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

Disorganization of the neurofilament network is a prominent feature of seve ral neurodegenerative disorders including amyotrophic lateral sclerosis (AL S), infantile spinal muscular atrophy and axonal Charcot-Marie-Tooth diseas e(1-4). Giant axonal neuropathy (GAN, MIM 256850), a severe, autosomal rece ssive sensorimotor neuropathy affecting both the peripheral nerves and the central nervous system, is characterized by neurofilament accumulation, lea ding to segmental distension of the axons(5,6) GAN corresponds to a general ized disorganization of the cytoskeletal intermediate filaments (IFs), to w hich neurofilaments belong, as abnormal aggregation of multiple tissue-spec ific IFs has been reported: vimentin in endothelial cells, Schwann cells an d cultured skin fibroblasts, and glial fibrillary acidic protein (GFAP) in astrocytes(7-11) Keratin Ifs also seem to be alterated, as most patients pr esent characteristic curly or kinky hairs(12). We report here identificatio n of the gene GAN, which encodes a novel, ubiquitously expressed protein we have named gigaxonin. We found one frameshift, four nonsense and nine miss ense mutations in GAN of GAN patients. Gigaxonin is composed of an amino-te rminal BTB (for Broad-Complex, Tramtrack and Bric a brac) domain followed b y a six kelch repeats, which are predicted to adopt a beta -propeller shape (13). Distantly related proteins sharing a similar domain organization have various functions associated with the cytoskeleton. predicting that gigaxo nin is a novel and distinct cytoskeletal protein that may represent a gener al pathological target for other neurodegenerative disorders with alteratio ns in the neurofilament network.