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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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Secretory free alpha-subunit (FAS) and gonadotropin responses to pulsatile GnRH administration.Panel A. FAS concentrations in a man with nCHH caused by a homozygous TAC3 c.209-1G>C mutation, before and on day 19 of pulsatile GnRH administration (patient reported in part in [3]). Arrows indicate exogenous GnRH boluses (7 µg). Panel B. FAS concentration in a woman with nCHH caused by a mutation in TACR3 (subject II-6 in family I, Fig. 1A), before and on day 13 of pulsatile GnRH administration. Arrows indicate exogenous GnRH boluses (5 µg). Asterixes denote detectable FAS pulses, using Thomas' algorithm [24]. See Patients and Methods for details. Panel C. Pattern of gonadotropin secretion in a woman with complete nCHH and TACR3 mutation (subject II-6 in family I, Fig. 1A). Basal LH concentration was very low and FSH concentration was in the normal range. Panel D. LH pulsatility in this woman was restored by pulsatile GnRH administration, and the serum FSH level fell slightly during pulsatile GnRH administration. Serum estradiol (E2) and inhibin B (IB) levels before and after GnRH administration are indicated respectively at the top of panel C and D.
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pone-0025614-g003: Secretory free alpha-subunit (FAS) and gonadotropin responses to pulsatile GnRH administration.Panel A. FAS concentrations in a man with nCHH caused by a homozygous TAC3 c.209-1G>C mutation, before and on day 19 of pulsatile GnRH administration (patient reported in part in [3]). Arrows indicate exogenous GnRH boluses (7 µg). Panel B. FAS concentration in a woman with nCHH caused by a mutation in TACR3 (subject II-6 in family I, Fig. 1A), before and on day 13 of pulsatile GnRH administration. Arrows indicate exogenous GnRH boluses (5 µg). Asterixes denote detectable FAS pulses, using Thomas' algorithm [24]. See Patients and Methods for details. Panel C. Pattern of gonadotropin secretion in a woman with complete nCHH and TACR3 mutation (subject II-6 in family I, Fig. 1A). Basal LH concentration was very low and FSH concentration was in the normal range. Panel D. LH pulsatility in this woman was restored by pulsatile GnRH administration, and the serum FSH level fell slightly during pulsatile GnRH administration. Serum estradiol (E2) and inhibin B (IB) levels before and after GnRH administration are indicated respectively at the top of panel C and D.

Mentions: Serum FAS pulsatility was analyzed in subject II.6 from family 1 (Fig. 1A and Table 2), who harbored a homozygous mutation in TACR3, and in two subjects partially described elsewhere [3] with either a homozygous TAC3 or a homozygous TACR3 mutation. Endogenous serum FAS levels are shown for two of these subjects in Fig. 3A and 3B.


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)

Secretory free alpha-subunit (FAS) and gonadotropin responses to pulsatile GnRH administration.Panel A. FAS concentrations in a man with nCHH caused by a homozygous TAC3 c.209-1G>C mutation, before and on day 19 of pulsatile GnRH administration (patient reported in part in [3]). Arrows indicate exogenous GnRH boluses (7 µg). Panel B. FAS concentration in a woman with nCHH caused by a mutation in TACR3 (subject II-6 in family I, Fig. 1A), before and on day 13 of pulsatile GnRH administration. Arrows indicate exogenous GnRH boluses (5 µg). Asterixes denote detectable FAS pulses, using Thomas' algorithm [24]. See Patients and Methods for details. Panel C. Pattern of gonadotropin secretion in a woman with complete nCHH and TACR3 mutation (subject II-6 in family I, Fig. 1A). Basal LH concentration was very low and FSH concentration was in the normal range. Panel D. LH pulsatility in this woman was restored by pulsatile GnRH administration, and the serum FSH level fell slightly during pulsatile GnRH administration. Serum estradiol (E2) and inhibin B (IB) levels before and after GnRH administration are indicated respectively at the top of panel C and D.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198730&req=5

pone-0025614-g003: Secretory free alpha-subunit (FAS) and gonadotropin responses to pulsatile GnRH administration.Panel A. FAS concentrations in a man with nCHH caused by a homozygous TAC3 c.209-1G>C mutation, before and on day 19 of pulsatile GnRH administration (patient reported in part in [3]). Arrows indicate exogenous GnRH boluses (7 µg). Panel B. FAS concentration in a woman with nCHH caused by a mutation in TACR3 (subject II-6 in family I, Fig. 1A), before and on day 13 of pulsatile GnRH administration. Arrows indicate exogenous GnRH boluses (5 µg). Asterixes denote detectable FAS pulses, using Thomas' algorithm [24]. See Patients and Methods for details. Panel C. Pattern of gonadotropin secretion in a woman with complete nCHH and TACR3 mutation (subject II-6 in family I, Fig. 1A). Basal LH concentration was very low and FSH concentration was in the normal range. Panel D. LH pulsatility in this woman was restored by pulsatile GnRH administration, and the serum FSH level fell slightly during pulsatile GnRH administration. Serum estradiol (E2) and inhibin B (IB) levels before and after GnRH administration are indicated respectively at the top of panel C and D.
Mentions: Serum FAS pulsatility was analyzed in subject II.6 from family 1 (Fig. 1A and Table 2), who harbored a homozygous mutation in TACR3, and in two subjects partially described elsewhere [3] with either a homozygous TAC3 or a homozygous TACR3 mutation. Endogenous serum FAS levels are shown for two of these subjects in Fig. 3A and 3B.

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