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

Oleh:

Goncalves, Catarina ; Bastos, Margarida ; Pignatelli, Duarte ; Borges, Teresa ; Aragues, Jose M. ; Fonseca, Fernando ; Pereira, Bernardo D. ; Socorro, Sílvia ; Lemos, Manuel C.

Jenis: Article from Journal - ilmiah internasional
Dalam koleksi: Fertility and Sterility (keterangan: ada di ClinicalKey) vol. 104 no. 05 (Nov. 2015), page 1261–1267.
Topik: Hypogonadotropic Hypogonadism; Kallmann Syndrome; FGFR1; KAL2; Genetics
Fulltext: F02 v104 n5 p1261 kelik2016.pdf (1,011.63KB)

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Perpustakaan FK Nomor Panggil: F02.K Non-tandon: 1 (dapat dipinjam: 0) Tandon: tidak ada

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Isi artikel

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.

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