Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse


During early mouse development the homeobox gene Hesx1 is expressed in prospective forebrain tissue, but later becomes restricted to Rathke's pouch, the primordium of the anterior pituitary gland. Mice lacking Hesx1 exhibit variable anterior CNS defects and pituitary dysplasia. Mutants have a reduced prosencephalon, anopthalmia or micropthalmia, defective olfactory development and bifurcations in Rathke's pouch. Neonates exhibit abnormalities in the corpus callosum, the anterior and hippocampal commissures, and the septum pellucidum. A comparable and equally variable phenotype in humans is septo-optic dysplasia (SOD). We have cloned human HESX1 and screened for mutations in affected individuals. Two siblings with SOD were homozygous for an Arg53Cys missense mutation within the HESX1 homeodomain which destroyed its ability to bind target DNA. These data suggest an important role for Hesx1/HESX1 in forebrain, midline and pituitary development in mouse and human.

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Figure 1: Targeted inactivation of Hesx1.
Figure 2: Histological analysis of the Hesx1 mutants.
Figure 3: Whole-mount analysis of anterior neural markers in Hesx1 mutant (a,c,e,g,i,j) and wild-type (b,d,f,h,k) embryos.
Figure 4: Predicted open reading frame of human HESX1 compared with the mouse Hesx1 and Xenopus XANF1 proteins.
Figure 5: Mapping of HESX1. Fluorescent in situ hybridization of HESX1 on normal male metaphase chromosomes showing hybridization to 3p21 (arrows).
Figure 6: Detection of a homozygous missense mutation in HESX1 of the probands IV.4 and IV.5.
Figure 7: Electromobility shift assay of wild-type and mutant HESX1.


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We thank L. Erlandsson for help with the ES cell work, R.L. Gardner and M.A. Sällström for blastocyst injections, S. Povey for help with the FISH analysis and MRC HGMP for use of equipment. We also thank G. Martin, A. McMahon, D. Wilkinson, R. Di Lauro and P. Gruss for probes, and S. Da Rocha and members of Biological Services and Histology at NIMR for excellent technical assistance. We particularly thank K. Mahon for sharing unpublished data. J.-P.M.-B., a recipient of a Lund-Oxford Developmental Biology Programme fellowship, thanks A. Björklund and T. Leanderson for continuous support. J.M.B. is an HFSP fellow. M.T.D. acknowledges funding support from C.G.D. Brook and the Special Trustees of the Middlesex Hospital. We are grateful to C.G.D. Brook, A. Aynsley-Green, M. Preece, R. Stanhope and P. Bareille for their help with the recruitment of patients. We also thank the patients and their families for their help in this study.

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Correspondence to Iain C. A. F. Robinson.

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Dattani, M., Martinez-Barbera, J., Thomas, P. et al. Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet 19, 125–133 (1998).

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