TAC3 and TACR3 Mutations in Familial Hypogonadotropic Hypogonadism Reveal a Key Role for Neurokinin B in the Central Control of Reproduction

By A. Topaloğlu, F. Reimann, M. Guclu, A. Yalin, L. D. Kotan, K. Porter, Ayse Serin, N. Mungan, Joshua R. Cook, M. Ozbek and 5 more. Nature Genetics, 2008

891 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Reproductive Medicine

View Paper: https://www.semanticscholar.org/paper/9d1e77700055e9d34234af6bebb0712937a8a6fe

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In Reproductive Medicine

1. D. Clifton
2. R. Steiner

Citations in the corpus

• Kisspeptins and reproduction: physiological roles and regulatory mechanisms. (2012, background): “Although NKB had been previously involved in the control of the HPG axis in mammals (367), its physiological importance did not gain general recognition until the association between inactivating mutations in TAC3/TACR3 and human cases of HH was first reported (475).”
• Regulation of gonadotropin-releasing hormone secretion by kisspeptin/dynorphin/neurokinin B neurons in the arcuate nucleus of the mouse (2009, background): “Moreover, disabling mutations of either NKB (known as TAC3 in humans) or the NKB type 3 receptor gene (NK3) (known as TAC3R in humans) are associated with reproductive failure (Topaloglu et al., 2009).”