1. Comparative functional analysis of two fibroblast growth factor receptor 1 (FGFR1) mutations affecting the same residue (R254W and R254Q) in isolated hypogonadotropic hypogonadism (IHH)
- Author
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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, and Vasiliki Koika
- Subjects
Male ,Isolated hypogonadotropic hypogonadism ,medicine.medical_specialty ,Adolescent ,Genotype ,Glycoside Hydrolases ,Mutant ,030209 endocrinology & metabolism ,Biology ,Gonadotropin-Releasing Hormone ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Chlorocebus aethiops ,Genetics ,medicine ,Animals ,Humans ,Computer Simulation ,Receptor, Fibroblast Growth Factor, Type 1 ,Receptor ,Protein maturation ,030304 developmental biology ,Regulation of gene expression ,0303 health sciences ,Hypogonadism ,Fibroblast growth factor receptor 1 ,Wild type ,Kallmann Syndrome ,General Medicine ,medicine.disease ,Phenotype ,Endocrinology ,Gene Expression Regulation ,COS Cells ,Mutation ,Signal transduction ,Signal Transduction - 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
- Published
- 2013