Alternative titles; symbols
HGNC Approved Gene Symbol: TACR3
Cytogenetic location: 4q24 Genomic coordinates (GRCh38) : 4:103,586,031-103,719,985 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q24 | Hypogonadotropic hypogonadism 11 with or without anosmia | 614840 | Autosomal recessive | 3 |
Tachykinin receptor-3 (TACR3) is the mediator of biologic actions encoded by the C-terminal sequence of tachykinins, for which neurokinin B (TAC3; 162330) is a more potent agonist than neurokinin A or substance P (see TAC1, 162320) (summary by Maggi, 1995).
Huang et al. (1992) isolated cDNA clones encoding the neurokinin-3 receptor from human brain mRNA. The deduced protein contains 465 amino acids.
Gross (2014) mapped the TACR3 gene to chromosome 4q24 based on an alignment of the TACR3 sequence (GenBank AY462099) with the genomic sequence (GRCh37).
Huang et al. (1992) expressed the cloned neurokinin-3 receptor in COS-7 cells and Xenopus oocytes, where peptide binding affinity and intracellular effector activation were determined. Neurokinin B was the most potent agonist.
Gill et al. (2012) identified expression of mouse Tac2, the ortholog of human TAC3, and of its receptor, Tacr3, in the arcuate nucleus as markers of pubertal activation in mouse. However, increased Tac2/Tacr3 signaling alone was insufficient to trigger onset of puberty.
In 1 Turkish and 2 Kurdish consanguineous families with normosmic hypogonadotropic hypogonadism (HH11; 614840) mapping to chromosome 4q, Topaloglu et al. (2009) analyzed the candidate gene TACR3 and identified homozygosity for 2 missense mutations that segregated with disease (162332.0001 and 162332.0002, respectively). Functional studies showed that the mutant receptors had impaired signaling, and the mutations were not found in 100 ethnically matched controls.
In 19 probands with normosmic HH, most of whom were known to be negative for mutation in 7 or 8 other HH-associated genes, Gianetti et al. (2010) identified 13 distinct variants in the TACR3 gene (see, e.g., 162332.0003 and 162332.0004). In some patients, a mutation was detected on only 1 allele of TACR3. Of 16 males carrying TACR3 variants for whom physical evidence was available, 15 (94%) had microphallus identified either neonatally or later in life. In addition, 10 (83%) of 12 patients who were assessed longitudinally after discontinuation of sex steroid therapy exhibited evidence of spontaneous partial or complete recovery of their reproductive axis. Gianetti et al. (2010) noted that the high prevalence of reversal suggested that the role of the NKB system in GnRH (152760) secretion may be less critical in adult life than during late gestation and the early neonatal period.
In a brother and sister with normosmic hypogonadotropic hypogonadism (HH11; 614840) from a consanguineous Turkish family, Topaloglu et al. (2009) identified homozygosity for a 278G-A transition in the TACR3 gene, resulting in a gly93-to-asp (G93D) substitution in the first transmembrane domain of NK3R. Although this residue is not highly conserved, the authors noted that introduction of a negatively charged side chain in this very hydrophobic domain is likely to be highly thermodynamically unstable. Studies in HEK293 cells showed unequivocal evidence of impaired receptor signaling with the mutant protein. The unaffected parents and 3 unaffected sibs were all heterozygous for the mutation, which was not found in 100 Turkish controls.
In affected members of 2 consanguineous Kurdish families with normosmic hypogonadotropic hypogonadism (HH11; 614840), Topaloglu et al. (2009) identified homozygosity for a 1057C-T transition in the TACR3 gene, resulting in a pro353-to-ser (P353S) substitution at a highly conserved residue within the sixth transmembrane domain. Studies in HEK293 cells showed unequivocal evidence of impaired receptor signaling with the mutant protein. All 4 unaffected parents were heterozygous for the mutation, which was not found in 100 Kurdish controls.
In 3 male probands with normosmic hypogonadotropic hypogonadism (HH11; 614840) who were negative for mutation in at least 7 other HH-associated genes, Gianetti et al. (2010) identified homozygosity for a c.824G-A transition in the TACR3 gene, resulting in a trp275-to-ter (W275X) substitution. In addition, W275X was found in heterozygosity in 4 more male probands with normosmic HH, who were also negative for mutation in 7 other HH-associated genes. One of the latter probands was also found to carry a synonymous variant (L58L) on the other allele of TACR3. There was evidence for neuroendocrine recovery in 3 of the 7 probands, with spontaneous fertility in 2 and increased LH pulses in 1 after discontinuation of sex steroid therapy.
In a male proband with normosmic hypogonadotropic hypogonadism (HH11; 614840) who was negative for mutation in 8 other HH-associated genes, Gianetti et al. (2010) identified homozygosity for a c.766T-C transition in the TACR3 gene, resulting in a tyr256-to-his (Y256H) substitution. Studies in transfected COS-7 cells showed complete loss of function with the Y256H mutant compared to wildtype. The patient had 'small phallus' noted at birth, with 'normal phallus' reported after treatment, and showed evidence for neuroendocrine recovery, with increased testosterone reported after discontinuation of sex steroid therapy.
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., Costa, E. M. F., de Mendonca, B. B., and 14 others. TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood. J. Clin. Endocr. Metab. 95: 2857-2867, 2010. [PubMed: 20332248] [Full Text: https://doi.org/10.1210/jc.2009-2320]
Gill, J. C., Navarro, V. M., Kwong, C., Noel, S. D., Martin, C., Xu, S., Clifton, D. K., Carroll, R. S., Steiner, R. A., Kaiser, U. B. Increased neurokinin B (Tac2) expression in the mouse arcuate nucleus is an early marker of pubertal onset with differential sensitivity to sex steroid-negative feedback than Kiss1. Endocrinology 153: 4883-4893, 2012. [PubMed: 22893725] [Full Text: https://doi.org/10.1210/en.2012-1529]
Gross, M. B. Personal Communication. Baltimore, Md. 5/27/2014.
Huang, R.-R. C., Cheung, A. H., Mazina, K. E., Strader, C. D., Fong, T. M. cDNA sequence and heterologous expression of the human neurokinin-3 receptor. Biochem. Biophys. Res. Commun. 184: 966-972, 1992. [PubMed: 1374246] [Full Text: https://doi.org/10.1016/0006-291x(92)90685-e]
Maggi, C. A. The mammalian tachykinin receptors. Gen. Pharmacol. 26: 911-944, 1995. [PubMed: 7557266] [Full Text: https://doi.org/10.1016/0306-3623(94)00292-u]
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. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction. Nature Genet. 41: 354-358, 2009. [PubMed: 19079066] [Full Text: https://doi.org/10.1038/ng.306]