title: Hypogonadotropic hypogonadism due to a novel missense mutation in the first extracellular loop of the neurokinin B receptor.
abstract: BACKGROUND
  The neurokinin B (NKB) receptor, encoded by TACR3, is widely expressed within the central nervous system, including hypothalamic nuclei involved in regulating GnRH release. We have recently reported two mutations in transmembrane segments of the receptor and a missense mutation in NKB in patients with normosmic isolated hypogonadotropic hypogonadism (nIHH).
  
  
  METHODS
  We sequenced the TACR3 gene in a family in which three siblings had nIHH. The novel mutant receptor thus identified was studied in a heterologous expression system using calcium flux as the functional readout.
  
  
  RESULTS
  All affected siblings were homozygous for the His148Leu mutation, in the first extracellular loop of the NKB receptor. The His148Leu mutant receptor exhibited profoundly impaired signaling in response to NKB (EC(50) = 3 +/- 0.1 nm and >5 microm for wild-type and His148Leu, respectively). The location of the mutation in an extracellular part of the receptor led us also to test whether senktide, a synthetic NKB analog, may retain ability to stimulate the mutant receptor. However, the signaling activity of the His148Leu receptor in response to senktide was also severely impaired (EC(50) = 1 +/- 1 nm for wild-type and no significant response of His148Leu to 10 microm).
  
  
  CONCLUSIONS
  Homozygosity for the TACR3 His148Leu mutation leads to failure of sexual maturation in humans, whereas signaling by the mutant receptor in vitro in response to either NKB or senktide is severely impaired. These observations further strengthen the link between NKB, the NKB receptor, and regulation of human reproductive function.
authors.affiliation: Pediatric Endocrinology (T.G., A.B., S.T., T.A., Z.A.), Marmara University Hospital, Altunizade, 34662 Istanbul, Turkey; University of Cambridge (F.R., F.M.G., G.T.), Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; University of Cambridge Metabolic Research Laboratories (N.R., K.P., S.O., R.K.S.), Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; Forensic Medicine (L.D.K., H.C., A.S.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey; and Pediatric Endocrinology and Metabolism (A.K.T.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey.
authors.forename: Tulay
authors.initials: T
authors.lastname: Guran
authors.affiliation: Pediatric Endocrinology (T.G., A.B., S.T., T.A., Z.A.), Marmara University Hospital, Altunizade, 34662 Istanbul, Turkey; University of Cambridge (F.R., F.M.G., G.T.), Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; University of Cambridge Metabolic Research Laboratories (N.R., K.P., S.O., R.K.S.), Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; Forensic Medicine (L.D.K., H.C., A.S.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey; and Pediatric Endocrinology and Metabolism (A.K.T.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey.
authors.forename: Gwen
authors.initials: G
authors.lastname: Tolhurst
authors.affiliation: Pediatric Endocrinology (T.G., A.B., S.T., T.A., Z.A.), Marmara University Hospital, Altunizade, 34662 Istanbul, Turkey; University of Cambridge (F.R., F.M.G., G.T.), Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; University of Cambridge Metabolic Research Laboratories (N.R., K.P., S.O., R.K.S.), Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; Forensic Medicine (L.D.K., H.C., A.S.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey; and Pediatric Endocrinology and Metabolism (A.K.T.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Bereket
authors.affiliation: Pediatric Endocrinology (T.G., A.B., S.T., T.A., Z.A.), Marmara University Hospital, Altunizade, 34662 Istanbul, Turkey; University of Cambridge (F.R., F.M.G., G.T.), Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; University of Cambridge Metabolic Research Laboratories (N.R., K.P., S.O., R.K.S.), Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; Forensic Medicine (L.D.K., H.C., A.S.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey; and Pediatric Endocrinology and Metabolism (A.K.T.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey.
authors.forename: Nuno
authors.initials: N
authors.lastname: Rocha
authors.affiliation: Pediatric Endocrinology (T.G., A.B., S.T., T.A., Z.A.), Marmara University Hospital, Altunizade, 34662 Istanbul, Turkey; University of Cambridge (F.R., F.M.G., G.T.), Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; University of Cambridge Metabolic Research Laboratories (N.R., K.P., S.O., R.K.S.), Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; Forensic Medicine (L.D.K., H.C., A.S.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey; and Pediatric Endocrinology and Metabolism (A.K.T.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey.
authors.forename: Keith
authors.initials: K
authors.lastname: Porter
authors.affiliation: Pediatric Endocrinology (T.G., A.B., S.T., T.A., Z.A.), Marmara University Hospital, Altunizade, 34662 Istanbul, Turkey; University of Cambridge (F.R., F.M.G., G.T.), Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; University of Cambridge Metabolic Research Laboratories (N.R., K.P., S.O., R.K.S.), Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; Forensic Medicine (L.D.K., H.C., A.S.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey; and Pediatric Endocrinology and Metabolism (A.K.T.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey.
authors.forename: Serap
authors.initials: S
authors.lastname: Turan
authors.affiliation: Pediatric Endocrinology (T.G., A.B., S.T., T.A., Z.A.), Marmara University Hospital, Altunizade, 34662 Istanbul, Turkey; University of Cambridge (F.R., F.M.G., G.T.), Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; University of Cambridge Metabolic Research Laboratories (N.R., K.P., S.O., R.K.S.), Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; Forensic Medicine (L.D.K., H.C., A.S.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey; and Pediatric Endocrinology and Metabolism (A.K.T.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Gribble
authors.affiliation: Pediatric Endocrinology (T.G., A.B., S.T., T.A., Z.A.), Marmara University Hospital, Altunizade, 34662 Istanbul, Turkey; University of Cambridge (F.R., F.M.G., G.T.), Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; University of Cambridge Metabolic Research Laboratories (N.R., K.P., S.O., R.K.S.), Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; Forensic Medicine (L.D.K., H.C., A.S.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey; and Pediatric Endocrinology and Metabolism (A.K.T.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey.
authors.forename: L Damla
authors.initials: LD
authors.lastname: Kotan
authors.affiliation: Pediatric Endocrinology (T.G., A.B., S.T., T.A., Z.A.), Marmara University Hospital, Altunizade, 34662 Istanbul, Turkey; University of Cambridge (F.R., F.M.G., G.T.), Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; University of Cambridge Metabolic Research Laboratories (N.R., K.P., S.O., R.K.S.), Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; Forensic Medicine (L.D.K., H.C., A.S.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey; and Pediatric Endocrinology and Metabolism (A.K.T.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey.
authors.forename: Teoman
authors.initials: T
authors.lastname: Akcay
authors.affiliation: Pediatric Endocrinology (T.G., A.B., S.T., T.A., Z.A.), Marmara University Hospital, Altunizade, 34662 Istanbul, Turkey; University of Cambridge (F.R., F.M.G., G.T.), Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; University of Cambridge Metabolic Research Laboratories (N.R., K.P., S.O., R.K.S.), Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; Forensic Medicine (L.D.K., H.C., A.S.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey; and Pediatric Endocrinology and Metabolism (A.K.T.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Atay
authors.affiliation: Pediatric Endocrinology (T.G., A.B., S.T., T.A., Z.A.), Marmara University Hospital, Altunizade, 34662 Istanbul, Turkey; University of Cambridge (F.R., F.M.G., G.T.), Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; University of Cambridge Metabolic Research Laboratories (N.R., K.P., S.O., R.K.S.), Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; Forensic Medicine (L.D.K., H.C., A.S.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey; and Pediatric Endocrinology and Metabolism (A.K.T.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey.
authors.forename: Husniye
authors.initials: H
authors.lastname: Canan
authors.affiliation: Pediatric Endocrinology (T.G., A.B., S.T., T.A., Z.A.), Marmara University Hospital, Altunizade, 34662 Istanbul, Turkey; University of Cambridge (F.R., F.M.G., G.T.), Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; University of Cambridge Metabolic Research Laboratories (N.R., K.P., S.O., R.K.S.), Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; Forensic Medicine (L.D.K., H.C., A.S.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey; and Pediatric Endocrinology and Metabolism (A.K.T.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey.
authors.forename: Ayse
authors.initials: A
authors.lastname: Serin
authors.affiliation: Pediatric Endocrinology (T.G., A.B., S.T., T.A., Z.A.), Marmara University Hospital, Altunizade, 34662 Istanbul, Turkey; University of Cambridge (F.R., F.M.G., G.T.), Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; University of Cambridge Metabolic Research Laboratories (N.R., K.P., S.O., R.K.S.), Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; Forensic Medicine (L.D.K., H.C., A.S.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey; and Pediatric Endocrinology and Metabolism (A.K.T.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey.
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.affiliation: Pediatric Endocrinology (T.G., A.B., S.T., T.A., Z.A.), Marmara University Hospital, Altunizade, 34662 Istanbul, Turkey; University of Cambridge (F.R., F.M.G., G.T.), Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; University of Cambridge Metabolic Research Laboratories (N.R., K.P., S.O., R.K.S.), Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; Forensic Medicine (L.D.K., H.C., A.S.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey; and Pediatric Endocrinology and Metabolism (A.K.T.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey.
authors.forename: Frank
authors.initials: F
authors.lastname: Reimann
authors.affiliation: Pediatric Endocrinology (T.G., A.B., S.T., T.A., Z.A.), Marmara University Hospital, Altunizade, 34662 Istanbul, Turkey; University of Cambridge (F.R., F.M.G., G.T.), Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; University of Cambridge Metabolic Research Laboratories (N.R., K.P., S.O., R.K.S.), Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; Forensic Medicine (L.D.K., H.C., A.S.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey; and Pediatric Endocrinology and Metabolism (A.K.T.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Semple
authors.affiliation: Pediatric Endocrinology (T.G., A.B., S.T., T.A., Z.A.), Marmara University Hospital, Altunizade, 34662 Istanbul, Turkey; University of Cambridge (F.R., F.M.G., G.T.), Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; University of Cambridge Metabolic Research Laboratories (N.R., K.P., S.O., R.K.S.), Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 8RP, United Kingdom; Forensic Medicine (L.D.K., H.C., A.S.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey; and Pediatric Endocrinology and Metabolism (A.K.T.), Cukurova University, Faculty of Medicine, Balcali, 01330 Adana, Turkey.
authors.forename: A Kemal
authors.initials: AK
authors.lastname: Topaloglu
mesh_terms: D000293:Adolescent; D000328:Adult; D000568:Amenorrhea / Q000235:genetics*; D001940:Breast / Q000002:abnormalities; D004252:DNA Mutational Analysis; D005260:Female; D006639:Histidine; D006720:Homozygote; D006728:Hormones / Q000097:blood; D006801:Humans; D007006:Hypogonadism / Q000097:blood / Q000235:genetics*; D007930:Leucine; D008297:Male; D020125:Mutation, Missense; D015287:Neurokinin B / Q000031:analogs & derivatives* / Q000235:genetics; D010375:Pedigree; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use*; D011627:Puberty / Q000097:blood / Q000235:genetics; D018042:Receptors, Neurokinin-3 / Q000235:genetics*; D035781:Siblings; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013373:Substance P / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D006728:Hormones; D010446:Peptide Fragments; D018042:Receptors, Neurokinin-3; C054724:senktide; D013373:Substance P; D006639:Histidine; D015287:Neurokinin B; D007930:Leucine