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Characterization and Prevalence of PITX2 Microdeletions and Mutations in Axenfeld-Rieger Malformations

¹From the Department of Ophthalmology, University of Alberta, Edmonton, Alberta, Canada; ²Duke University Eye Center, Durham, North Carolina; the ³Department of Ophthalmology, The Hospital for Sick Children, Toronto, Ontario, Canada; ⁴The New York Ear and Eye Infirmary, New York, New York; the ⁵Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Connecticut; the ⁶University of Ottawa Eye Institute and Ottawa Health Research Institute, Ottawa, Ontario, Canada; and the ⁷University of Illinois at Chicago Eye Center, Chicago, Illinois.

PURPOSE. Mutations of the homeodomain protein PITX2 produce Axenfeld-Rieger (AR) malformations of the anterior chamber, an autosomal dominant disorder accompanied by a 50% risk of glaucoma. Twenty-nine mutations of PITX2 have been described, with a mutational prevalence estimated between 10% and 60% in AR. In the current study, the possible role of altered PITX2 gene dosage in the etiology of AR was investigated. Gross gene deletions and duplications should alter PITX2 activity analogously to hypomorphic and hypermorphic mutations, respectively.

METHODS. Sixty-four patients with AR, iridogoniodysgenesis (IGD), iris hypoplasia (IH), or anterior segment dysgenesis (ASD) were screened for PITX2 mutations by sequencing. PITX2 gene dosage was concurrently examined in these patients by real-time quantitative PCR. Microsatellite markers were used to map 4q25 microdeletions at a contig scale, as well as for haplotype analysis in an extended AR kindred. An additional 27 patients with other assorted ocular phenotypes were evaluated by similar methods, amounting to a total of 91 cases analyzed.

RESULTS. Three novel mutations of PITX2 (4.7%) were identified among 64 patients with AR, IGD, IH, or ASD. Deletions of PITX2 were as frequent as mutations in our sample. Chromosome 4q25 microdeletions were physically mapped relative to several microsatellite markers in each patient. Cosegregation of AR and a PITX2 deletion was demonstrated in an extended kindred.

CONCLUSIONS. Point mutations and gross deletions of PITX2 appear to produce an equivalent haploinsufficiency phenotype. Quantitative PCR is an efficient means of detecting causative PITX2 deletions in patients with AR and may increase the detection rate at this locus.

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