A mutation in a novel connexin-like gene affects early lens development in the mouse

Purpose: Aim of the study was the morphological and genetical characterization of Aey12, a novel dominant mouse mutant suffering from microphthalmia, lens and corneal opacities. Methods: A genome wide linkage analysis was performed using micro-satellite markers. The Aey12 mutation was identified by sequence analysis of positional candidate genes. Histological analysis and in-situ hybridizations were performed at the stages E10.5 - E17.5. Results: Aey12 (abnormality of the eye) is a new dominant mouse mutant, which was recovered in an ENU mutagenesis program at the GSF. Aey12 animals are characterized by small eyes with cornea opacities and lenses with cataracts and vacuoles. Both, heterozygotes and homozygotes, are viable and fully fertile. As major histological defect, the elongation of the primary lens fibres is blocked resulting in the stop of lens development at this stage. Genome-wide linkage analysis mapped the Aey12 mutation on mouse chromosome 10 between the markers D10Mit206 and D10Mit189. Among the positional candidate genes, one EST (D230044M03Rik) encodes a connexin-like protein, which is similar to Connexin 43.4. A G-T point mutation was identified at cDNA position 96 resulting in an R32Q amino acid exchange in a transmembrane domain. D230044M03Rik is expressed in the posterior part of the lens vesicle exactly at the position where the primary fiber elongation starts. Furthermore, an additional expression was observed in many other tissues like brain, lung, heart, liver and kidney. Conclusions: The new mouse mutant Aey12 is characterized by an early block of the eye development caused by a point mutation in a novel connexin-like gene.