Sequence and location of SIX3, a homeobox gene expressed in the human eye

Mouse Six3 is a homeobox gene expressed almost exclusively in the developing retina, lens, hypothalamus, and pituitary. It belongs to the same family as sine oculis, a Drosophila regulatory gene that encodes a transcription factor essential for eye development. The optix gene is its closest known Drosophila homologue, with a homeodomain that is 95% identical in sequence to the Six3 protein. We have isolated the homologous human gene, SIX3, which is expressed in the adult retina and encodes a 332 amino acid protein that is 98% identical to its mouse counterpart. The SIX3 protein coding region is interrupted by a single intron located just downstream of the homeobox. A surprising feature of the SIX3 gene is a 533 nucleotide 5' untranslated region that contains long polypyrimidine tracts with 96% identity to mouse Six3. We have used in-situ hybridization to map SIX3 to 2p21-p22, a site that is syntenic with the Six3 region of mouse chromosome 17. Large heterozygous deletions associated with human holoprosencephaly type 2 have been previously mapped to 2p21, opening the possibility that SIX3 could be involved in the development of midline structures of the head. Alternatively, the expression pattern of mouse Six3 suggests that human SIX3 could be involved in disorders of eye and pituitary development.