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R. C. Tyler, L. M. Reis, O. Abdul-Rahman, E. V. Semina; Identification of Novel PITX2 Mutations Associated With Various Ocular Phenotypes. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1308.
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PITX2 is a homeodomain transcription factor that was shown to be involved in Axenfeld-Rieger syndrome (ARS). Known PITX2 mutations in ARS are clustered in the regions that encode for the homeodomain and C-terminal arm of the protein; missense and truncation mutations in the homeodomain region and truncation mutations in the C-terminal region are usually observed. The association of ARS with certain types/positions of mutations in PITX2 suggests that other types of alterations may result in somewhat different phenotypes. To determine the spectrum of PITX2 mutations, we screened patients with diverse ocular phenotypes for variants in PITX2.
A total of 55 human DNA samples were included in the study. Six patients exhibited classic eye, dental and umbilical features of ARS. The remaining 49 patients demonstrated various anterior segment anomalies, juvenile/adult glaucoma and severe myopia. Screening of the DNA sequence was performed by direct sequencing of PCR products.
We identified a novel single nucleotide insertion mutation that disrupts the homeodomain and C-terminal sequences of PITX2 in a patient with classic features of ARS associated with short stature. The father of the proband was reported to be affected with the same phenotype, but was not available for testing. Another variant was identified in a patient with adult glaucoma and positive family history and results in a missense change in the C-terminal region of the protein. A third variant was found in a proband with severe myopia and leads to an amino acid change in the C-terminal region of PITX2. There is a positive family history of moderate myopia in this family. All three variants were not detected in 100 control individuals; comparative analysis of Pitx2 sequences from different species demonstrated that these variants affect amino acids that are highly conserved in vertebrate Pitx2 proteins.
PITX2 plays various roles during human development and is likely to be involved in multiple phenotypes. Our data indicate a possible involvement of PITX2 in short stature in addition to ARS in one family and in adult glaucoma and severe myopia in two other families. Studies that are currently in progress include analysis of additional family members and control samples to further investigate a potential role of the identified variants in disease development.
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