Identification of seven novel mutations in theGAN gene

Abstract

Giant axonal neuropathy (GAN) is a severe early onset neurodegenerative disorder affecting both the peripheral nerves and the central nervous system. The diagnosis is based on the presence of characteristic giant axons on nerve biopsy. In GAN, the integrity of the intermediate filament network is altered. Indeed, abnormal accumulation of the intermediate filaments has been reported in different cell types, including in the swollen axons, which are filled with neurofilaments. We identified the defective protein, gigaxonin, of unknown function, and reported fourteen distinct mutations in twelve families of various origins. Two additional mutations have been recently reported. In the present study, we analysed the GAN gene in 6 families, and identified seven novel mutations: three nonsense and two missense mutations and two deletions. In addition, the molecular result for an already reported family was re-evaluated. In this family, the R269Q "polymorphism" is in fact the pathogenic mutation.

One at a time, live tracking of NGF axonal transport using quantum dots

“…The ''blinking'' property and electron-dense core of QDs led to the surprising discovery that most endosomes carried a single NGF dimer at physiological concentrations. In view of recent findings revealing impaired NGF transport in mouse models of giant axonal neuropathy (40,41) and Down syndrome (42), these technologies may well facilitate studies of those systems in which failed NGF transport contributes to neurodegeneration.…”

Ubiquitination of Keap1, a BTB-Kelch Substrate Adaptor Protein for Cul3, Targets Keap1 for Degradation by a Proteasome-independent Pathway

“…Thus, for example, the Kelch protein of Drosophila melanogaster, is required for proper cross-linking of actin filaments at ring canals that enable macromolecular transport between the nurse cells and the oocyte during oogenesis (46,47). Mutations in the human GAN1 protein, which are the cause of a sensorimotor neuropathy termed giant axonal neuropathy, result in the accumulation of disorganized intermediate filaments in affected neurons (48,49). Sarcosin associates with a musclespecific isoform of N-RAP and may play a role in regulation of myofibril assembly and pseudopod formation in fibroblasts (43,50).…”

Giant axonal neuropathy–associated gigaxonin mutations impair intermediate filament protein degradation

“…Over 30 distinct mutations distributed throughout the GAN gene have been identified (9,11,16). GAN patients are born apparently normal, but typically by 3-5 years of age, they display progressive muscle weakness, diminished tendon reflexes, and pronounced gait disturbances.…”