title: Genotype-phenotype analysis in patients with giant axonal neuropathy (GAN).
abstract: Giant axonal neuropathy (GAN, MIM: 256850) is a devastating autosomal recessive disorder characterized by an early onset severe peripheral neuropathy, varying central nervous system involvement and strikingly frizzly hair. Giant axonal neuropathy is usually caused by mutations in the gigaxonin gene (GAN) but genetic heterogeneity has been demonstrated for a milder variant of this disease. Here, we report ten patients referred to us for molecular genetic diagnosis. All patients had typical clinical signs suggestive of giant axonal neuropathy. In seven affected individuals, we found disease causing mutations in the gigaxonin gene affecting both alleles: two splice-site and four missense mutations, not reported previously. Gigaxonin binds N-terminally to ubiquitin activating enzyme E1 and C-terminally to various microtubule associated proteins causing their ubiquitin mediated degradation. It was shown for a number of gigaxonin mutations that they impede this process leading to accumulation of microtubule associated proteins and there by impairing cellular functions.
authors.affiliation: Department of Neurology, University of Münster, Albert-Schweitzer Strasse 33, D-48129 Münster, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Koop
authors.forename: Anja
authors.initials: A
authors.lastname: Schirmacher
authors.forename: Eva
authors.initials: E
authors.lastname: Nelis
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.forename: Bernd
authors.initials: B
authors.lastname: Ringelstein
authors.forename: Vedrana Milic
authors.initials: VM
authors.lastname: Rasic
authors.forename: Philippe
authors.initials: P
authors.lastname: Evrard
authors.forename: Jutta
authors.initials: J
authors.lastname: Gärtner
authors.forename: Kristl G
authors.initials: KG
authors.lastname: Claeys
authors.forename: Silke
authors.initials: S
authors.lastname: Appenzeller
authors.forename: Bernd
authors.initials: B
authors.lastname: Rautenstrauss
authors.forename: Kathrin
authors.initials: K
authors.lastname: Hühne
authors.forename: Maria A
authors.initials: MA
authors.lastname: Ramos-Arroyo
authors.forename: Helmut
authors.initials: H
authors.lastname: Wörle
authors.forename: Jukka S
authors.initials: JS
authors.lastname: Moilanen
authors.forename: Simon
authors.initials: S
authors.lastname: Hammans
authors.forename: Gregor
authors.initials: G
authors.lastname: Kuhlenbäumer
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism*; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010523:Peripheral Nervous System Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D003598:Cytoskeletal Proteins; C416508:GAN protein, human; D008869:Microtubule-Associated Proteins; D025801:Ubiquitin