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F Idrees, S Fraser, G Brice, A Childs, PT Khaw, K Willis, JC Sowden; Identification of PITX2 Mutations in Axenfeld-Rieger Syndrome Patients . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3402.
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Purpose: To screen the PITX2 gene for mutations in a cohort of patients with anterior segment dysgenesis to establish the mutation spectrum. Mutations in the PITX2 bicoid-like homeobox gene cause Axenfeld-Rieger Syndrome (AXRS) (Semina et al. Nature Genetics 14:392 (1996)). Axenfeld-Rieger Syndrome is an autosomal dominant human disorder characterised by developmental glaucoma with anterior segment abnormalities of the eye as well as dental hypoplasia, mild craniofacial dysmorphism and umbilical abnormalities. PITX2 has also been implicated in the development of multiple organs and left-right asymmetry in the body plan. Methods: 38 families with at least one affected member diagnosed with anterior segment dysgenesis, were analysed for sequence changes in the four exons of the PITX2 gene. Exon-specific primers were used to PCR amplify patient DNA. Heteroduplex analysis and direct sequencing was used to identify sequence alterations. All patients referred for the study had their clinical history taken and underwent a general physical examination. Patients were also examined using a slit lamp and gonioscopy lens. Results: Probable disease-causing mutations were identified in a small number of patients with AXRS. These mutations were not present in 50 control chromosomes and in unaffected family members. We report a novel missense Arg43Trp mutation within the homeobox, found in a family with three generations affected with AXRS. The significance of mutations and polymorphisms for PITX2 protein function will be evaluated. No mutations were identified in patients with Axenfeld-Rieger anomaly (a condition with only eye involvement and no systemic abnormalities) and in patients with other anterior segment dysgeneses. Conclusions: There is significant phenotypic variability in patients with AXRS, both within and between families. The umbilical and dental abnormalities are highly penetrant and define families most likely to carry mutations in the PITX2 gene. These features may be used to guide diagnostic mutation analysis. Genotyping of more patients may reveal whether particular sequence alterations are associated with early onset glaucoma.
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