title: Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism.
abstract: Mutations in KAL1 and FGFR1 cause Kallmann syndrome (KS), whereas mutations in the GNRHR and GPR54 genes cause idiopathic hypogonadotropic hypogonadism with normal olfaction (nIHH). Mixed pedigrees containing both KS and nIHH have also been described; however, the genetic cause of these rare cases is unknown. We examined the FGFR1 gene in seven nIHH subjects who either belonged to a mixed pedigree (n = 5) or who had associated midline defects (n = 2). Heterozygous FGFR1 mutations were found in three of seven unrelated nIHH probands with normal MRI of the olfactory system: (i) G237S in an nIHH female and a KS brother; (ii) (P722H and N724K) in an nIHH male missing two teeth and his mother with isolated hyposmia; and (iii) Q680X in a nIHH male with cleft lip/palate and missing teeth, his brother with nIHH, and his father with delayed puberty. We show that these mutations lead to receptor loss-of-function. The Q680X leads to an inactive FGFR1, which lacks a major portion of the tyrosine kinase domain (TKD). The G237S mutation inhibits proper folding of D2 of the FGFR1 and likely leads to the loss of cell-surface expression of FGFR1. In contrast, the (P722H and N724K) double mutation causes structural perturbations in TKD, reducing the catalytic activity of TKD. We conclude that loss-of-function mutations in FGFR1 cause nIHH with normal MRI of the olfactory system. These mutations also account for some of the mixed pedigrees, thus challenging the current idea that KS and nIHH are distinct entities.
authors.affiliation: Reproductive Endocrine Unit of the Department of Medicine and Harvard Reproductive Endocrine Science Centers, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. npitteloud@partners.org
authors.forename: Nelly
authors.initials: N
authors.lastname: Pitteloud
authors.forename: James S
authors.initials: JS
authors.lastname: Acierno
authors.forename: Astrid
authors.initials: A
authors.lastname: Meysing
authors.forename: Anna V
authors.initials: AV
authors.lastname: Eliseenkova
authors.forename: Jinghong
authors.initials: J
authors.lastname: Ma
authors.forename: Omar A
authors.initials: OA
authors.lastname: Ibrahimi
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Metzger
authors.forename: Frances J
authors.initials: FJ
authors.lastname: Hayes
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Dwyer
authors.forename: Virginia A
authors.initials: VA
authors.lastname: Hughes
authors.forename: Maria
authors.initials: M
authors.lastname: Yialamas
authors.forename: Janet E
authors.initials: JE
authors.lastname: Hall
authors.forename: Ellen
authors.initials: E
authors.lastname: Grant
authors.forename: Moosa
authors.initials: M
authors.lastname: Mohammadi
authors.forename: William F
authors.initials: WF
authors.lastname: Crowley
mesh_terms: D019943:Amino Acid Substitution; D005260:Female; D005838:Genotype; D006062:Gonadotropins / Q000172:deficiency* / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D017436:Kallmann Syndrome / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011487:Protein Conformation; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D006062:Gonadotropins; D051496:Receptor, Fibroblast Growth Factor, Type 1