Nature Genetics
24, 387 - 390 (2000)
doi:10.1038/74224
Functional haploinsufficiency of the human homeobox gene MSX2
causes defects in skull ossificationAndrew O.M. Wilkie1, 2, 3, Zequn Tang4, Navaratnam Elanko1, Sinead Walsh1, Stephen R.F. Twigg1, Jane A. Hurst2, Steven A. Wall3, Krystyna H. Chrzanowska5
& Robert E. Maxson Jr41
Institute of Molecular Medicine, John Radcliffe Hospital
, Headington, Oxford, UK. 2
Department of Clinical Genetics, The Churchill
, Oxford, UK. 3
Craniofacial Unit, Radcliffe Infirmary,
Oxford, UK. 4
University of Southern California/Norris Hospital,
USC Medical School, Los Angeles, California,
USA. 5
Department of Medical Genetics, Children's Memorial
Health Institute, Warsaw, Poland.
Correspondence should be addressed to Andrew O.M. Wilkie awilkie@enterprise.molbiol.ox.ac.ukThe genetic analysis of congenital skull malformations provides insight
into normal mechanisms of calvarial osteogenesis1. Enlarged
parietal foramina (PFM) are oval defects of the parietal bones caused by deficient
ossification around the parietal notch, which is normally obliterated during
the fifth fetal month2. PFM are usually asymptomatic, but may
be associated with headache, scalp defects and structural or vascular malformations
of the brain3,
4. Inheritance is frequently autosomal dominant,
but no causative mutations have been identified in non-syndromic cases. We
describe here heterozygous mutations of the homeobox gene MSX2 (located
on 5q34−q35) in three unrelated families with PFM. One is a deletion
of approximately 206 kb including the entire gene and the others are intragenic
mutations of the DNA-binding homeodomain (RK159-160del and R172H) that predict
disruption of critical intramolecular and DNA contacts. Mouse Msx2 protein
with either of the homeodomain mutations exhibited more than 85% reduction
in binding to an optimal Msx2 DNA-binding site. Our findings contrast with
the only described MSX2 homeodomain mutation5 (P148H),
associated with craniosynostosis, that binds with enhanced affinity to the
same target6. This demonstrates that MSX2 dosage is critical
for human skull development and suggests that PFM and craniosynostosis result,
respectively, from loss and gain of activity in an MSX2-mediated pathway of
calvarial osteogenic differentiation.
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