Endocrine Abstracts (2011) 26 P178

Normosmic congenital hypogonadotropic hypogonadism due to TAC3/TACR3 mutations: characterization of neuroendocrine phenotypes and novel mutations

B Francou1,2, J Bouligand1,2, A Voican1,3, L Amazit1, S Brailly-Tabard1,2, P Lecomte4, J Young1,2 & A Guiochon-Mantel1,2

1INSERM U693, Le Kremlin-Bicêtre, France; 2Hôpital Bicêtre, Le Kremlin-Bicêtre, France; 3Universitatea de medicina si farmacie, Craiova, Romania; 4Hôpital de Tours, Tours, France.

Introduction: TAC3/TACR3 mutations have been reported in normosmic congenital hypogonadotropic hypogonadism (nCHH). In the absence of animal models, studies of human neuroendocrine phenotypes associated with neurokinin B and NK3R receptor dysfunction can help to decipher the pathophysiology of this signaling pathway. Our objective was to characterize novel TACR3 mutations and to analyze neuroendocrine profiles in nCHH patients with TAC3/TACR3 biallelic mutations.

Results: From a cohort of 352 CHH, we selected 173 nCHH patients and identified eight TACR3 variants (one frameshift, four missense and three nonsense mutation) in five adults (four sporadic cases, one familial). Molecular analyses, modeling and functional studies demonstrated the pathogenic nature of four novel variants. Three patients with TAC3/TACR3 biallelic mutations had an apulsatile LH profile and low-frequency α-subunit pulses. Using the same assays, we found a statistically significant higher mean FSH/LH ratio in 11 patients with TAC3/TACR3 biallelic mutations than in nCHH patients with biallelic mutations in GPR54/KISS1R (n=4), GNRH1 (n=2) or GNRHR (n=11), and nCHH patients with no identified mutations (n=32) or mutations in KAL1 (n=19), FGFR1 (n=17) or PROK2/PROKR2 (n=14) (P<0.0001). Pulsatile GnRH administration to three patients harboring TAC3/TACR3 mutations increased α-subunit pulsatile frequency and reduced the FSH/LH ratio.

Conclusion: The gonadotropin axis dysfunction associated with nCHH due to TAC3/TACR3 mutations is related to a low GnRH pulsatile frequency leading to a low frequency of α-subunit pulses and to an elevated FSH/LH ratio. This ratio might be useful for pre-screening nCHH patients for TAC3/TACR3 mutations.

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