Haploinsufficiency of the human homeobox gene ALX4 causes skull ossification defects

Abstract

Inherited defects of skull ossification often manifest as symmetric parietal foramina (PFM; MIM 168500). We previously identified mutations of MSX2 in non-syndromic PFM and demonstrated genetic heterogeneity1. Deletions of 11p11–p12 (proximal 11p deletion syndrome, P11pDS; MIM 601224; ref. 2) are characterized by multiple exostoses, attributable to haploinsufficiency of EXT2 (refs. 3,4) and PFM. Here we identify ALX4, which encodes a paired-related homeodomain transcription factor, as the PFM disease gene in P11pDS.

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Figure 1: Physical mapping of the P11pDS region and identification of ALX4 mutations in PFM.
Figure 2: Human skull phenotypes associated with ALX4 mutations and expression of Alx4 in developing mouse calvaria.

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Acknowledgements

We thank the families for cooperation; R. Wisdom for the Alx4 probe; N. Elanko and S. Twigg for technical support; K. Clark for DNA sequencing; J. Peden, the OUBC group and the HGMP-RC for computing support; and P. Anslow for radiological expertise. This work was funded by the Alexander S. Onassis Foundation (Greece) and Medical Research Council (UK) (L.A.M.), The Anatomical Society of Great Britain and Ireland (I.A., G.M.M.-K.), Action Research (G.M.M.-K.) and the Wellcome Trust (A.O.M.W.).

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Correspondence to Andrew O.M. Wilkie.

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Mavrogiannis, L., Antonopoulou, I., Baxová, A. et al. Haploinsufficiency of the human homeobox gene ALX4 causes skull ossification defects. Nat Genet 27, 17–18 (2001) doi:10.1038/83703

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