A dominant negative FGFR1 mutation identified in a Kallmann syndrome patient.

Kallmann syndrome (KS) is characterized by isolated hypogonadotropic hypogonadism (IHH) with anosmia. Fibroblast growth factor receptor 1 (FGFR1) is one of KS-associated genes, accounts for approximately 10% of total patients. FGFR1 mutations have also been identified in more severe craniosynostosis syndromes, and a subset of craniosynostosis syndromes-associated FGFR1 mutations show dominant negative effect. In this study, we identified a novel FGFR1 mutation (c.867G>A; p.W289X) in a KS patient. The p.W289X mutation leads premature termination, producing a truncated FGFR1 without the transmembrane and intracellular domains. Indeed, the W289X FGFR1 was secreted into culture medium. Further, W289X FGFR1 interfered with the function of wild type receptor to induce ERK1/2 phosphorylation. We therefore identified a dominant negative FGFR1 mutation in the KS patient, and this mutant FGFR1 may be used to decipher the physiological function of FGFR1.