Our findings establish gigaxonin as a key E3 ligase that positively controls the initiation of Shh transduction, and reveal the causal role of Shh dysfunction in motor deficits, thus highlighting the developmental origin of GAN.
Abnormal accumulation of IFs is involved in the pathogenesis of number neurodegenerative diseases, but none as clearly as giant axonal neuropathy (GAN), a ravaging disease caused by mutations in GAN, encoding gigaxonin.
Conversely, silencing the expression of gigaxonin in control fibroblasts leads to changes in IF organization similar to that of GAN patient fibroblasts and a coincident loss of mitochondrial motility.
Indeed, in a set of seven new families presenting a neuropathy resembling GAN/CMT2, only five exhibiting a reduced Gigaxonin abundance have been subsequently genetically linked to GAN.
We describe a toddler with clinical features suggesting giant axonal neuropathy (GAN), whose diagnosis was confirmed by minimally invasive skin biopsy and corroborated by the finding of compound heterozygous mutations involving the GAN gene, including a novel interstitial microdeletion at 16q23.2 detected by microarray and a point mutation detected by direct sequencing.
Giant axonal neuropathy (GAN), a severe childhood disorder affecting both the peripheral nerves and the central nervous system, is due to mutations in the GAN gene encoding gigaxonin, a protein implicated in the cytoskeletal functions and dynamics.
In this family, missense mutation of c.224 T>A and missense mutation of c.1634G>A in GAN gene caused the phenotype of giant axonal neuropathy in the proband.
Despite deficiency of full length gigaxonin, the Gan(Deltaexon1;Deltaexon1) mice do not develop overt neurological phenotypes and giant axons reminiscent of the human GAN disease.
We report some unusual clinical features associated with GAN and Gigaxonin mutations as well as confirm the heterogeneity in GAN and the identification of two families with manifesting carriers.