Posterior Polar Cataract Caused by a Recurrent Mutation in PITX3

Abstract

Abstract: : Purpose: Congenital cataracts affect about 6 patients per 10,000 births and frequently cause blindness in infants. Inherited cataracts account for up to half of all congenital cataracts. They are clinically and genetically heterogeneous. Loci for autosomal dominant posterior polar cataracts have been mapped to chromosomes 1p36, 16q22, 20p12-q12 and 11q22-q22.3. Mutations in PITX3 gene have been observed in a single patient with total congenital cataract and in anterior segment mesenchymal dysgenesis (ASMD). The purpose of this study is to present the clinical findings and the genetic analysis in a large family with autosomal dominant congenital posterior polar cataracts. Methods: A four-generation American family with congenital posterior polar cataracts was identified. Forty-four members of the family were examined ophthalmologically and a total of 20 patients were affected. Blood samples were collected with consent for genetic analysis of 28 patients of whom 15 were affected. After exclusion of known loci for posterior polar cataract, a genome-wide screen was conducted with a set of 170 markers spaced at 25-cM intervals. Results: We mapped dominant congenital posterior polar cataract to chromosome 10q24.The maximal LOD score of 4.52 at recombination fraction θ = 0 was obtained for marker D10S574. On haplotype analysis a 13cM interval between loci D10S1680 and D10S467was identified, which included the PITX3 gene. On sequencing the coding region of PITX3, we found a 17 base pair duplication in exon 3.. The insertion resulted in a frameshift, altering 82 C-terminal amino acids. The mutation was co-inherited with the disease in all instances. The comparison of the haplotype of this family and a patient with anterior segment mesenchymal dysgenesis (ASMD) carrying the same mutation, showed the presence of a shared allele over a 10 cM region. Conclusion: This study provides further evidence for genetic heterogeneity of autosomal dominant posterior polar cataract. Although the same genotype was present in the patient with ASMD, the common phenotype of this mutation is probably posterior polar cataract. The haplotype analysis showed that the patient with ASMD and the family with posterior polar cataract share a common ancestor. A modifier gene may cause the anterior segment abnormalities in the ASMD patient.

Keywords: gene mapping • cataract • linkage analysis