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. M utants have a reduced prosencephalon, anopthalmia or micropthalmia, de fective olfactory development and bifurcations in Rathke's pouch. Neon ates exhibit abnormalities in the corpus callosum, the anterior and hi ppocampal commissures, and the septum pellucidum. A comparable and equ ally variable phenotype in humans is septo-optic dysplasia (SOD). We h ave cloned human HESX1 and screened for mutations in affected individu als. Two siblings with SOD were homozygous for an Arg53Cys missense mu tation within the HESX1 homeodomain which destroyed its ability to bin d target DNA. These data suggest an important role for Hesx1/HESX1 in forebrain, midline and pituitary development in mouse and human.