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

Francou B, Bouligand J, Voican A, Amazit L, Trabado S, Fagart J, Meduri G, Brailly-Tabard S, Chanson P, Lecomte P, Guiochon-Mantel A, Young J - PLoS ONE (2011)

Bottom Line: We found a statistically significant (p<0.0001) higher mean FSH/LH ratio in 11 nCHH patients with TAC3/TACR3 biallelic mutations than in 47 nCHH patients with either biallelic mutations in KISS1R, GNRHR, or with no identified mutations and than in 50 Kallmann patients with mutations in KAL1, FGFR1 or PROK2/PROKR2.Pulsatile GnRH administration increased alpha-subunit pulsatile frequency and reduced the FSH/LH ratio.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 alpha-subunit pulses and to an elevated FSH/LH ratio.

View Article: PubMed Central - PubMed

Affiliation: Univ Paris-Sud, Faculté de Médecine Paris-Sud UMR-S693, Le Kremlin Bicêtre, France.

ABSTRACT

Context: TAC3/TACR3 mutations have been reported in normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110). 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.

Objective: To evaluate the prevalence of TAC3/TACR3 mutations, characterize novel TACR3 mutations and to analyze neuroendocrine profiles in nCHH caused by deleterious TAC3/TACR3 biallelic mutations.

Results: From a cohort of 352 CHH, we selected 173 nCHH patients and identified nine patients carrying TAC3 or TACR3 variants (5.2%). We describe here 7 of these TACR3 variants (1 frameshift and 2 nonsense deleterious mutations and 4 missense variants) found in 5 subjects. Modeling and functional studies of the latter demonstrated the deleterious consequence of one missense mutation (Tyr267Asn) probably caused by the misfolding of the mutated NK3R protein. We found a statistically significant (p<0.0001) higher mean FSH/LH ratio in 11 nCHH patients with TAC3/TACR3 biallelic mutations than in 47 nCHH patients with either biallelic mutations in KISS1R, GNRHR, or with no identified mutations and than in 50 Kallmann patients with mutations in KAL1, FGFR1 or PROK2/PROKR2. Three patients with TAC3/TACR3 biallelic mutations had an apulsatile LH profile but low-frequency alpha-subunit pulses. Pulsatile GnRH administration increased alpha-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 alpha-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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FSH/LH ratio in 11 patients with nCHH caused by biallelic TAC3/TACR3 mutations.Panel A. Significantly higher serum FSH/ serum LH ratios in 11 patients with nCHH caused by TAC3/TACR3 biallelic mutations than in patients with other genetic forms of CHH or in CHH patients with no mutation found in known genes. Note the Log scale on Y axis. A whole variance analysis by Kruskal-Wallis test (p<0.0001) was performed followed by post-hoc Newman-Keuls multiple comparison test; *indicates a significant difference between 2 groups (p<0.001). The threshold separating FSH/LH ratio in TAC3/TACR3 mutated nCHH subjects from those of patients with other genetic forms of CHH is indicated by an horizontal line. Panel B. Decrease in the FSH/LH ratio in one patient with TAC3 and two patients with TACR3 mutations (see Patients) during pulsatile GnRH administration. Note the Log scale on Y axis.
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pone-0025614-g004: FSH/LH ratio in 11 patients with nCHH caused by biallelic TAC3/TACR3 mutations.Panel A. Significantly higher serum FSH/ serum LH ratios in 11 patients with nCHH caused by TAC3/TACR3 biallelic mutations than in patients with other genetic forms of CHH or in CHH patients with no mutation found in known genes. Note the Log scale on Y axis. A whole variance analysis by Kruskal-Wallis test (p<0.0001) was performed followed by post-hoc Newman-Keuls multiple comparison test; *indicates a significant difference between 2 groups (p<0.001). The threshold separating FSH/LH ratio in TAC3/TACR3 mutated nCHH subjects from those of patients with other genetic forms of CHH is indicated by an horizontal line. Panel B. Decrease in the FSH/LH ratio in one patient with TAC3 and two patients with TACR3 mutations (see Patients) during pulsatile GnRH administration. Note the Log scale on Y axis.

Mentions: The FSH/LH ratios in 11 subjects with biallelic TAC3/TACR3 mutations (Table 2) are shown in Fig. 4A. Compared to subjects with other known genetic causes of nCHH KISS1R (mean (±SD) FSH/LH = 3.2±2.4), GNRHR (mean FSH/LH = 1.3±0.5) mutations or Kallmann syndrome (KAL1:mean FSH/LH = 1.2±0.6), FGFR1 (mean FSH/LH = 1.5±0.5) and PROK2 or PROKR2 mutations (mean FSH/LH = 1.7±1.4)(Information S1) and to 32 patients with nCHH (mean FSH/LH = 1.2±0.8) and no identified genetic anomalies, patients with TAC3/TACR3 mutations had very significantly (p<0.001 for each comparison, see Fig. 4A) higher FSH/LH ratios (mean FSH/LH =  23.6±22.4). Finally, we observed a decline in the FSH/LH ratio in the three subjects (patient II-6 family 1 and in the two nCHH subjects with respectively TAC3 and TACR3 mutations in part reported in ref 3) who received pulsatile GnRH administration (from 18.4±17.9 to 0.8±0.2)(Fig. 4B).


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

Francou B, Bouligand J, Voican A, Amazit L, Trabado S, Fagart J, Meduri G, Brailly-Tabard S, Chanson P, Lecomte P, Guiochon-Mantel A, Young J - PLoS ONE (2011)

FSH/LH ratio in 11 patients with nCHH caused by biallelic TAC3/TACR3 mutations.Panel A. Significantly higher serum FSH/ serum LH ratios in 11 patients with nCHH caused by TAC3/TACR3 biallelic mutations than in patients with other genetic forms of CHH or in CHH patients with no mutation found in known genes. Note the Log scale on Y axis. A whole variance analysis by Kruskal-Wallis test (p<0.0001) was performed followed by post-hoc Newman-Keuls multiple comparison test; *indicates a significant difference between 2 groups (p<0.001). The threshold separating FSH/LH ratio in TAC3/TACR3 mutated nCHH subjects from those of patients with other genetic forms of CHH is indicated by an horizontal line. Panel B. Decrease in the FSH/LH ratio in one patient with TAC3 and two patients with TACR3 mutations (see Patients) during pulsatile GnRH administration. Note the Log scale on Y axis.
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pone-0025614-g004: FSH/LH ratio in 11 patients with nCHH caused by biallelic TAC3/TACR3 mutations.Panel A. Significantly higher serum FSH/ serum LH ratios in 11 patients with nCHH caused by TAC3/TACR3 biallelic mutations than in patients with other genetic forms of CHH or in CHH patients with no mutation found in known genes. Note the Log scale on Y axis. A whole variance analysis by Kruskal-Wallis test (p<0.0001) was performed followed by post-hoc Newman-Keuls multiple comparison test; *indicates a significant difference between 2 groups (p<0.001). The threshold separating FSH/LH ratio in TAC3/TACR3 mutated nCHH subjects from those of patients with other genetic forms of CHH is indicated by an horizontal line. Panel B. Decrease in the FSH/LH ratio in one patient with TAC3 and two patients with TACR3 mutations (see Patients) during pulsatile GnRH administration. Note the Log scale on Y axis.
Mentions: The FSH/LH ratios in 11 subjects with biallelic TAC3/TACR3 mutations (Table 2) are shown in Fig. 4A. Compared to subjects with other known genetic causes of nCHH KISS1R (mean (±SD) FSH/LH = 3.2±2.4), GNRHR (mean FSH/LH = 1.3±0.5) mutations or Kallmann syndrome (KAL1:mean FSH/LH = 1.2±0.6), FGFR1 (mean FSH/LH = 1.5±0.5) and PROK2 or PROKR2 mutations (mean FSH/LH = 1.7±1.4)(Information S1) and to 32 patients with nCHH (mean FSH/LH = 1.2±0.8) and no identified genetic anomalies, patients with TAC3/TACR3 mutations had very significantly (p<0.001 for each comparison, see Fig. 4A) higher FSH/LH ratios (mean FSH/LH =  23.6±22.4). Finally, we observed a decline in the FSH/LH ratio in the three subjects (patient II-6 family 1 and in the two nCHH subjects with respectively TAC3 and TACR3 mutations in part reported in ref 3) who received pulsatile GnRH administration (from 18.4±17.9 to 0.8±0.2)(Fig. 4B).

Bottom Line: We found a statistically significant (p<0.0001) higher mean FSH/LH ratio in 11 nCHH patients with TAC3/TACR3 biallelic mutations than in 47 nCHH patients with either biallelic mutations in KISS1R, GNRHR, or with no identified mutations and than in 50 Kallmann patients with mutations in KAL1, FGFR1 or PROK2/PROKR2.Pulsatile GnRH administration increased alpha-subunit pulsatile frequency and reduced the FSH/LH ratio.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 alpha-subunit pulses and to an elevated FSH/LH ratio.

View Article: PubMed Central - PubMed

Affiliation: Univ Paris-Sud, Faculté de Médecine Paris-Sud UMR-S693, Le Kremlin Bicêtre, France.

ABSTRACT

Context: TAC3/TACR3 mutations have been reported in normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110). 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.

Objective: To evaluate the prevalence of TAC3/TACR3 mutations, characterize novel TACR3 mutations and to analyze neuroendocrine profiles in nCHH caused by deleterious TAC3/TACR3 biallelic mutations.

Results: From a cohort of 352 CHH, we selected 173 nCHH patients and identified nine patients carrying TAC3 or TACR3 variants (5.2%). We describe here 7 of these TACR3 variants (1 frameshift and 2 nonsense deleterious mutations and 4 missense variants) found in 5 subjects. Modeling and functional studies of the latter demonstrated the deleterious consequence of one missense mutation (Tyr267Asn) probably caused by the misfolding of the mutated NK3R protein. We found a statistically significant (p<0.0001) higher mean FSH/LH ratio in 11 nCHH patients with TAC3/TACR3 biallelic mutations than in 47 nCHH patients with either biallelic mutations in KISS1R, GNRHR, or with no identified mutations and than in 50 Kallmann patients with mutations in KAL1, FGFR1 or PROK2/PROKR2. Three patients with TAC3/TACR3 biallelic mutations had an apulsatile LH profile but low-frequency alpha-subunit pulses. Pulsatile GnRH administration increased alpha-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 alpha-subunit pulses and to an elevated FSH/LH ratio. This ratio might be useful for pre-screening nCHH patients for TAC3/TACR3 mutations.

Show MeSH
Related in: MedlinePlus