Alternative titles; symbols
HGNC Approved Gene Symbol: TAC3
Cytogenetic location: 12q13.3 Genomic coordinates (GRCh38) : 12:57,010,000-57,016,529 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.3 | Hypogonadotropic hypogonadism 10 with or without anosmia | 614839 | Autosomal recessive | 3 |
Searching for causes of preeclampsia (189800), Page et al. (2000) sought vasoactive placental neuropeptides using mRNA fingerprinting and human databases and found 9 matches that showed high similarity to bovine NKB precursor. Cloning the full-length gene revealed an open reading frame of 363 bases, predicting a 121-residue human proneurokinin B. The precursor protein gives rise to a mature peptide of 10 amino acids that is identical to neurokinin B of other mammalian species. Expression of placental NKB mRNA was detected in the first trimester and increased 5-fold at term. In situ hybridization studies on human placenta at term located it to the outer syncytiotrophoblasts, ideally positioned to secrete its peptide into the maternal blood. Significant amounts of immunoreactive human NKB were found in early and term placentae. Samples taken from nonpregnant laboratory personnel all had low or undetectable levels of the peptide, as did most samples taken from normotensive women throughout gestation, a proportion of whom exhibited slight increases at term. Patients in the third trimester suffering from pregnancy-induced hypertension and preeclampsia had concentrations in the nanomolar range. Simultaneous samples taken from maternal and cord blood showed levels in cord blood that were roughly one-third that of the mother, indicating that hypersecretion of NKB could also affect neurokinin receptors in the fetoplacental circulation. When NKB was undetectable in maternal blood, it was also undetectable in cord blood. In female rats, concentrations of NKB several-fold above that of an animal 20 days into pregnancy caused substantial pressor activity.
Gill et al. (2012) identified expression of mouse Tac2, the ortholog of human TAC3, and of its receptor, Tacr3 (162332), 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 a consanguineous Turkish family with normosmic hypogonadotropic hypogonadism (HH10; 614389) mapping to chromosome 12q, Topaloglu et al. (2009) analyzed the candidate gene TAC3 and identified homozygosity for a missense mutation in 2 affected sisters (162330.0001). Functional studies showed that the mutant protein had 10-fold less activity than wildtype, and the mutation was not found in 100 Turkish controls.
In 4 sisters from a consanguineous Asian family with hypogonadotropic hypogonadism, 3 of whom were normosmic and 1 anosmic, Gianetti et al. (2010) identified homozygosity for a 1-bp deletion in the TAC3 gene (162330.0002). There was evidence for neuroendocrine recovery after discontinuation of sex steroid therapy in the affected sisters, suggesting 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.
Hug et al. (2019) reported a 3-year-old male domestic shorthair cat with persistent primary dentition and testicular hypoplasia. The cat also had a small body with unkempt hair coat, and its blood testosterone level was lower than the reference range for cats. The authors identified a homozygous val74-to-met (V74M) substitution in the Tas3 gene as a possible causative variant in the affected cat. Two domestic shorthair cats without testicular hypoplasia or persistent primary dentition were heterozygous for the V74M mutation in Tas3.
In 2 sisters with normosmic hypogonadotropic hypogonadism (HH10; 614839) from a consanguineous Turkish family, Topaloglu et al. (2009) identified homozygosity for a 269T-C transition in the TAC3 gene, resulting in a met90-to-thr (M90T) substitution of the C-terminal residue of the mature NKB decapeptide, within the universally conserved tachykinin motif phe-xaa-gly-leu-met-NH(2). Functional studies with the wildtype receptor (TACR3; 162332) showed that the amidated mutant peptide had markedly reduced activity, being approximately 10-fold less potent than amidated wildtype NKB at stimulating the receptor. The unaffected parents and an unaffected sister were heterozygous for the mutation, which was not found in 100 Turkish controls.
In 4 sisters from a consanguineous Asian family with hypogonadotropic hypogonadism, 3 of whom were normosmic and 1 anosmic (HH10; 614839), Gianetti et al. (2010) identified homozygosity for a 1-bp deletion (c.60delG) in the TAC3 gene, causing a frameshift (Gly20fsTer39) and a premature termination codon in the precursor upstream of the NKB decapeptide. An unaffected sister was heterozygous for the deletion.
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]
Hug, P., Kern, P., Jagannathan, V., Leeb, T. A TAC3 missense variant in a domestic shorthair cat with testicular hypoplasia and persistent primary dentition. Genes (Basel) 10: E806, 2019. Note: Electronic Article. [PubMed: 31615056] [Full Text: https://doi.org/10.3390/genes10100806]
Page, N. M., Woods, R. J., Gardiner, S. M., Lomthaisong, K., Gladwell, R. T., Butlin, D. J., Manyonda, I. T., Lowry, P. J. Excessive placental secretion of neurokinin B during the third trimester causes pre-eclampsia. Nature 405: 797-800, 2000. [PubMed: 10866201] [Full Text: https://doi.org/10.1038/35015579]
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]