title: 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.
authors.affiliation: Cukurova University, Faculty of Medicine, Department of Pediatric Endocrinology and Metabolism, Balcali, Adana, TURKEY.
authors.forename: A Kemal
authors.initials: AK
authors.lastname: Topaloglu
authors.affiliation: Cambridge Institute for Medical Research and Department of Clinical Biochemistry, University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: Frank
authors.initials: F
authors.lastname: Reimann
authors.affiliation: Uludag University, Faculty of Medicine, Department of Endocrinology and Metabolism, Bursa, TURKEY.
authors.forename: Metin
authors.initials: M
authors.lastname: Guclu
authors.affiliation: Marmara University, Faculty of Medicine, Department of Endocrinology and Metabolism, Istanbul, TURKEY.
authors.forename: Ayse Serap
authors.initials: AS
authors.lastname: Yalin
authors.affiliation: Cukurova University, Faculty of Medicine, Department of Forensic Medicine, Balcali, Adana, TURKEY.
authors.forename: L Damla
authors.initials: LD
authors.lastname: Kotan
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Porter
authors.affiliation: Cukurova University, Faculty of Medicine, Department of Forensic Medicine, Balcali, Adana, TURKEY.
authors.forename: Ayse
authors.initials: A
authors.lastname: Serin
authors.affiliation: Cukurova University, Faculty of Medicine, Department of Pediatric Endocrinology and Metabolism, Balcali, Adana, TURKEY.
authors.forename: Neslihan O
authors.initials: NO
authors.lastname: Mungan
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Cook
authors.affiliation: Uludag University, Faculty of Medicine, Department of Endocrinology and Metabolism, Bursa, TURKEY.
authors.forename: Sazi
authors.initials: S
authors.lastname: Imamoglu
authors.affiliation: Marmara University, Faculty of Medicine, Department of Endocrinology and Metabolism, Istanbul, TURKEY.
authors.forename: N Sema
authors.initials: NS
authors.lastname: Akalin
authors.affiliation: Cukurova University, Faculty of Medicine, Department of Pediatric Endocrinology and Metabolism, Balcali, Adana, TURKEY.
authors.forename: Bilgin
authors.initials: B
authors.lastname: Yuksel
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Semple
mesh_terms: D000595:Amino Acid Sequence; D002894:Chromosomes, Human, Pair 4; D004252:DNA Mutational Analysis; D005190:Family; D006066:Gonads / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D059648:Kisspeptins; D008954:Models, Biological; D009154:Mutation / Q000502:physiology; D015287:Neurokinin B / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D010375:Pedigree; D018042:Receptors, Neurokinin-3 / Q000235:genetics* / Q000378:metabolism; D012098:Reproduction / Q000235:genetics* / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C106628:KISS1 protein, human; D059648:Kisspeptins; D018042:Receptors, Neurokinin-3; D025521:Tumor Suppressor Proteins; D015287:Neurokinin B