Genotype-phenotype analysis in patients with giant axonal neuropathy (GAN).
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.
Koop
Olga
O
Department of Neurology, University of Münster, Albert-Schweitzer Strasse 33, D-48129 Münster, Germany.
Schirmacher
Anja
A
Nelis
Eva
E
Timmerman
Vincent
V
De Jonghe
Peter
P
Ringelstein
Bernd
B
Rasic
Vedrana Milic
VM
Evrard
Philippe
P
Gärtner
Jutta
J
Claeys
Kristl G
KG
Appenzeller
Silke
S
Rautenstrauss
Bernd
B
Hühne
Kathrin
K
Ramos-Arroyo
Maria A
MA
Wörle
Helmut
H
Moilanen
Jukka S
JS
Hammans
Simon
S
Kuhlenbäumer
Gregor
G
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
D003598:Cytoskeletal Proteins; C416508:GAN protein, human; D008869:Microtubule-Associated Proteins; D025801:Ubiquitin