title: Expanding the Spectrum of Founder Mutations Causing Isolated Gonadotropin-Releasing Hormone Deficiency.
abstract: BACKGROUND
  Loss of function (LoF) mutations in more than 20 genes are now known to cause isolated GnRH deficiency (IGD) in humans. Most causal IGD mutations are typically private, ie, limited to a single individual/pedigree. However, somewhat paradoxically, four IGD genes (GNRH1, TAC3, PROKR2, and GNRHR) have been shown to harbor LoF founder mutations that are shared by multiple unrelated individuals. It is not known whether similar founder mutations occur in other IGD genes.
  
  
  OBJECTIVE
  The objective of the study was to determine whether shared deleterious mutations in IGD-associated genes represent founder alleles.
  
  
  METHODS
  This study was an international collaboration among academic medical centers.
  
  
  METHODS
  IGD patients with shared mutations, defined as those documented in three or more unrelated probands in 14 IGD-associated genes, were identified from various academic institutions, the Human Gene Mutation Database, and literature reports by other international investigators. Haplotypes of single-nucleotide polymorphisms and short tandem repeats surrounding the mutations were constructed to assess genetic ancestry.
  
  
  RESULTS
  A total of eight founder mutations in five genes, GNRHR (Q106R, R262Q, R139H), TACR3 (W275X), PROKR2 (R85H), FGFR1 (R250Q, G687R), and HS6ST1 (R382W) were identified. Most founder alleles were present at low frequency in the general population. The estimated age of these mutant alleles ranged from 1925 to 5600 years and corresponded to the time of rapid human population expansion.
  
  
  CONCLUSIONS
  We have expanded the spectrum of founder alleles associated with IGD to a total of eight founder mutations. In contrast to the approximately 9000-year-old PROKR2 founder allele that may confer a heterozygote advantage, the rest of the founder alleles are relatively more recent in origin, in keeping with the timing of recent human population expansion and any selective heterozygote advantage of these alleles requires further evaluation.
authors.affiliation: Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Jin-Ho
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Balasubramanian
authors.affiliation: Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Phil H
authors.initials: PH
authors.lastname: Lee
authors.affiliation: Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Natalie D
authors.initials: ND
authors.lastname: Shaw
authors.affiliation: Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Janet E
authors.initials: JE
authors.lastname: Hall
authors.affiliation: Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Lacey
authors.initials: L
authors.lastname: Plummer
authors.affiliation: Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Cassandra L
authors.initials: CL
authors.lastname: Buck
authors.affiliation: Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Kottler
authors.affiliation: Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Jarzabek
authors.affiliation: Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Sławomir
authors.initials: S
authors.lastname: Wołczynski
authors.affiliation: Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Richard
authors.initials: R
authors.lastname: Quinton
authors.affiliation: Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: Latronico
authors.affiliation: Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Catherine
authors.initials: C
authors.lastname: Dode
authors.affiliation: Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
authors.affiliation: Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Hyung-Goo
authors.initials: HG
authors.lastname: Kim
authors.affiliation: Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Layman
authors.affiliation: Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.affiliation: Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit (J.-H.C., R.B., N.D.S., J.E.H., L.P., C.L.B., W.F.C.), and Department of Medicine, Psychiatric, and Neurodevelopmental Genetics Unit (P.H.L.), Analytic and Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Center for Human Genetic Research (J.F.G.), Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts Boston, Massachusetts 02114; Department of Genetics (M.-L.K.), University Hospital, Caen, 14003, Caen Cedex, France; Department of Biology and Pathology of Human Reproduction in Bialystok (K.J.), Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, and Department of Reproduction and Gynecological Endocrinology (S.W.), Medical University of Bialystok, Sklodowskiej 24A, 15-276 Bialystok, Poland; Institute for Genetic Medicine (R.Q.), Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom; Disciplina de Endocrinologia (A.C.L.), Hospital das Clinicas da Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Laboratoire de Biochimie et Génétique Moléculaire (C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, 75014 Paris, France; Departments of Molecular Endocrinology and Pediatrics (T.O.), Hamamatsu University of School of Medicine, Hamamatsu 431-3192, Japan; Section of Reproductive Endocrinology, Infertility, and Genetics (H.-G.K., L.C.L.), Departments of Obstetrics and Gynecology and Neuroscience and Regenerative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia 30912; and Department of Pediatrics (J.-H.C.), Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: William F
authors.initials: WF
authors.lastname: Crowley
mesh_terms: D000483:Alleles; D007987:Gonadotropin-Releasing Hormone / Q000172:deficiency* / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007027:Hypothalamic Diseases / Q000235:genetics*; D009154:Mutation; D015287:Neurokinin B / Q000235:genetics*; D010375:Pedigree; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D011966:Receptors, LHRH / Q000235:genetics*; D018000:Receptors, Peptide / Q000235:genetics*
chemical_list: C470838:PROKR2 protein, human; D043562:Receptors, G-Protein-Coupled; D011966:Receptors, LHRH; D018000:Receptors, Peptide; C000601382:TAC3 protein, human; D007987:Gonadotropin-Releasing Hormone; D015287:Neurokinin B