title: Impaired fibroblast growth factor receptor 1 signaling as a cause of normosmic idiopathic hypogonadotropic hypogonadism.
abstract: BACKGROUND
  FGFR1 mutations have been identified in about 10% of patients with Kallmann syndrome. Recently cases of idiopathic hypogonadotropic hypogonadism (IHH) with a normal sense of smell (nIHH) have been reported.
  
  
  OBJECTIVE
  The objective of the study was to define the frequency of FGFR1 mutations in a large cohort of nIHH, delineate the spectrum of reproductive phenotypes, assess functionality of the FGFR1 mutant alleles in vitro, and investigate genotype-phenotype relationships.
  
  
  METHODS
  FGFR1 sequencing of 134 well-characterized nIHH patients (112 men and 22 women) and 270 healthy controls was performed. The impact of the identified mutations on FGFR1 function was assessed using structural prediction and in vitro studies.
  
  
  RESULTS
  Nine nIHH subjects (five males and four females; 7%) harbor a heterozygous mutation in FGFR1 and exhibit a wide spectrum of pubertal development, ranging from absent puberty to reversal of IHH in both sexes. All mutations impair receptor function. The Y99C, Y228D, and I239T mutants impair the tertiary folding, resulting in incomplete glycosylation and reduced cell surface expression. The R250Q mutant reduces receptor affinity for FGF. The K618N, A671P, and Q680X mutants impair tyrosine kinase activity. However, the degree of functional impairment of the mutant receptors did not always correlate with the reproductive phenotype, and variable expressivity of the disease was noted within family members carrying the same FGFR1 mutation. These discrepancies were partially explained by additional mutations in known IHH loci.
  
  
  CONCLUSIONS
  Loss-of-function mutations in FGFR1 underlie 7% of nIHH with different degrees of impairment in vitro. These mutations act in concert with other gene defects in several cases, consistent with oligogenicity.
authors.affiliation: Reproductive Endocrine Unit, Department of Medicine, The Harvard Center for Reproductive Endocrine Sciences, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Taneli
authors.initials: T
authors.lastname: Raivio
authors.forename: Yisrael
authors.initials: Y
authors.lastname: Sidis
authors.forename: Lacey
authors.initials: L
authors.lastname: Plummer
authors.forename: Huaibin
authors.initials: H
authors.lastname: Chen
authors.forename: Jinghong
authors.initials: J
authors.lastname: Ma
authors.forename: Abir
authors.initials: A
authors.lastname: Mukherjee
authors.forename: Elka
authors.initials: E
authors.lastname: Jacobson-Dickman
authors.forename: Richard
authors.initials: R
authors.lastname: Quinton
authors.forename: Guy
authors.initials: G
authors.lastname: Van Vliet
authors.forename: Helene
authors.initials: H
authors.lastname: Lavoie
authors.forename: Virginia A
authors.initials: VA
authors.lastname: Hughes
authors.forename: Andrew
authors.initials: A
authors.lastname: Dwyer
authors.forename: Frances J
authors.initials: FJ
authors.lastname: Hayes
authors.forename: Shuyun
authors.initials: S
authors.lastname: Xu
authors.forename: Susan
authors.initials: S
authors.lastname: Sparks
authors.forename: Ursula B
authors.initials: UB
authors.lastname: Kaiser
authors.forename: Moosa
authors.initials: M
authors.lastname: Mohammadi
authors.forename: Nelly
authors.initials: N
authors.lastname: Pitteloud
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D015331:Cohort Studies; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D004958:Estradiol / Q000097:blood; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005838:Genotype; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D008297:Male; D009154:Mutation; D010641:Phenotype; D019000:Phosphotyrosine / Q000378:metabolism; D011628:Puberty, Delayed / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D012016:Reference Values; D013739:Testosterone / Q000097:blood
chemical_list: D016222:Fibroblast Growth Factor 2; D019000:Phosphotyrosine; D013739:Testosterone; D004958:Estradiol; D004247:DNA; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1