Combined in vitro and in silico analyses of FGFR1 variants: genotype-phenotype study in idiopathic hypogonadotropic hypogonadism.
Adolescent
Adult
Alternative Splicing
/ genetics
Child, Preschool
Computer Simulation
Exons
/ genetics
Genetic Association Studies
Genotype
Humans
Hypogonadism
/ genetics
Infant
Male
Mitogen-Activated Protein Kinase Kinases
/ genetics
Mutation, Missense
/ genetics
Pedigree
Phenotype
Receptor, Fibroblast Growth Factor, Type 1
/ genetics
Young Adult
Journal
Clinical genetics
ISSN: 1399-0004
Titre abrégé: Clin Genet
Pays: Denmark
ID NLM: 0253664
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
02
04
2020
revised:
03
07
2020
accepted:
07
07
2020
pubmed:
16
7
2020
medline:
3
7
2021
entrez:
16
7
2020
Statut:
ppublish
Résumé
Fibroblast growth factor receptor 1 (FGFR1) is an idiopathic hypogonadotropic hypogonadism (IHH)-associated gene, mutated in approximately 10% of the patients with this condition. Through targeted gene sequencing of 153 males with IHH and 100 healthy controls, we identified 10 mutations in FGFR1 from IHH patients with a frequency of 5.9% in the Chinese population of central China. These included nine missense mutations(NM_023110.2, p.Gly687Arg, p.Ala608Asp, p.Gly348Glu, p.Asn296Ser, p.Gly226Asp, p.Arg209Cys, p.Gly97Arg, p.Val71Met, p.Gly70Arg) and a splicing mutation c.1430 + 1G > T. in vitro and in silico analyses of FGFR1 variants were conducted to study the impact of the identified mutations. Our findings indicated that the splicing mutation dramatically affected premRNA processing, causing exon 10 and 6 nucleotides in the 3' end of exon 9 to be completely skipped. Two variants (p.Gly687Arg and p.Ala608Asp) markedly impaired tyrosine kinase activity, while the other variants had limited impact on the mitogen-activated protein kinase (MAPK) signaling pathway. However, the functional impairment of the mutant receptors was not always consistent with the phenotypes, indicating that FGFR1 mutations might cause IHH in conjunction with other mutant genes. In this study, we expanded the knowledge on the mutation spectrum of FGFR1 in IHH patients and explored the genotype-phenotype relationship.
Substances chimiques
FGFR1 protein, human
EC 2.7.10.1
Receptor, Fibroblast Growth Factor, Type 1
EC 2.7.10.1
Mitogen-Activated Protein Kinase Kinases
EC 2.7.12.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
341-352Informations de copyright
© 2020 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.
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