Acid-sensing ion channel (ASCI) 4 gene: physical mapping, genomic organisation, and evaluation as a candidate for paroxysmal dystonia

Acid-sensing ion channels (ASICs) are protongated Na+ channels. They have b een implicated with synaptic transmission, pain perception as well as mecha noperception. ASIC4 is the most recent member of this gene family. It shows expression throughout the central nervous system with strongest expression in pituitary gland. ASIC4 is inactive by itself and its function is unknow n. Mutations in ion channel subunits, which are homologues of ASICs lead to neurodegeneration in Caenorhabditis elegans. It has, therefore, been specu lated that similar mutations in ASICs may be responsible for neurodegenerat ion in humans. Here, we show that ASIC4 maps to the long arm of chromosome 2 in close proximity to the locus for paroxysmal dystonic choreoathetosis ( PDC), a movement disorder with unknown cause. Ion channel genes have been s hown to cause several other paroxysmal neurologic disorders and are importa nt candidate genes for PDC. We established the genomic organisation of the ASIC4 gene and screened a PDC pedigree for mutations in the coding region. Although we identified three polymorphisms in the Cterminal part of the ASI C4 protein, these were not present in each affected subject in the PDC kind red we analysed. Therefore, although the ASIC4 gene is physically mapped to the PDC locus, our data indicates that ASIC4 gene mutation is not the caus e of PDC. It remains to be established if mutations in ASIC4 or other ASIC subunits may cause neurological disorders.