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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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Related in: MedlinePlus

Family pedigrees and consequences of TACR3 mutations on NK3R structure.Panel A. Pedigree of the family with homozygous TACR3 c.483_499 deletion. The proband, subject II-6 (arrow), and her two affected sisters (subjects II-5 and II-8), were homozygous for the c.483_499 deletion. The unaffected father (I-1) was heterozygous for the mutation. The unaffected sister (II-1) carried homozygous wild-type alleles. This deletion results in the emergence of a premature stop codon (Q161HfsX23), truncating NK3R after the third transmembrane segment. Panel B. Pedigree of the family with compound heterozygous TACR3 mutations c.824G>A and c.1003C>T. The proband, subject II-1 (arrow), was compound heterozygous for TACR3 mutations c.824G>A and c.1003C>T. The unaffected father (I-1) was heterozygous for the c.824G>A mutation and the unaffected mother was heterozygous for the c.1003C>T mutation. The c.824G>A substitution produces a stop codon in the 5th transmembrane segment (p.W275X) of NK3R. The c.1003C>T substitution produces a stop codon in the junction between the third extracellular loop and the seventh transmembrane domain (p.Q335X) of NK3R. Panel C. Pedigree of the family with compound heterozygous TACR3 mutations c.799T>A and c.824G>A. The proband, subject II-1 (arrow), was compound heterozygous for TACR3 mutations c.799T>A and c.824G>A. The unaffected father (I-1) was heterozygous for the recurent c.824G>A mutation and the unaffected mother was heterozygous for the c.799T>A mutation. This latter mutation affects a conserved amino acid in the fifth transmembrane domain (p.Y267N). Solid symbols indicate affected subjects and half-shaded symbols indicate unaffected heterozygotes. Circles represent female family members and squares male family members.
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pone-0025614-g001: Family pedigrees and consequences of TACR3 mutations on NK3R structure.Panel A. Pedigree of the family with homozygous TACR3 c.483_499 deletion. The proband, subject II-6 (arrow), and her two affected sisters (subjects II-5 and II-8), were homozygous for the c.483_499 deletion. The unaffected father (I-1) was heterozygous for the mutation. The unaffected sister (II-1) carried homozygous wild-type alleles. This deletion results in the emergence of a premature stop codon (Q161HfsX23), truncating NK3R after the third transmembrane segment. Panel B. Pedigree of the family with compound heterozygous TACR3 mutations c.824G>A and c.1003C>T. The proband, subject II-1 (arrow), was compound heterozygous for TACR3 mutations c.824G>A and c.1003C>T. The unaffected father (I-1) was heterozygous for the c.824G>A mutation and the unaffected mother was heterozygous for the c.1003C>T mutation. The c.824G>A substitution produces a stop codon in the 5th transmembrane segment (p.W275X) of NK3R. The c.1003C>T substitution produces a stop codon in the junction between the third extracellular loop and the seventh transmembrane domain (p.Q335X) of NK3R. Panel C. Pedigree of the family with compound heterozygous TACR3 mutations c.799T>A and c.824G>A. The proband, subject II-1 (arrow), was compound heterozygous for TACR3 mutations c.799T>A and c.824G>A. The unaffected father (I-1) was heterozygous for the recurent c.824G>A mutation and the unaffected mother was heterozygous for the c.799T>A mutation. This latter mutation affects a conserved amino acid in the fifth transmembrane domain (p.Y267N). Solid symbols indicate affected subjects and half-shaded symbols indicate unaffected heterozygotes. Circles represent female family members and squares male family members.

Mentions: In family 1, three sisters were affected. The proband (subject II-6, Fig. 1A) was a young woman from a consanguineous family originating from Reunion Island. She was referred at age 24 years because pubertal development and menses had not occurred. She had typical signs of complete hypogonadism, with no breast development but the presence of pubic hair (P4). Her height was 164 cm, her weight 58 kg, and her bone age 14 years. Pelvic sonography showed a small uterus (34 mm high, 28 mm wide, 22 mm thick) and two small ovaries (right, 0.84 mL; left, 1.48 mL), with a few follicles less than 4 mm in diameter. Her karyotype was normal (46, XX). Combined estrogen-progestin replacement therapy induced breast development, an increase in uterus length, and regular menses. Hormonal evaluation after the end of this therapy showed that she still had very low estradiol and LH levels, an undetectable serum inhibin B level, but normal FSH levels as well as a nonpulsatile LH secretion, and an unchanged ovarian aspect on sonography. Pulsatile GnRH administration (90 ng/kg/pulse, every 90 minutes, subcutaneously) was started because she wished to conceive, resulting in increased circulating levels of LH, estradiol and inhibin B, appropriate endometrial thickening, and recruitment of a single dominant follicle of 20 mm. Eleven days later, while still receiving pulsatile GnRH therapy, her progesterone concentration rose to a luteal-phase level (19 ng/mL) and ultrasonography showed the typical aspect of a corpus luteum. This patient's older affected sister (subject II-5, Fig. 1A), who was evaluated at age 21 years, also had complete hypogonadism and a normal sense of smell. At diagnosis, she had no breast development and sparse pubic hair. Menarche had not occurred. The proband's younger affected sister (subject II-8, Fig. 1A) was 19 years old when first seen for primary amenorrhea and absent breast development. She was born at term with a normal birth weight after an uncomplicated pregnancy, and grew and developed normally until her early to mid-teen years. On examination, her height was 168 cm and her BMI 23 kg/m2. She was at Tanner breast stage 1, pubic hair stage 3, and axillary hair stage 2. Her bone age was 13.5 years at diagnosis.


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)

Family pedigrees and consequences of TACR3 mutations on NK3R structure.Panel A. Pedigree of the family with homozygous TACR3 c.483_499 deletion. The proband, subject II-6 (arrow), and her two affected sisters (subjects II-5 and II-8), were homozygous for the c.483_499 deletion. The unaffected father (I-1) was heterozygous for the mutation. The unaffected sister (II-1) carried homozygous wild-type alleles. This deletion results in the emergence of a premature stop codon (Q161HfsX23), truncating NK3R after the third transmembrane segment. Panel B. Pedigree of the family with compound heterozygous TACR3 mutations c.824G>A and c.1003C>T. The proband, subject II-1 (arrow), was compound heterozygous for TACR3 mutations c.824G>A and c.1003C>T. The unaffected father (I-1) was heterozygous for the c.824G>A mutation and the unaffected mother was heterozygous for the c.1003C>T mutation. The c.824G>A substitution produces a stop codon in the 5th transmembrane segment (p.W275X) of NK3R. The c.1003C>T substitution produces a stop codon in the junction between the third extracellular loop and the seventh transmembrane domain (p.Q335X) of NK3R. Panel C. Pedigree of the family with compound heterozygous TACR3 mutations c.799T>A and c.824G>A. The proband, subject II-1 (arrow), was compound heterozygous for TACR3 mutations c.799T>A and c.824G>A. The unaffected father (I-1) was heterozygous for the recurent c.824G>A mutation and the unaffected mother was heterozygous for the c.799T>A mutation. This latter mutation affects a conserved amino acid in the fifth transmembrane domain (p.Y267N). Solid symbols indicate affected subjects and half-shaded symbols indicate unaffected heterozygotes. Circles represent female family members and squares male family members.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0025614-g001: Family pedigrees and consequences of TACR3 mutations on NK3R structure.Panel A. Pedigree of the family with homozygous TACR3 c.483_499 deletion. The proband, subject II-6 (arrow), and her two affected sisters (subjects II-5 and II-8), were homozygous for the c.483_499 deletion. The unaffected father (I-1) was heterozygous for the mutation. The unaffected sister (II-1) carried homozygous wild-type alleles. This deletion results in the emergence of a premature stop codon (Q161HfsX23), truncating NK3R after the third transmembrane segment. Panel B. Pedigree of the family with compound heterozygous TACR3 mutations c.824G>A and c.1003C>T. The proband, subject II-1 (arrow), was compound heterozygous for TACR3 mutations c.824G>A and c.1003C>T. The unaffected father (I-1) was heterozygous for the c.824G>A mutation and the unaffected mother was heterozygous for the c.1003C>T mutation. The c.824G>A substitution produces a stop codon in the 5th transmembrane segment (p.W275X) of NK3R. The c.1003C>T substitution produces a stop codon in the junction between the third extracellular loop and the seventh transmembrane domain (p.Q335X) of NK3R. Panel C. Pedigree of the family with compound heterozygous TACR3 mutations c.799T>A and c.824G>A. The proband, subject II-1 (arrow), was compound heterozygous for TACR3 mutations c.799T>A and c.824G>A. The unaffected father (I-1) was heterozygous for the recurent c.824G>A mutation and the unaffected mother was heterozygous for the c.799T>A mutation. This latter mutation affects a conserved amino acid in the fifth transmembrane domain (p.Y267N). Solid symbols indicate affected subjects and half-shaded symbols indicate unaffected heterozygotes. Circles represent female family members and squares male family members.
Mentions: In family 1, three sisters were affected. The proband (subject II-6, Fig. 1A) was a young woman from a consanguineous family originating from Reunion Island. She was referred at age 24 years because pubertal development and menses had not occurred. She had typical signs of complete hypogonadism, with no breast development but the presence of pubic hair (P4). Her height was 164 cm, her weight 58 kg, and her bone age 14 years. Pelvic sonography showed a small uterus (34 mm high, 28 mm wide, 22 mm thick) and two small ovaries (right, 0.84 mL; left, 1.48 mL), with a few follicles less than 4 mm in diameter. Her karyotype was normal (46, XX). Combined estrogen-progestin replacement therapy induced breast development, an increase in uterus length, and regular menses. Hormonal evaluation after the end of this therapy showed that she still had very low estradiol and LH levels, an undetectable serum inhibin B level, but normal FSH levels as well as a nonpulsatile LH secretion, and an unchanged ovarian aspect on sonography. Pulsatile GnRH administration (90 ng/kg/pulse, every 90 minutes, subcutaneously) was started because she wished to conceive, resulting in increased circulating levels of LH, estradiol and inhibin B, appropriate endometrial thickening, and recruitment of a single dominant follicle of 20 mm. Eleven days later, while still receiving pulsatile GnRH therapy, her progesterone concentration rose to a luteal-phase level (19 ng/mL) and ultrasonography showed the typical aspect of a corpus luteum. This patient's older affected sister (subject II-5, Fig. 1A), who was evaluated at age 21 years, also had complete hypogonadism and a normal sense of smell. At diagnosis, she had no breast development and sparse pubic hair. Menarche had not occurred. The proband's younger affected sister (subject II-8, Fig. 1A) was 19 years old when first seen for primary amenorrhea and absent breast development. She was born at term with a normal birth weight after an uncomplicated pregnancy, and grew and developed normally until her early to mid-teen years. On examination, her height was 168 cm and her BMI 23 kg/m2. She was at Tanner breast stage 1, pubic hair stage 3, and axillary hair stage 2. Her bone age was 13.5 years at diagnosis.

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