title: Inactivation of cardiotrophin-like cytokine, a second ligand for ciliary neurotrophic factor receptor, leads to cold-induced sweating syndrome in a patient.
abstract: Ciliary neurotrophic factor (CNTF) receptor controls a pathway supporting the differentiation and survival of a wide range of neural cell types during development and in adulthood. Cardiotrophin-like cytokine (CLC)-cytokine-like factor 1 (CLF) composite cytokine is a second ligand for the CNTF alpha-component receptor (CNTFRalpha). This composite cytokine is built on the structural model of IL-12, with a complex formed by a four-helix bundle type I cytokine, CLC (also referred to as CLCF1), bound to a soluble receptor subunit, CLF (also known as CRLF1). We have reported mutations in the chaperone soluble receptor CLF, causing cold-induced sweating syndrome (CISS). In this study, we studied the CLC-mutated alleles in a patient suffering from a similar disease. This patient was compound heterozygous for two different CLC mutations. The first allele was inactivated by a stop codon at position 107 (Y107X). In the second allele, a R197L mutation in the CLC-predicted binding site to the CNTFRalpha was detected. Functional analysis of the mutated protein revealed an incapacity for R197L CLC to bind to CNTFRalpha and activate the subsequent signaling events. Structural and docking interaction studies showed that the R197L substitution destabilized the contact site between CLC and CNTFRalpha.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U564, F-49033 Angers, France.
authors.forename: François
authors.initials: F
authors.lastname: Rousseau
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Gauchat
authors.forename: James G
authors.initials: JG
authors.lastname: McLeod
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chevalier
authors.forename: Catherine
authors.initials: C
authors.lastname: Guillet
authors.forename: Florence
authors.initials: F
authors.lastname: Guilhot
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cognet
authors.forename: Josy
authors.initials: J
authors.lastname: Froger
authors.forename: Angelika F
authors.initials: AF
authors.lastname: Hahn
authors.forename: Per M
authors.initials: PM
authors.lastname: Knappskog
authors.forename: Hugues
authors.initials: H
authors.lastname: Gascan
authors.forename: Helge
authors.initials: H
authors.lastname: Boman
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001120:Arginine / Q000235:genetics; D018388:Codon, Terminator / Q000235:genetics; D003080:Cold Temperature; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D006945:Hyperhidrosis / Q000235:genetics*; D008024:Ligands; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D020801:Receptor, Ciliary Neurotrophic Factor / Q000819:agonists / Q000378:metabolism*; D013546:Sweating / Q000235:genetics*; D013577:Syndrome
chemical_list: D018388:Codon, Terminator; D016207:Cytokines; D008024:Ligands; D020801:Receptor, Ciliary Neurotrophic Factor; C121169:cardiotrophin-like cytokine; D001120:Arginine