Heterozygous and homozygous mutations in PITX3 in a large Lebanese family with posterior polar cataracts and neurodevelopmental abnormalities

PURPOSE. The PITX3 gene, which codes for a homeobox bicoidlike transcription factor is responsible for dominant cataract and anterior segment mesenchymal dysgenesis in humans. In the current study, a family with autosomal dominant posterior polar cataract (PPC) and a PITX3 mutation that cosegregates with the disease was examined. Also studied were two siblings who were homozygous for the PITX3 mutation who had microphthalmia and significant neurologic impairment. METHODS. A genome-wide screen, linkage analysis in the PITX3 chromosomal region 10q25, haplotype analysis, and sequencing of the PITX3 gene were performed on 28 affected and 14 unaffected member of a three-gene ration Lebanese family. RESULTS. Genome-wide linkage analysis showed a lod score of 3.56 at theta = 0.00 on chromosome 10 at area q25. Analysis of the haplotypes and phenotypes confined the disease locus to a region on 10q25 between the markers D10S1239 and D10S1268. A candidate gene, PITX3, maps to that region. Sequencing of the PITX3 gene revealed a heterozygous G deletion mutation in 25 of the 42 family members. In addition, two siblings from a consanguineous marriage were found to be homozygous for the deletion. CONCLUSIONS. This is the first report of homozygous PITX3 mutations in humans. The phenotype in these individuals highlights the role of PITX3 in ocular and central nervous system (CNS) development.