Normosmic Congenital Hypogonadotropic Hypogonadism Due to TAC3/TACR3 Mutations: Characterization of Neuroendocrine Phenotypes and Novel Mutations

• DOI: 10.1371/journal.pone.0025614
• Publication Date: 2011-10-21T21:30:19Z
• Authors: Bruno Francou; Jérôme Bouligand; Adela Voican; Larbi Amazit; Séverine Trabado; Jérôme Fagart; Geri Meduri; Sylvie Brailly-Ta...; Philippe Chanson; Pierre Lecomte; Anne Guiochon-Mantel; Jacques Young
• Keywords: Adult; Male; Science; Hypogonadism; Q; R; Pedigree; 3. Good health; Young Adult; 03 medical and health sciences; 0302 clinical medicine; Tachykinins; Mutation; Medicine; Humans; Female; Receptors, Tachykinin; Research Article; Signal Transduction

Context TAC3/TACR3 mutations have been reported in normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110). In the absence of animal models, studies human neuroendocrine phenotypes associated with neurokinin B and NK3R receptor dysfunction can help to decipher pathophysiology this signaling pathway. Objective To evaluate prevalence mutations, characterize novel TACR3 analyze profiles nCHH caused by deleterious biallelic mutations. Results From a cohort 352 CHH, we selected 173 patients identified nine carrying TAC3 or variants (5.2%). We describe here 7 these (1 frameshift 2 nonsense 4 missense variants) found 5 subjects. Modeling functional latter demonstrated consequence one mutation (Tyr267Asn) probably misfolding mutated protein. statistically significant (p<0.0001) higher mean FSH/LH ratio 11 than 47 either KISS1R, GNRHR, no 50 Kallmann KAL1, FGFR1 PROK2/PROKR2. Three had an apulsatile LH profile but low-frequency alpha-subunit pulses. Pulsatile GnRH administration increased pulsatile frequency reduced ratio. Conclusion The gonadotropin axis due is related low leading pulses elevated This might be useful for pre-screening