Human Molecular Genetics, Vol 5, 1915-1920, Copyright © 1996 by Oxford University Press
L Ma, S Golden, L Wu and R Maxson
Craniosynostosis, Boston type is an autosomal dominant disorder that
results in the premature fusion of calvarial bones and ensuing
abnormalities in skull shape. We showed previously that this disorder is
tightly linked to the Msx2 homeobox gene on the long arm of chromosome 5,
and that affected individuals bear a mutated copy of Msx2. In addition,
transgenic mice in which either mutant or wild-type mouse Msx2 is
overexpressed in the developing skull also exhibit craniosynostosis. That
both mutant and wild-type Msx2 elicit craniosynostosis in transgenic mice
and that the Boston type mutation is dominant led us to hypothesize that
the mutation might enhance the normal function of Msx2. The mutation is
located in position 7 of the N- terminal arm of the homeodomain, a region
implicated in both target sequence recognition and protein-protein
interactions. Here we test the hypothesis that the Pro148-->His mutation
alters the DNA binding properties of Msx2. Using gel shift and binding site
selection analyses, we show that the mutation enhances the affinity of Msx2
for a set of known Msx2 target sequences but has little or no effect on the
site specificity of Msx2 binding. The enhancement of Msx2 binding is due
largely if not entirely to an increased stability of the mutant Msx2-DNA
complex. These data provide a molecular-level explanation of how the
Pro148-->His mutation enhances Msx2 function and thus leads to the
dominant craniosynostosis phenotype.
ARTICLES
The molecular basis of Boston-type craniosynostosis: the Pro148-->His mutation in the N-terminal arm of the MSX2 homeodomain stabilizes DNA binding without altering nucleotide sequence preferences
Department of Biochemistry and Molecular Biology, Kenneth R. Norris Cancer Hospital, Los Angeles, CA, USA.
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