Genotype–phenotype analysis in patients with giant axonal neuropathy (GAN)

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Neuromuscular Disorders

Volume 17, Issue 8, Pages 624-630 (August 2007)

Genotype–phenotype analysis in patients with giant axonal neuropathy

(GAN)

Olga Koopa1, Anja Schirmachera1, Eva Nelisbcd, Timmermancde,

De Jonghebcdf, Bernd Ringelsteina, Vedrana Milic Rasicg,

Philippe Evrardh, Jutta Gärtneri, Kristl G. Claeysbcdf, Silke

Appenzellera, Bernd Rautenstraussj, Kathrin Hühnej, A. Ramos-

Arroyok, Helmut Wörlel, Jukka S. Moilanenm, Simon Hammansn, Gregor

Kuhlenbäumeracde

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.