Titre du document / Document title

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

Auteur(s) / Author(s)

BOMONT Pascale ⁽¹⁾ ; CAVALIER Laurent ⁽²⁾ ; BLONDEAU Francois ⁽¹⁾ ; BEN HAMIDA Christiane ⁽³⁾ ; BELAL Samir ⁽³⁾ ; TAZIR Meriem ⁽⁴⁾ ; DEMIR Ercan ⁽⁵⁾ ; TOPALOGLU Haluk ⁽⁵⁾ ; KORINTHENBERG Rudolf ⁽⁶⁾ ; TÜYSÜZ Beyhan ⁽⁷⁾ ; LANDRIEU Pierre ⁽⁸⁾ ; HENTATI Faycal ⁽³⁾ ; KOENIG Michel ⁽¹⁾ ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, B.P. 163, C.U. de Strasbourg, 67404 Illkirch, FRANCE
⁽²⁾ Laboratoire de Génétique Moléculaire et Chromosonique, Institut de Génétique Humaine, Institut de Biologie, Montpellier, FRANCE
⁽³⁾ Laboratoire de Neuropathologie et neurobiologie Moléculaire, Institut National de Neurologie, La Rabta, Tunis, TUNISIE
⁽⁴⁾ Service de Neurologie, CHU Mustapha, Alger, ALGERIE
⁽⁵⁾ Department of Pediatric Neurology, Hacettepe Üniversitesi, Ankara, TURQUIE
⁽⁶⁾ Universitäts-Kinderklinik, Abteilung Neuropädiatrie und Muskelerkrankungen, Freiburg, ALLEMAGNE
⁽⁷⁾ Department of Pediatrics, Division of Genetics, Cerrahpasa Tip Fakültesi, Istanbul Üniversitesi, Istanbul, TURQUIE
⁽⁸⁾ Département de Pédiatrie, Service de Neurologie, Hôpital Universitatre de Bicêtre, Kremlin-Bicêtre, FRANCE

Résumé / 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^1-4. 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 axons^5,6. 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 astrocytes^7-11. 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.

Revue / Journal Title

Nature genetics   ISSN 1061-4036   CODEN NGENEC 

Source / Source

2000, vol. 26, n^o3, pp. 370-374 (29 ref.)

Langue / Language

Anglais

Editeur / Publisher

Nature Publishing Group, London, ROYAUME-UNI  (1992) (Revue)

Mots-clés anglais / English Keywords

Human ; Case study ; Mutation ; Nucleotide sequence ; Homology ; Domain structure ; Cytoskeleton ; Neurofilament ; Gene organization ; Giant axonal neuropathy ; Genetic disease ; Nervous system diseases ;

Mots-clés français / French Keywords

Homme ; Etude cas ; Mutation ; Séquence nucléotide ; Homologie ; Structure domaine ; Cytosquelette ; Neurofilament ; Organisation gène ; Neuropathie axone géant ; Gène GAS ; Gigatoxine ; Maladie héréditaire ; Système nerveux pathologie ;

Mots-clés espagnols / Spanish Keywords

Hombre ; Estudio caso ; Mutación ; Secuencia nucleótido ; Homología ; Estructura dominio ; Citoesqueleto ; Neurofilamento ; Organización gene ; Neuropatía axón gigante ; Enfermedad hereditaria ; Sistema nervioso patología ;

Localisation / Location

INIST-CNRS, Cote INIST : 22883, 35400009324287.0270