title: Nonsense mutations in FGF8 gene causing different degrees of human gonadotropin-releasing deficiency.
abstract: BACKGROUND
  FGFR1 mutations cause isolated hypogonadotropic hypogonadism (IHH) with or without olfactory abnormalities, Kallmann syndrome, and normosmic IHH respectively. Recently, missense mutations in FGF8, a key ligand for fibroblast growth factor receptor (FGFR) 1 in the ontogenesis of GnRH, were identified in IHH patients, thus establishing FGF8 as a novel locus for human GnRH deficiency.
  
  
  OBJECTIVE
  Our objective was to analyze the clinical, hormonal, and molecular findings of two familial IHH patients due to FGF8 gene mutations.
  
  
  METHODS
  The entire coding region of the FGF8 gene was amplified and sequenced in two well-phenotyped IHH probands and their relatives.
  
  
  RESULTS
  Two unique heterozygous nonsense mutations in FGF8 (p.R127X and p.R129X) were identified in two unrelated IHH probands, which were absent in 150 control individuals. These two mutations, mapped to the core domain of FGF8, impact all four human FGF8 isoforms, and lead to the deletion of a large portion of the protein, generating nonfunctional FGF8 ligands. The p.R127X mutation was identified in an 18-yr-old Kallmann syndrome female. Her four affected siblings with normosmic IHH or delayed puberty also carried the p.R127X mutation. Additional developmental anomalies, including cleft lip and palate and neurosensorial deafness, were also present in this family. The p.R129X mutation was identified in a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency.
  
  
  CONCLUSIONS
  We identified the first nonsense mutations in the FGF8 gene in familial IHH with variable degrees of GnRH deficiency and olfactory phenotypes, confirming that loss-of-function mutations in FGF8 cause human GnRH deficiency.
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42 da Disciplina de Endocrinologia do Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, 05403-900, São Paulo, Brasil. ericka@lim25.fm.usp.br
authors.forename: Ericka B
authors.initials: EB
authors.lastname: Trarbach
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Abreu
authors.forename: Leticia Ferreira Gontijo
authors.initials: LF
authors.lastname: Silveira
authors.forename: Heraldo Mendes
authors.initials: HM
authors.lastname: Garmes
authors.forename: Maria Tereza M
authors.initials: MT
authors.lastname: Baptista
authors.forename: Milena Gurgel
authors.initials: MG
authors.lastname: Teles
authors.forename: Elaine M F
authors.initials: EM
authors.lastname: Costa
authors.forename: Moosa
authors.initials: M
authors.lastname: Mohammadi
authors.forename: Nelly
authors.initials: N
authors.lastname: Pitteloud
authors.forename: Berenice B
authors.initials: BB
authors.lastname: Mendonca
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: Latronico
mesh_terms: D018389:Codon, Nonsense / Q000235:genetics*; D051524:Fibroblast Growth Factor 8 / Q000235:genetics*; D005640:Follicle Stimulating Hormone / Q000097:blood; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D011863:Radioimmunoassay; D012720:Severity of Illness Index
chemical_list: D018389:Codon, Nonsense; C496456:FGF8 protein, human; D051524:Fibroblast Growth Factor 8; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone
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