title: Role of gonadotropin-releasing hormone receptor mutations in patients with a wide spectrum of pubertal delay.
abstract: OBJECTIVE
  To analyze the GNRHR in patients with normosmic isolated hypogonadotropic hypogonadism (IHH) and constitutional delay of growth and puberty (CDGP).
  
  
  METHODS
  Molecular analysis and in vitro experiments correlated with phenotype.
  
  
  METHODS
  Academic medical center.
  
  
  METHODS
  A total of 110 individuals with normosmic IHH (74 male patients) and 50 with CDGP.
  
  
  METHODS
  GNRHR coding region was amplified and sequenced.
  
  
  METHODS
  Novel variants were submitted to in vitro analysis. Frequency of mutations and genotype-phenotype correlation were analyzed. Microsatellite markers flanking GNRHR were examined in patients carrying the same mutation to investigate a possible founder effect.
  
  
  RESULTS
  Eleven IHH patients (10%) carried biallelic GNRHR mutations. In vitro analysis of novel variants (p.Y283H and p.V134G) demonstrated complete inactivation. The founder effect study revealed that Brazilian patients carrying the p.R139H mutation shared the same haplotype. Phenotypic spectrum in patients with GNRHR mutations varied from complete GnRH deficiency to partial and reversible IHH, with a relatively good genotype-phenotype correlation. One boy with CDGP was heterozygous for the p.Q106R variant, which was not considered to be pathogenic.
  
  
  CONCLUSIONS
  GNRHR mutations are a frequent cause of congenital normosmic IHH and should be the first candidate gene for genetic screening in this condition, especially in autosomal recessive familial cases. The founder effect study suggested that the p.R139H mutation arises from a common ancestor in the Brazilian population. Finally, mutations in GNRHR do not appear to be involved in the pathogenesis of CDGP.
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Disciplina de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Daiane
authors.initials: D
authors.lastname: Beneduzzi
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Disciplina de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; Unidade de Endocrinologia Genética/LIM 25, Disciplina de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Ericka B
authors.initials: EB
authors.lastname: Trarbach
authors.affiliation: Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Le
authors.initials: L
authors.lastname: Min
authors.affiliation: Unidade de Endocrinologia Genética/LIM 25, Disciplina de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Alexander A L
authors.initials: AA
authors.lastname: Jorge
authors.affiliation: Unidade de Endocrinologia Departamento de Clínica Médica, Faculdade de Ciências Médicas da Universidade de Campinas, Campinas, Brazil.
authors.forename: Heraldo M
authors.initials: HM
authors.lastname: Garmes
authors.affiliation: Departamento de Endocrinologia, Hospital Santa Marcelina, São Paulo, Brazil.
authors.forename: Alessandra Covallero
authors.initials: AC
authors.lastname: Renk
authors.affiliation: Institute of Human Genetics, Polish Academy of Sciences and Department of Endocrinology and Metabolism, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Fichna
authors.affiliation: Department of Pediatric Diabetes and Obesity, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Fichna
authors.affiliation: Unidade de Endocrinologia Genética/LIM 25, Disciplina de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Karina A
authors.initials: KA
authors.lastname: Arantes
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Disciplina de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Elaine M F
authors.initials: EM
authors.lastname: Costa
authors.affiliation: Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Anna
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Oluwaseun
authors.initials: O
authors.lastname: Adeola
authors.affiliation: Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Junping
authors.initials: J
authors.lastname: Wen
authors.affiliation: Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Rona S
authors.initials: RS
authors.lastname: Carroll
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Disciplina de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Berenice B
authors.initials: BB
authors.lastname: Mendonça
authors.affiliation: Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Ursula B
authors.initials: UB
authors.lastname: Kaiser
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Disciplina de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: Latronico
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Disciplina de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. Electronic address: leticia.silveira@hc.fm.usp.br.
authors.forename: Letícia F G
authors.initials: LF
authors.lastname: Silveira
mesh_terms: D000293:Adolescent; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D006130:Growth Disorders / Q000150:complications / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011628:Puberty, Delayed / Q000150:complications / Q000235:genetics*; D011966:Receptors, LHRH / Q000235:genetics*
chemical_list: D011966:Receptors, LHRH
keywords: GnRH receptor; founder effect; hypogonadotropic hypogonadism; mutation; pubertal delay