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Novel FGFR1 mutations in Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism: evidence for the involvement of an alternatively spliced isoform
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Orientador(es)
Resumo(s)
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
Descrição
Palavras-chave
Hipogonadismo Síndrome de Kallmann Mutação de Sentido Incorrecto Receptor Tipo 1 de Factor de Crescimento de Fibroblastos
Contexto Educativo
Citação
Fertil Steril. 2015 Nov;104(5):1261-7.e1.