Human Molecular Genetics, Vol 6, 681-688, Copyright © 1997 by Oxford University Press
HB Nguyen, M Estacion and JJ Gargus
Mutations in the fibroblast growth factor receptor (FGFR) gene family
recently have been shown to underlie several hereditary disorders of bone
development, with specific FGFR3 mutations causing achondroplasia (Ach) and
thanatophoric dysplasia (TD). However, for none of these mutations has the
defect in receptor function been demonstrated directly and, therefore, for
none has the pathophysiological mechanism of the disease been defined.
Using our established techniques for single-cell ratiometric real-time
calcium image analysis, we defined the nature of the basic fibroblast
growth factor (bFGF)-induced calcium signal in human diploid fibroblasts,
and, in blinded studies, have analyzed the bFGF-induced signals from 18
independent fibroblast cell lines, including multiple lines from patients
with known mutant alleles of FGFR3 and syndromes of Ach or TD. Control
cells responded with transient increases in intracellular calcium, with
many cells showing oscillatory calcium waves. Homozygous Ach cell lines
failed to signal, whereas heterozygous Ach lines responded nearly normally.
We observed heterogeneous signals in TD heterozygotes: the unresponsive
lines all turned out to carry TD1 alleles, whereas all responsive lines had
TD2 alleles. Since FGFR1, 2 and 3 receptors are known to be expressed in
fibroblasts, our results suggest that specific mutant FGFR3 alleles can
function in a dosage-dependent dominant-negative fashion to inactivate FGFR
signaling.
ARTICLES
Mutations causing achondroplasia and thanatophoric dysplasia alter bFGF- induced calcium signals in human diploid fibroblasts
Department of Physiology and Biophysics, University of California, Irvine 92697-4560, USA.
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