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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


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 kisspeptin1, a recently identified regulator of gonadotropin-releasing hormone secretion2. 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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Figure 1: Identification of rare missense mutations in TACR3 associated with nIHH.
Figure 2: Identification of a rare missense mutation in TAC3 associated with nIHH.
Figure 3: Both missense mutations in NK3R result in loss of receptor function.
Figure 4: The missense mutations in NKB results in marked loss of agonist function at the NK3R.

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This work was supported by grants to A.K.T., N.O.M. and B.Y. from the Scientific and Technological Research Council of Turkey (TÜBİTAK): The Support Programme for Scientific and Technological Research Projects (1001), project 106S276; and from the Cukurova University Scientific Research Projects Support Unit, grant TF-2006-BAP20; by the Wellcome Trust (R.K.S., Intermediate Clinical Fellowship 080952/Z/06/Z; S.O., Programme Grant 078986/Z/06/Z; F.R., Senior Basic Science Fellowship) and the UK National Institute for Health Research Cambridge Biomedical Research Centre. F.R. has also received support from St. John's College, Cambridge, UK.

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This study was designed by A.K.T. Identification of subjects and phenotypic assessment were undertaken by A.K.T., M.G., A.S.Y., N.O.M, M.N.O., S.I., N.S.A. and B.Y. DNA extraction, autozygosity mapping, and DNA sequencing were performed by A.K.T., L.D.K. and A.S.; mutagenesis, cloning and functional studies were undertaken by F.R., K.M.P., R.K.S. and J.R.C. The manuscript was written by A.K.T., R.K.S., F.R. and S.O.

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Correspondence to A Kemal Topaloglu or Stephen O'Rahilly.

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Topaloglu, A., Reimann, F., Guclu, M. et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet 41, 354–358 (2009).

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