Molecular basis of craniosynostis
One in 2500 children are born with craniosynostosis, a devastating
medical disorder where the bones of the skull fuse prematurely,
resulting in abnormal skull development, visual and neurological
problems and mental impairment. There is a clear need to develop
adjunct therapies to minimize the need for repeated invasive
cranial surgery to enable proper skull and brain growth. The
underlying causes of the majority of craniosynostoses are
not known and to develop new therapies we need to know the
key molecular mechanisms that regulate skull growth and abnormal
bone fusion in craniosynostosis.
In collaboration with surgeons in the Australian Craniofacial
Unit we have recruited over 100 children to our program of
gene discovery to uncover the molecular basis of craniosynostosis.
A comparative gene microarray study enabled us to identify
a number of novel genes whose changes in expression may drive
craniosynostosis. We are currently focussing on a protein
that binds vitamin A, an important vitamin for bone growth,
and another protein called glypican which helps regulate signalling
by growth factors. To measure the levels of vitamin A metabolites
in the sutures of the skull we are developing detection methods
using mass spectrometry. We are conducting studies of what
happens to these molecules during fusion of the sutures in
mouse models of the Saethre-Chotzen and Crouzon craniosynostosis
syndromes. We have used microcomputed tomography to measure
skull formation and suture fusion during fetal and neonatal
development and have correlated how gene activity changes
during fusion. To test the function of these molecules in
normal suture activity and bone growth we are using viral
vectors to manipulate their activity in cells of the suture.
We have succeeded in establishing long term production of
molecules in cultured human suture cells and are now in the
process of testing their function in a variety of experimental
models using gene knockdown and overexpression techniques.
Our research is leading to novel insights into the molecular
processes of skull growth and abnormal suture fusion. In collaboration
with our clinical colleagues these studies will provide the
foundation to develop adjunctive treatments to prevent or
minimize repeated transcranial surgery and to treat other
disorders of bone growth.
Unicoronal craniosynostosis. Fusion of one of the coronal
sutures (arrows) is evident in the CT scan in the right panel.
Human suture cells glowing with an introduced fluorescent
protein after 35 days in culture.
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