Τίτλος:
Comparative functional analysis of two fibroblast growth factor receptor
1 (FGFR1) mutations affecting the same residue (R254W and R254Q) in
isolated hypogonadotropic hypogonadism (IHH)
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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 add 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. (C) 2012 Elsevier B.V. All rights
reserved.
Συγγραφείς:
Koika, Vasiliki
Varnavas, Petros
Valavani, Helen
Sidis,
Yisrael
Plummer, Lacey
Dwyer, Andrew
Quinton, Richard and
Kanaka-Gantenbein, Christine
Pitteloud, Nelly
Sertedaki, Amalia
and Dacou-Voutetakis, Catherine
Georgopoulos, Neoklis A.
Περιοδικό:
Genes and Nutrition
Εκδότης:
ELSEVIER SCIENCE BV
Λέξεις-κλειδιά:
Kallmann syndrome; Anosmia; IHH; KS; GnRH deficiency
DOI:
10.1016/j.gene.2012.12.041
