A novel homeobox gene PITX3 is mutated in families with autosomal-dominant cataracts and ASMD

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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 homologue 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 identity to the mouse protein, with 100% identity in the homeodomain and approximately 70% overall identity to other members of this family. We mapped the human PITX3 gene to 10q25 using a radiation-hybrid panel. A collection of 80 DNA samples from individuals with various eye anomalies was screened for mutations in the PITX3 gene. We identified two mutations 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 serine 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 Pitx3in the mouse supports a unique role in early ocular development, with later expression extending to the midbrain, tongue, incisors, sternum, vertebrae and limbs. These data strongly suggest a role for PITX3 in ASMD and cataracts and provide new evidence of the contribution of the RIEG/PITX gene family to the developmental program underpinning normal eye formation.

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Figure 1: Amino-acid sequence of the PITX3 protein (deduced from nucleotide sequence).
Figure 2: In situ hybridization with a Pitx3 riboprobe on section at the eye level of day-16-pc embryo.
Figure 3: In situ hybridization with a Pitx3 riboprobe of mouse embryo sections.
Figure 4: Variable expressivity in anterior segment mesenchymal dysgenesis family.
Figure 5: A mutation in PITX3 in the ASMD family.
Figure 6: A mutation in PITX3 in the family with dominant cataract (ADCC).


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We thank the many patients who contributed samples for analysis in this study. B. Ludwig provided outstanding technical assistance. This work was supported by the CARC grant no. DE09170 and grant no. EY08893 (K. Zadnik, Principal Investigator) from the U.S. National Institutes of Health.

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Correspondence to Jeffrey C. Murray.

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