Gonçalves, CBastos, MPignatelli, DBorges, TAragüés, JMFonseca, FPereira, BSocorro, SLemos, M2016-05-052016-05-052015-11Fertil Steril. 2015 Nov;104(5):1261-7.e1http://hdl.handle.net/10400.17/2465OBJECTIVE: To determine the prevalence of fibroblast growth factor receptor 1 (FGFR1) mutations and their predicted functional consequences in patients with idiopathic hypogonadotropic hypogonadism (IHH). DESIGN: Cross-sectional study. SETTING: Multicentric. PATIENT(S): Fifty unrelated patients with IHH (21 with Kallmann syndrome and 29 with normosmic IHH). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Patients were screened for mutations in FGFR1. The functional consequences of mutations were predicted by in silico structural and conservation analysis. RESULT(S): Heterozygous FGFR1 mutations were identified in six (12%) kindreds. These consisted of frameshift mutations (p.Pro33-Alafs*17 and p.Tyr654*) and missense mutations in the signal peptide (p.Trp4Cys), in the D1 extracellular domain (p.Ser96Cys) and in the cytoplasmic tyrosine kinase domain (p.Met719Val). A missense mutation was identified in the alternatively spliced exon 8A (p.Ala353Thr) that exclusively affects the D3 extracellular domain of FGFR1 isoform IIIb. Structure-based and sequence-based prediction methods and the absence of these variants in 200 normal controls were all consistent with a critical role for the mutations in the activity of the receptor. Oligogenic inheritance (FGFR1/CHD7/PROKR2) was found in one patient. CONCLUSION(S): Two FGFR1 isoforms, IIIb and IIIc, result from alternative splicing of exons 8A and 8B, respectively. Loss-of-function of isoform IIIc is a cause of IHH, whereas isoform IIIb is thought to be redundant. Ours is the first report of normosmic IHH associated with a mutation in the alternatively spliced exon 8A and suggests that this disorder can be caused by defects in either of the two alternatively spliced FGFR1 isoforms.engHCC ENDAlternative SplicingComputer SimulationCross-Sectional StudiesDNA Mutational AnalysisDatabases, GeneticExonsGene FrequencyGenetic Predisposition to DiseaseHypogonadism/diagnosisHypogonadism/geneticsHypogonadism/metabolismKallmann Syndrome/diagnosisKallmann Syndrome/geneticsKallmann Syndrome/metabolismMutation, MissenseProtein ConformationReceptor, Fibroblast Growth Factor, Type 1/chemistryReceptor, Fibroblast Growth Factor, Type 1/geneticsReceptor, Fibroblast Growth Factor, Type 1/metabolismStructure-Activity Relationshipjournal article10.1016/j.fertnstert.2015.07.1142