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The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy

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.

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Figure 1: Physical map of the GAN region in 16q24.1 and genomic structure of GAN.
Figure 2: Expression of the mouse Gan homologue in different tissues.
Figure 3: Gigaxonin sequence.
Figure 4: GAN family studies a, Allele segregation of 16q24.1 markers in GAN families.

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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).

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Correspondence to Michel Koenig.

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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

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