The CRLF1 gene encodes a member of the cytokine type I receptor family. The CRLF1 protein heterodimerizes with cardiotrophin-like cytokine factor 1 (CLCF1) to bind ciliary neurotrophic factor receptors (CNFTR), in doing so it competes with ciliary neurotrophic factor (CNTF) for binding to CNTFR. This binding activates the JAK/STAT signaling pathway and promotes survival of signal-receiving neuronal cells.
The human CRLF1 protein consists of 422 amino acids. CRLF1 is a secreted protein that comprises one immunoglobulin (Ig)-like domain and two fibronectin type III (FNIII) domains. CRLF1 expression was detected in lymph nodes, spleen, thymus, appendix, placenta, stomach, and fetal lung.
The CRLF1 gene is composed of 9 exons and spans over 13 kb. Mutations in CRLF1 result in Crisponi syndrome and cold-induced sweating syndrome. Examples include many types of loss-of-function mutations such as deletions (2-bp del, 844GT) and duplications (1-bp dup, 713C) as well as missense, nonsense (p.K368X) and frameshift mutations.
CRLF1 mutations are thought to result in disrupting the function of the abovementioned cytokine complex. Considering that sweating is controlled by the sympathetic nervous system, and the neurons that innervate sweat glands differentiate in a neurokine-dependent manner, such disruption causes a defect in cholinergic differentiation in sweat glands during development.
Dagoneau et al. (2007) reported a female patient of a Yemenite origin, whose parents were first cousins. Symptoms included many indicative features of Crisponi syndrome. The baby girl harbored a c.527+5G>A mutation at the 3' end of exon 3 of the CRLF1 gene. The affected region codes for a fibronectin type III (FNIII) domain.
[See: United Arab Emirates > Dagoneau et al., 2007].