title: 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 disease. 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 axons. 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 astrocytes. Keratin IFs also seem to be alterated, as most patients present characteristic curly or kinky hairs. 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 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 that may represent a general pathological target for other neurodegenerative disorders with alterations in the neurofilament network.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, B.P. 163, 67404 Illkirch cedex, C.U. de Strasbourg, France.
authors.forename: P
authors.initials: P
authors.lastname: Bomont
authors.forename: L
authors.initials: L
authors.lastname: Cavalier
authors.forename: F
authors.initials: F
authors.lastname: Blondeau
authors.forename: C
authors.initials: C
authors.lastname: Ben Hamida
authors.forename: S
authors.initials: S
authors.lastname: Belal
authors.forename: M
authors.initials: M
authors.lastname: Tazir
authors.forename: E
authors.initials: E
authors.lastname: Demir
authors.forename: H
authors.initials: H
authors.lastname: Topaloglu
authors.forename: R
authors.initials: R
authors.lastname: Korinthenberg
authors.forename: B
authors.initials: B
authors.lastname: Tüysüz
authors.forename: P
authors.initials: P
authors.lastname: Landrieu
authors.forename: F
authors.initials: F
authors.lastname: Hentati
authors.forename: M
authors.initials: M
authors.lastname: Koenig
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000483:Alleles; D000595:Amino Acid Sequence; D001369:Axons / Q000473:pathology*; D002607:Charcot-Marie-Tooth Disease / Q000145:classification / Q000235:genetics; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics; D005091:Exons / Q000235:genetics; D016368:Frameshift Mutation; D018740:Genetic Heterogeneity; D005838:Genotype; D006197:Hair / Q000473:pathology*; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008969:Molecular Sequence Data; D005810:Multigene Family; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000473:pathology; D016900:Neurofilament Proteins / Q000172:deficiency / Q000235:genetics; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D020449:Repetitive Sequences, Amino Acid; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D013329:Structure-Activity Relationship
chemical_list: D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; C416508:GAN protein, human; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; C044882:neurofilament protein L