Catarina Gonçalves1, Margarida Bastos2, Duarte Pignatelli3, Teresa Borges4, José M Aragüés5, Fernando Fonseca6, Bernardo D Pereira7, Sílvia Socorro1, Manuel C Lemos8. 1. CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal. 2. Serviço de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal. 3. Serviço de Endocrinologia, Diabetes e Metabolismo, Hospital de São João e Faculdade de Medicina do Porto, Porto, Portugal. 4. Serviço de Pediatria Médica, Centro Hospitalar do Porto, Porto, Portugal. 5. Serviço de Endocrinologia, Diabetes e Metabolismo, Hospital de Santa Maria, Lisbon, Portugal. 6. Serviço de Endocrinologia, Diabetes e Metabolismo, Hospital de Curry Cabral, Lisbon, Portugal. 7. Serviço de Endocrinologia e Diabetes, Hospital Garcia de Orta, Almada, Portugal. 8. CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal. Electronic address: mclemos@fcsaude.ubi.pt.
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.
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.
Authors: Catarina Inês Gonçalves; Filipa Marina Patriarca; José Maria Aragüés; Davide Carvalho; Fernando Fonseca; Sofia Martins; Olinda Marques; Bernardo Dias Pereira; José Martinez-de-Oliveira; Manuel Carlos Lemos Journal: Sci Rep Date: 2019-02-07 Impact factor: 4.379
Authors: Lúcia Fadiga; Mariana Lavrador; Nuno Vicente; Luísa Barros; Catarina I Gonçalves; Asma Al-Naama; Luis R Saraiva; Manuel C Lemos Journal: Int J Mol Sci Date: 2022-04-17 Impact factor: 6.208