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Kallmann syndrome (KS) is characterized by the association of anosmia and hypogonadotropic hypogonadism. The hypogonadotropic hypogonadism is due to deficient production, secretion or action of gonadotropin-releasing hormone (GnRH). Mutations in transcription factor SOX10 have been recently identified in patients with KS and hearing loss. In this study, we identified three novel SOX10 mutations in a cohort of Chinese KS patients by using exome sequencing. Two mutations (A44G and L80V) are in heterozygous state whereas the other one (G41V) is a homozygous mutation. The patient with a homozygous G41V mutation had impaired hearing in both ears, whereas the patient with a heterozygous L80V mutation showed subtle hearing impairment in the left ear. Functional studies indicated that all three SOX10 mutations showed reduced capacity to transactivate the MITF promoter alone or in synergy with PAX3, although they showed similar subcellular localization, and DNA binding ability. Our study further highlighted the significance of SOX10 haploinsufficiency as a genetic cause of KS with hearing problem.

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.