Comparative functional analysis of two fibroblast growth factor receptor 1 (FGFR1) mutations affecting the same residue (R254W and R254Q) in isolated hypogonadotropic hypogonadism (IHH).

Details

Serval ID
serval:BIB_C8ED658E45BF
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Comparative functional analysis of two fibroblast growth factor receptor 1 (FGFR1) mutations affecting the same residue (R254W and R254Q) in isolated hypogonadotropic hypogonadism (IHH).
Journal
Gene
Author(s)
Koika V., Varnavas P., Valavani H., Sidis Y., Plummer L., Dwyer A., Quinton R., Kanaka-Gantenbein C., Pitteloud N., Sertedaki A., Dacou-Voutetakis C., Georgopoulos N.A.
ISSN
1879-0038 (Electronic)
ISSN-L
0378-1119
Publication state
Published
Issued date
2013
Volume
516
Number
1
Pages
146-151
Language
english
Notes
Publication types: Journal ArticlePublication Status: ppublish. PDF type: Short Communication
Abstract
FGFR1 mutations have been identified in both Kallmann syndrome and normosmic HH (nIHH). To date, few mutations in the FGFR1 gene have been structurally or functionally characterized in vitro to identify molecular mechanisms that contribute to the disease pathogenesis. We attempted to define the in vitro functionality of two FGFR1 mutants (R254W and R254Q), resulting from two different amino acid substitutions of the same residue, and to correlate the in vitro findings to the patient phenotypes. Two unrelated GnRH deficient probands were found to harbor mutations in FGFR1 (R254W and R254Q). Mutant signaling activity and expression levels were evaluated in vitro and compared to a wild type (WT) receptor. Signaling activity was determined by a FGF2/FGFR1 dependent transcription reporter assay. Receptor total expression levels were assessed by Western blot and cell surface expression was measured by a radiolabeled antibody binding assay. The R254W maximal receptor signaling capacity was reduced by 45% (p<0.01) while R254Q activity was not different from WT. However, both mutants displayed diminished total protein expression levels (40 and 30% reduction relative to WT, respectively), while protein maturation was unaffected. Accordingly, cell surface expression levels of the mutant receptors were also significantly reduced (35% p<0.01 and 15% p<0.05, respectively). The p.R254W and p.R254Q are both loss-of-function mutations as demonstrated by their reduced overall and cell surface expression levels suggesting a deleterious effect on receptor folding and stability. It appears that a tryptophan substitution at R254 is more disruptive to receptor structure than the more conserved glutamine substitution. No clear correlation between the severity of in vitro loss-of-function and phenotypic presentation could be assigned.
Keywords
Adolescent, Animals, COS Cells, Cercopithecus aethiops, Computer Simulation, Gene Expression Regulation, Genotype, Glycoside Hydrolases/genetics, Glycoside Hydrolases/metabolism, Gonadotropin-Releasing Hormone/genetics, Humans, Hypogonadism/genetics, Kallmann Syndrome/genetics, Male, Mutation, Phenotype, Receptor, Fibroblast Growth Factor, Type 1/genetics, Receptor, Fibroblast Growth Factor, Type 1/metabolism, Signal Transduction
Pubmed
Web of science
Create date
12/04/2013 17:48
Last modification date
20/08/2019 15:44
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