TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction

Topaloglu, A Kemal; Reimann, Frank; Guclu, Metin; Yalin, Ayse Serap; Kotan, L Damla; Porter, Keith M; Serin, Ayse; Mungan, Neslihan O; Cook, Joshua R; Ozbek, Mehmet N; Imamoglu, Sazi; Akalin, N Sema; Yuksel, Bilgin; O'Rahilly, Stephen; Semple, Robert K

doi:10.1038/ng.306

Cited by 961Hypothalamic control of reproductive hormonesNeuropeptides and Animal PhysiologyGenetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities

TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction

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Topaloglu, A Kemal, Reimann, Frank, Guclu, Metin, Yalin, Ayse Serap, Kotan, L Damla, Porter, Keith M, Serin, Ayse, Mungan, Neslihan O +7 more·2009·Nature Genetics

DOI 10.1038/ng.306PMC PMC4312696

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Abstract

The timely secretion of gonadal sex steroids is essential for the initiation of puberty, the postpubertal maintenance of secondary sexual characteristics and the normal perinatal development of male external genitalia. Normal gonadal steroid production requires the actions of the pituitary-derived gonadotropins, luteinizing hormone and follicle-stimulating hormone. We report four human pedigrees with severe congenital gonadotropin deficiency and pubertal failure in which all affected individuals are homozygous for loss-of-function mutations in TAC3 (encoding Neurokinin B) or its receptor TACR3 (encoding NK3R). Neurokinin B, a member of the substance P-related tachykinin family, is known to be highly expressed in hypothalamic neurons that also express kisspeptin, a recently identified regulator of gonadotropin-releasing hormone secretion. These findings implicate Neurokinin B as a critical central regulator of human gonadal function and suggest new approaches to the pharmacological control of human reproduction and sex hormone-related diseases.

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Two of the most important excitatory components of the GnRH network were identified with the demonstration that the genetic loss of such inputs results in failure to initiate the GnRH pulse generator at the expected time of puberty, resulting in isolated hypogonadotropic hypogonadism.
“Two of the most important excitatory components of the GnRH network were identified with the demonstration that the genetic loss of such inputs results in failure to initiate the GnRH pulse generator at the expected time of puberty, resulting in isolated hypogonadotropic hypogonadism.42–45”
From Pubertal development and regulation (2016) · cites this paper as [44]
In 2009, Topaloglu and colleagues identified NKB as an important factor for human puberty initiation, studying ten consanguineous families with multiple affected members who had isolated hypogonadotropic hypogonadism.
“It was not until 2009 that Topaloglu and colleagues44 identified NKB as an important factor for human puberty initiation, studying ten consanguineous families with multiple affected members who had isolated hypogonadotropic hypogonadism.”
From Pubertal development and regulation (2016) · cites this paper as [44]
Homozygous loss-of-function mutations in the genes encoding the NKB receptor (TACR3) and neurokinin B (TAC3) were identified, providing compelling evidence that the NKB system is necessary for the activation of the hypothalamic-pituitary-gonadal axis in puberty.
“Homozygous loss-of-function mutations in the genes encoding the NKB receptor (TACR3) and neurokinin B (TAC3) were identified, providing compelling evidence that the NKB system is necessary for the activation of the hypothalamic-pituitary-gonadal axis in puberty (table, figure 2).”
From Pubertal development and regulation (2016) · cites this paper as [44]
Although studies in animals have led to identification of regulators of GnRH such as catecholamines, GABA, and glutamate, genetic studies of patients with pubertal disorders have resulted in the identification of a major regulatory hub for the GnRH neurons-ie, the hypothalamic neurons expressing kisspeptin and neurokinin B.
“Although studies in animals have led to identification of regulators of GnRH such as catecholamines, GABA, and glutamate, genetic studies of patients with pubertal disorders have resulted in the identification of a major regulatory hub for the GnRH neurons—ie, the hypothalamic neurons expressing kisspeptin and neurokinin B.42–44”
From Pubertal development and regulation (2016) · cites this paper as [44]
In vitro studies showed that the Gly93Asn and Pro353Ser mutations impair the ability of NKR to activate signal transduction.
“In vitro studies showed that these two mutations impair the ability of NKR to activate signal transduction.63”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [63]

Two mutations found in TACR3 replace highly conserved amino acids located in the first (Gly93Asn) or sixth (Pro353Ser) transmembrane domain of NKR.
“Two mutations found in TACR3 replace highly conserved amino acids located in the first (Gly93Asn) or sixth (Pro353Ser) transmembrane domain of NKR.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [63]
The Met90Thr mutation is located within the canonical tachykinin motif in the carboxyl terminus of the mature ligand.
“This mutation is located within the canonical tachykinin motif in the carboxyl terminus of the mature ligand.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [63]
NKB and its receptor have a possible role in the regulation of GnRH secretion.
“NKB is expressed in the arcuate nucleus and its receptor is expressed in GnRH neurons of rodents, which suggests it has a possible role in the regulation of GnRH secretion.63”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [63]
In one family, a Met90Thr amino acid substitution of NKB affected individuals homozygous for the mutation but not those who were heterozygous.
“In one family, a Met90Thr amino acid substitution of NKB affected individuals homozygous for the mutation but not those who were heterozygous.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [63]
NKB is expressed in the arcuate nucleus and its receptor is expressed in GnRH neurons of rodents.
“NKB is expressed in the arcuate nucleus and its receptor is expressed in GnRH neurons of rodents, which suggests it has a possible role in the regulation of GnRH secretion.63”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [63]
The Gly93Asn mutation was found in all affected members of one family, whereas the Pro353Ser mutation was found in all affected members of two other families.
“The Gly93Asn mutation was found in all affected members of one family, whereas the Pro353Ser mutation was found in all affected members of two other families.63”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [63]
In vitro studies showed that stimulation of NKR by NKB is markedly impaired by the Met90Thr substitution.
“In vitro studies showed that the stimulation of NKR by NKB is markedly impaired by the Met90Thr substitution.63”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [63]
The tachykinin motif is predicted to undergo post-translational amidation for full activation of NKB.
“The tachykinin motif is predicted to undergo post-translational amidation for full activation of NKB.63”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [63]
A genome-wide single nucleotide polymorphism analysis identified homozygous mutations in TAC3 or TACR3 that segregated with the IHH phenotype in four of nine unrelated consanguineous families.
“A recent genome-wide single nucleotide polymorphism analysis identified homozygous mutations in TAC3 or TACR3 that segregated with the IHH phenotype in four (of nine) unrelated consanguineous families.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [63]
Kisspeptin and neurokinin B are essential for pubertal development and fertility in humans.
“Moreover, two of the peptides in the hypertrophied neurons, kisspeptin and neurokinin B, are essential for pubertal development and fertility in the human (Chan et al., 2011; Topaloglu et al., 2009, 2012).”
From Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: A novel hypothesis on the mechanism of hot flushes (2013) · cites this paper as Topaloglu et al., 2009
Individuals with mutations in the genes encoding NKB or its receptor NK3R are infertile and do not transition through puberty.
“The significance of this line of inquiry became apparent with the discovery that individuals with mutations in the genes encoding NKB or its receptor (NK3R) are infertile and do not transition through puberty (Gianetti et al., 2010; Topaloglu et al., 2009; Young et al., 2010).”
From Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: A novel hypothesis on the mechanism of hot flushes (2013) · cites this paper as Topaloglu et al., 2009
Rare deleterious mutations in TAC3R and its ligand TAC3 have been found in families affected by hypogonadotropic hypogonadism and pubertal failure.
“Rare deleterious mutations in TAC3R, encoding a receptor for Neurokinin B, and in its ligand TAC3 have been found in families affected by hypogonadotropic hypogonadism and pubertal failure31.”
From Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies (2010) · cites this paper as [31]

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“Indeed, Topaloglu et al. (2009) have recently shown that mutations of either Trc3 or Tacr3, which encode NKB and NK3, respectively, produce gonadotropin deficiency and pubertal failure in humans.”
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TAC3andTACR3Defects Cause Hypothalamic Congenital Hypogonadotropic Hypogonadism in Humans
Young, J., Bouligand, J., Francou, B., Raffin-Sanson, M.-L., Gaillez, S., Jeanpierre, M., Grynberg, M., Kamenicky, P., Chanson, P., Brailly-Tabard, S., et al. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-2600 · Cited by 249 · see citing works
TAC3/TACR3 Mutations Reveal Preferential Activation of GnRH Release by Neurokinin B in Neonatal Life Followed by Reversal in Adulthood
Gianetti, E., Tusset, C., Noel, S. D., Au, M., Dwyer, A. A., HUGHES, V. A., Abreu, A. P., Carroll, J., Trarbach, E. B., Silveira, L. F., et al. (2010) · Endocrine Reviews · doi:10.1210/edrv.31.2.9979 · Cited by 1 · see citing works
TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood
Gianetti, E., Tusset, C., Noel, S. D., Au, M. G., Dwyer, A. A., Hughes, V. A., Abreu, A. P., Carroll, J., Trarbach, E., Silveira, L. F. G., et al. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-2320 · Cited by 294 · see citing works
Neurokinin B Signalling in Human Puberty
Topaloglu, A. K., Kotan, L. D., & Yüksel, B. (2010) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2010.02013.x · Cited by 11 · see citing works
Self-citation
Neurokinin B and its receptor in idiopathic hypogonadotropic hypogonadism
Jiang, Y., Sun, S., & Wang, W. (2013) · Zhonghua neifenmi daixie zazhi · doi:10.3760/cma.j.issn.1000-6699.2013.01.025

Authors: Topaloglu, A. K., Reimann, F., Guclu, M., Yalin, A. S., Kotan, L. D., Porter, K. M., Serin, A., Mungan, N. O., Cook, J. R., Ozbek, M. N., Imamoglu, S., Akalin, N. S., Yuksel, B., O'Rahilly, S., & Semple, R. K.
Affiliations: Cukurova University (TR)
University of Cambridge (GB)
Marmara University (TR)
Corresponding author: Topaloglu, A Kemal
ORCID: Topaloglu, A Kemal
Reimann, Frank
Kotan, L Damla
Cook, Joshua R
Semple, Robert K
Venue: Nature Genetics
Publisher: Springer Science and Business Media LLC
Published: 2008-12-11
Volume: 41
Issue: 3
Pages: 354-358
ISSN: 1061-4036 (ISSN-L)
1546-1718
DOI: 10.1038/ng.306
PMC: PMC4312696
OpenAlex: W2010920434
Cited by: 961
References: 33
Citations by year: 2026: 19 · 2025: 31 · 2024: 43 · 2023: 45 · 2022: 47 · 2021: 57 · 2020: 49 · 2019: 63 · 2018: 55 · 2017: 54 · 2016: 63 · 2015: 69 · 2014: 74 · 2013: 63 · 2012: 63
FWCI: 63.33
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Genetics (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Bursa Uludag University - AVESIS (submittedVersion)
Dspace Repository (Marmara Üniversitesi) (submittedVersion, other-oa)
Dspace Repository (Marmara Üniversitesi) (submittedVersion)
Funders: Wellcome Trust (078986/Z/06/Z, 078986, 080952/Z/06/Z, 080952, 084210)
Topics: Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
Keywords: TAC3, TACR3, neurokinin B, NK3 receptor, pubertal failure, loss-of-function mutations, tachykinins, kisspeptin, hypothalamus, gonadotropin-releasing hormone
MeSH terms: Amino Acid Sequence, Chromosomes, Human, Pair 4, DNA Mutational Analysis, Family, Gonads, Humans, Hypogonadism, Models, Biological, Mutation, Neurons, Pedigree, Reproduction, Neurokinin B, Sequence Homology, Amino Acid, Receptors, Neurokinin-3, Tumor Suppressor Proteins, Kisspeptins

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TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction

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