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

Authors :
Amalia Sertedaki
Christine Kanaka-Gantenbein
Lacey Plummer
Helen Valavani
Andrew A. Dwyer
Petros Varnavas
Catherine Dacou-Voutetakis
Richard Quinton
Neoklis A. Georgopoulos
Nelly Pitteloud
Yisrael Sidis
Vasiliki Koika
Source :
Gene
Publication Year :
2013

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

Details

Volume :
516
Issue :
1
Database :
OpenAIRE
Journal :
Gene
Accession number :
edsair.doi.dedup.....4bc3901c73bb5c2923d6d5265592299b