A double-deletion mutation in the Pitx3 gene causes arrested lens development in aphakia mice

The recessive aphakia (ak) mouse mutant is characterized by bilateral micro phthalmia due to a failure of lens morphogenesis. We fine-mapped the ak loc us to the interval between D19Umil and D19Mit9, developed new polymorphic m arkers, and mapped candidate genes by construction of a BAC contig. The Pit x3 gene, known to be expressed in lens primordia, shows zero recombination with the ak mutation on our inter-subspecific intercross panel representing 1170 meioses. A recent report described a deletion in the intergenic regio n between Gbf1 and Pitx3 as the possible ak mutation. Our results differ in that we find not only the distant intergenic deletion, but also a much lar ger deletion directly in the Pitx3 gene, eliminating exon 1 and extending i nto intron 1 and the promoter region. Pitx3 transcript levels are severely reduced in ak/ak mice from E11.5 to newborn (5 +/- 1% of the wildtype level s at E13.5), while an involvement of the flanking Gbf1 and Cig30 genes in t he aberrant lens development is highly unlikely based on expression analysi s. We conclude that the ak mutation consists of two deletions, the larger o f which removes part of Pitx3, indicating a crucial role of this gene in ea rly lens development. (C) 2001 Academic Press.