A NOVEL HOMEOBOX GENE PITX3 IS MUTATED IN FAMILIES WITH AUTOSOMAL-DOMINANT CATARACTS AND ASMD

We report here the identification of a new human homeobox gene, PITX3, and its involvement in anterior segment mesenchymal dysgenesis (ASMD) and congenital cataracts in humans. The PITX3 gene is the human homol ogue of the mouse Pitx3 gene and is a member of the RIEG/PITX homeobox gene family. The protein encoded by PITX3 shows 99% amino-acid identi ty to the mouse protein, with 100% identity in the homeodomain and app roximately 70% overall identity to other members of this family. We ma pped the human PITX3 gene to 10q25 using a radiation-hybrid panel. A c ollection of 80 DNA samples from individuals with various eye anomalie s was screened for mutations in the PITX3 gene. We identified two muta tions in independent patients. A 17-bp insertion in the 3'-end of the coding sequence, resulting in a frame shift, occured in a patient with ASMD and cataracts, and a G-->A substitution, changing a codon for se rine into a codon for asparagine, in the 5'-end of the gene occured in a patient with congenital cataracts. Both mutations cosegregate with the disease phenotype in families, and neither were found in up to 300 control individuals studied, Further expression analysis of Pitx3 in the mouse supports a unique role in early ocular development, with lat er expression extending to the midbrain, tongue, incisors, sternum, ve rtebrae and limbs. These data strongly suggest a role for PITX3 in ASM D and cataracts and provide new evidence of the contribution of the RI EG/PITX gene family to the developmental program underpinning normal e ye formation.