Mutations in Fibroblast Growth Factor Receptor 1 Cause Both Kallmann Syndrome and Normosmic Idiopathic Hypogonadotropic Hypogonadism

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 16; pp. 6281 - 6286
• Main Authors: Pitteloud, Nelly, Acierno, James S., Meysing, Astrid, Eliseenkova, Anna V., Ma, Jinghong, Ibrahimi, Omar A., Metzger, Daniel L., Hayes, Frances J., Dwyer, Andrew A., Hughes, Virginia A., Yialamas, Maria, Hall, Janet E., Grant, Ellen, Mohammadi, Moosa, Crowley, William F.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 18.04.2006
• Subjects: Amino Acid Substitution; Anosmia; Biochemistry; Biological Sciences; Delayed puberty; Female; Genes; Genetic disorders; Genetic mutation; Genetics; Genotype; Gonadotropins - deficiency; Gonadotropins - genetics; Heterozygote; Humans; Hypogonadism - genetics; Kallmann Syndrome - genetics; Ligands; Male; Mutation; Olfaction; Olfactory bulb; Olfactory perception; Pedigree; Phenotype; Phenotypes; Protein Conformation; Puberty; Receptor, Fibroblast Growth Factor, Type 1 - chemistry; Receptor, Fibroblast Growth Factor, Type 1 - genetics; Receptor, Fibroblast Growth Factor, Type 1 - metabolism; Receptors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0600962103

Mutations in KAL1 and FGFR1 cause Kallmann syndrome (KS), whereas mutations in the GNRHR and GPR54 genes cause idiopathic hypogonadotropic hypogonadism with normal olfaction (nlHH). Mixed pedigrees containing both KS and nlHH have also been described; however, the genetic cause of these rare cases is unknown. We examined the FGFR1 gene in seven nlHH 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 nlHH probands with normal MRI of the olfactory system: (i) G237S in an nlHH female and a KS brother; (ii) (P722H and N724K) in an nlHH male missing two teeth and his mother with isolated hyposmia; and (iii) Q680X in a nlHH male with cleft lip/palate and missing teeth, his brother with nlHH, 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 nlHH 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 nlHH are distinct entities.