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

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.

Current and future applications of GnRH, kisspeptin and neurokinin B analogues

“…Inactivating mutations of two of these, kisspeptin (KP) and neurokinin B (NKB), or their cognate receptors, recently highlighted the crucial role of these neuropeptides in GnRH neurone activation, as these mutations result in a failure to progress through puberty and in adult infertility [6][7][8][9][10][11] . In addition to these major modulators of GnRH secretion, neuropeptide Y, products of the pro-opiomelanocortin protein, gonadotropin-inhibitory-hormone (GnIH) and neurotransmitters such as gamma amino butyric acid and glutamine also regulate GnRH neurone activity 12,13 .…”

“…Thus, Phe 6 , Arg 9 and Phe 10 appears to constitute a binding pharmacophore with proposed stacking of phenyl rings of Phe 6 and Phe 10 flanked by Arg 9 and Leu 8 with side chains orientated on the opposite side of the peptide 107 . Another approach utilizing knowledge of KP-10 structure involves conservative changes at target positions, such as changing the side chain but not the overall charge of a residue, substituting L-amino acids with D-amino acids to assess the positioning of side chains and making radical structural changes to change overall charge or flexibility of the analogue.…”

“…Amongst a large number of analogues it is evident from ensuing patents that the critical pharmacophore of Phe 6 , Arg 9 , and Phe10 mentioned above is retained or altered with conservative amino acid substitutions. Other positions in the KP-10 sequence were subject to a range of substitutions to provide resistance to degradation and improved pharmacokinetics.…”

“…In 2009, inactivating mutations in the human genes encoding NKB and its cognate receptor, TACR3/NK3R, were shown, like GPR54 mutations, to result in a failure to progress through puberty and in hypogonadotropic hypogonadism in adulthood [9][10][11] . In contrast, the original study of an inactivating mutation in the Tacr3 gene (encoding TACR3) in mice, did not observe reproductive impairment 127 .…”

“…Other studies in monkeys 130 , goats 131 and sheep 132 show a clear stimulatory role for NKB in gonadotropin secretion; in keeping with the observations in humans of decreased LH in the absence of NKB signaling. The patients with inactivating mutations of genes encoding NKB or its receptor were characterized by very low LH but normal or near-normal circulating FSH levels 9 . This situation would be produced by a low GnRH pulse frequency 133 .…”