• PMID: 26277103
• Gene Name: FGFR1
• Condition: Kallmann syndrome, idiopathic hypogonadotropic hypogonadism (IHH)
• Association: 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
• Mutation: (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), exon 8A (p.Ala353Thr)
• Population size: 250
• Population details: 250 (21 with Kallmann syndrome, 29 with normosmic IHH, 200 controls)
• Sex: Male, Female
• Infertility type: Male infertility, Female infertility
• Other associated phenotypes: Kallmann syndrome, idiopathic hypogonadotropic hypogonadism (IHH)

Novel FGFR1 mutations in Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism: evidence for the involvement of an alternatively spliced isoform

Gonçalves C, Bastos M, Pignatelli D, Borges T, Aragüés JM, Fonseca F, Pereira BD, Socorro S, Lemos MC.

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. CI - Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved. FAU - Gonçalves, Catarina AU - Gonçalves C AD - CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal. FAU - Bastos, Margarida AU - Bastos M AD - Serviço de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal. FAU - Pignatelli, Duarte AU - Pignatelli D AD - Serviço de Endocrinologia, Diabetes e Metabolismo, Hospital de São João e Faculdade de Medicina do Porto, Porto, Portugal. FAU - Borges, Teresa AU - Borges T AD - Serviço de Pediatria Médica, Centro Hospitalar do Porto, Porto, Portugal. FAU - Aragüés, José M AU - Aragüés JM AD - Serviço de Endocrinologia, Diabetes e Metabolismo, Hospital de Santa Maria, Lisbon, Portugal. FAU - Fonseca, Fernando AU - Fonseca F AD - Serviço de Endocrinologia, Diabetes e Metabolismo, Hospital de Curry Cabral, Lisbon, Portugal. FAU - Pereira, Bernardo D AU - Pereira BD AD - Serviço de Endocrinologia e Diabetes, Hospital Garcia de Orta, Almada, Portugal. FAU - Socorro, Sílvia AU - Socorro S AD - CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal.