Journal Article

Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification

Wilkie, Andrew O.M., Twigg, Stephen R.F., Tang, Zequn, Chrzanowska, Krystyna H., Elanko, Navaratnam, Maxson, Robert E., Walsh, Sinead, Hurst, Jane A., Wall, Steven A.

2000

Overview

The genetic analysis of congenital skull malformations provides insight into normal mechanisms of calvarial osteogenesis 1 . 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 month 2 . PFM are usually asymptomatic, but may be associated with headache, scalp defects and structural or vascular malformations of the brain 3 , 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 mutation 5 (P148H), associated with craniosynostosis, that binds with enhanced affinity to the same target 6 . 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Adult / Agriculture / Animal Genetics and Genomics / Animals / Base Sequence / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Birth defects / Blotting, Southern / Bone diseases / Cancer Research / Child / Child, Preschool / chromosome 5 / Chromosomes, Human, Pair 5 - genetics / Cranial Sutures - abnormalities / Cranial Sutures - diagnostic imaging / Cranial Sutures - growth & development / Deoxyribonucleic acid / Diseases of the osteoarticular system / DNA / DNA Mutational Analysis / DNA-Binding Proteins - deficiency / DNA-Binding Proteins - genetics / Female / Gene Function / Genes / Genetic aspects / Genetics / Genotype & phenotype / Health aspects / Homeobox genes / Homeodomain Proteins - genetics / Homeotic genes / Human Genetics / Humans / Infant / letter / Male / Medical sciences / Mice / Microsatellite Repeats / Miscellaneous. Osteoarticular involvement in other diseases / Molecular Sequence Data / MSX2 gene / Mutation / Ossification / Osteogenesis - genetics / Parietal Bone - abnormalities / Parietal Bone - growth & development / parietal foramina / Pedigree / Physiological aspects / Radiography / Risk factors / Sequence Deletion / Skull - abnormalities / Skull - diagnostic imaging / Skull - growth & development