Publication
Novel FGFR1 mutations in Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism: evidence for the involvement of an alternatively spliced isoform
| dc.contributor.author | Gonçalves, C | |
| dc.contributor.author | Bastos, M | |
| dc.contributor.author | Pignatelli, D | |
| dc.contributor.author | Borges, T | |
| dc.contributor.author | Aragüés, JM | |
| dc.contributor.author | Fonseca, F | |
| dc.contributor.author | Pereira, BD | |
| dc.contributor.author | Socorro, S | |
| dc.contributor.author | Lemos, MC | |
| dc.date.accessioned | 2016-05-06T16:43:53Z | |
| dc.date.available | 2016-05-06T16:43:53Z | |
| dc.date.issued | 2015-11 | |
| dc.description.abstract | OBJECTIVE: 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.citation | Fertil Steril. 2015 Nov;104(5):1261-7.e1. | pt_PT |
| dc.identifier.doi | 10.1016/j.fertnstert.2015.07.1142 | pt_PT |
| dc.identifier.uri | http://hdl.handle.net/10400.4/1888 | |
| dc.language.iso | eng | pt_PT |
| dc.peerreviewed | yes | pt_PT |
| dc.subject | Hipogonadismo | pt_PT |
| dc.subject | Síndrome de Kallmann | pt_PT |
| dc.subject | Mutação de Sentido Incorrecto | pt_PT |
| dc.subject | Receptor Tipo 1 de Factor de Crescimento de Fibroblastos | pt_PT |
| dc.title | Novel FGFR1 mutations in Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism: evidence for the involvement of an alternatively spliced isoform | pt_PT |
| dc.type | journal article | |
| dspace.entity.type | Publication | |
| rcaap.rights | openAccess | pt_PT |
| rcaap.type | article | pt_PT |