238, 794–814 (1994).
Ben Hamida, C. et al. Homozygosity mapping of giant axonal neuropathy gene to chromosome 16q24.1. Neurogenetics 1, 129– 133 (1997).
Cavalier, L. et al. Giant axonal neuropathy locus refinement to a <590 kb critical interval. Eur. J. Hum. Genet . 8, 527– 534 (2000).
Adams, J., Kelso, R. & Cooley, L. The kelch repeat superfamily of proteins: propellers of cell function. Trends Cell. Biol. 10, 17–24 (2000).
Bardwell, V.J. & Treisman, R. The POZ domain: a conserved protein-protein interaction motif. Genes Dev. 8, 1664–1677 (1994).
Zollman, S., Godt, D., Prive, G.G., Couderc, J.L. & Laski, F.A. The BTB domain, found primarily in zinc finger proteins, defines an evolutionarily conserved family that includes several developmentally regulated genes in Drosophila. Proc. Natl Acad. Sci. USA 91, 10717–10721 (1994).
Xue, F. & Cooley, L. kelch encodes a component of intercellular bridges in Drosophila egg chambers. Cell 72, 681–693 (1993).
Soltysik-Espanola, M. et al. Characterization of Mayven, a novel actin-binding protein predominantly expressed in brain. Mol. Biol. Cell 10 , 2361–2375 (1999).
Itoh, K. et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 13, 76–86 ( 1999).
Hernandez, M.C., Andres-Barquin, P.J., Holt, I. & Israel, M.A. Cloning of human ENC-1 and evaluation of its expression and regulation in nervous system tumors. Exp. Cell. Res. 242, 470–477 (1998).
Robinson, D.N. & Cooley, L. Drosophila kelch is an oligomeric ring canal actin organizer. J. Cell Biol. 138, 799–810 (1997).
Zemmouri, R. et al. Charcot-Marie-Tooth 2-like presentation of an Algerian family with giant axonal neuropathy. Neuromuscul. Disord. (in press).
Hernandez, M.C. et al. ENC-1: a novel mammalian kelch-related gene specifically expressed in the nervous system encodes an actin-binding protein. J. Neurosci. 17, 3038–3051 ( 1997).
von Bulow, M., Heid, H., Hess, H. & Franke, W.W. Molecular nature of calicin, a major basic protein of the mammalian sperm head cytoskeleton. Exp. Cell. Res. 219, 407–413 (1995).
Tu, P.H., Gurney, M.E., Julien, J.P., Lee, V.M. & Trojanowski, J.Q. Oxidative stress, mutant SOD1, and neurofilament pathology in transgenic mouse models of human motor neuron disease. Lab. Invest. 76, 441– 456 (1997).
Julien, J.P., Couillard-Despres, S. & Meier, J. Transgenic mice in the study of ALS: the role of neurofilaments . Brain Pathol. 8, 759– 769 (1998).
Couillard-Despres, S. et al. Protective effect of neurofilament heavy gene overexpression in motor neuron disease induced by mutant superoxide dismutase. Proc. Natl Acad. Sci. USA 95, 9626– 9630 (1998).
Acknowledgements
We thank J.-L. Mandel, M. Ben Hamida, C. Yalcinkaya, S. Nizard, R. Zemmouri, J. Mancini, B. Tüysüz, M. Claustres, P. Guicheney, J.M. Garnier, H. Puccio, D. Devys, O. Poch and D. Grid for discussions and sharing of patient material; and N. Lagarde, S. Vicaire, D. Sommer-Stephan, L. Reutenauer, O. Bennour, S. Ben Achour, S. Carles and common services for technical help. This work was supported by funds from the Institut National de la Recherche Médicale (INSERM); the Centre National de la Recherche Scientifique (CNRS) and the Hôpitaux Universitaires de Strasbourg (HUS); and the Secrétariat d'Etat à la Recherche Scientifique et à la Technologie Tunisienne (to C.B.H. and F.H.); and from the International Atomic Energy Agency (F.H.). P.B. was supported by a fellowship from the Association Française contre l'Ataxie de Friedreich (AFAF).
Author information
Authors and Affiliations
Corresponding author
Supplementary information
Rights and permissions
About this article
Cite this article
Bomont, P., Cavalier, L., Blondeau, F. et al. The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy. Nat Genet 26, 370–374 (2000). https://doi.org/10.1038/81701
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/81701
This article is cited by
-
Axonal Transport Defect in Gigaxonin Deficiency Rescued by Tubastatin A
Neurotherapeutics (2023)
-
Lnc-GAN1 expression is associated with good survival and suppresses tumor progression by sponging mir-26a-5p to activate PTEN signaling in non-small cell lung cancer
Journal of Experimental & Clinical Cancer Research (2021)
-
Sequencing of neurofilament genes identified NEFH Ser787Arg as a novel risk variant of sporadic amyotrophic lateral sclerosis in Chinese subjects
BMC Medical Genomics (2021)
-
Giant axonal neuropathy with novel GAN pathogenic variant in a patient of consanguineous origin from Poonch Jammu and Kashmir-India
Molecular Biology Reports (2021)
-
Identification of novel pathogenic copy number variations in Charcot-Marie-Tooth disease
Journal of Human Genetics (2020)