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Novel FGFR1 Mutations in Kallmann Syndrome and Normosmic Idiopathic Hypogonadotropic Hypogonadism: Evidence for the Involvement of an Alternatively Spliced Isoform

2015-11Journal article Open access
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dc.contributor.authorGonçalves, C
dc.contributor.authorBastos, M
dc.contributor.authorPignatelli, D
dc.contributor.authorBorges, T
dc.contributor.authorAragüés, JM
dc.contributor.authorFonseca, F
dc.contributor.authorPereira, B
dc.contributor.authorSocorro, S
dc.contributor.authorLemos, M
dc.date.accessioned2016-05-05T11:48:24Z
dc.date.available2016-05-05T11:48:24Z
dc.date.issued2015-11
dc.description.abstractOBJECTIVE: 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.pt_PT
dc.identifier.citationFertil Steril. 2015 Nov;104(5):1261-7.e1pt_PT
dc.identifier.doi10.1016/j.fertnstert.2015.07.1142pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.17/2465
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevierpt_PT
dc.subjectHCC ENDpt_PT
dc.subjectAlternative Splicingpt_PT
dc.subjectComputer Simulationpt_PT
dc.subjectCross-Sectional Studiespt_PT
dc.subjectDNA Mutational Analysispt_PT
dc.subjectDatabases, Geneticpt_PT
dc.subjectExonspt_PT
dc.subjectGene Frequencypt_PT
dc.subjectGenetic Predisposition to Diseasept_PT
dc.subjectHypogonadism/diagnosispt_PT
dc.subjectHypogonadism/geneticspt_PT
dc.subjectHypogonadism/metabolismpt_PT
dc.subjectKallmann Syndrome/diagnosispt_PT
dc.subjectKallmann Syndrome/geneticspt_PT
dc.subjectKallmann Syndrome/metabolismpt_PT
dc.subjectMutation, Missensept_PT
dc.subjectProtein Conformationpt_PT
dc.subjectReceptor, Fibroblast Growth Factor, Type 1/chemistrypt_PT
dc.subjectReceptor, Fibroblast Growth Factor, Type 1/geneticspt_PT
dc.subjectReceptor, Fibroblast Growth Factor, Type 1/metabolismpt_PT
dc.subjectStructure-Activity Relationshippt_PT
dc.titleNovel FGFR1 Mutations in Kallmann Syndrome and Normosmic Idiopathic Hypogonadotropic Hypogonadism: Evidence for the Involvement of an Alternatively Spliced Isoformpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage1267pt_PT
oaire.citation.startPage1261pt_PT
oaire.citation.titleFertility and Sterilitypt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT

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