As demonstrated by results in both humans and mouse, each of the three subunits in the signaling tripartite complex CLC:CLF-1:CNTFRα is indispensable in vivo; i.e., a functional deficiency in either one of the three subunits is enough to cause neonatal death in mice and full-blown CISS in humans. This evidence concerns the gene CLC and cold-induced sweating syndrome.