Originally published as Genetics Published Articles Ahead of Print on May 27, 2009.

Genetics, Vol. 182, 1077-1088, August 2009, Copyright © 2009
doi:10.1534/genetics.109.104562

Analysis of Pax6 Contiguous Gene Deletions in the Mouse, Mus musculus, Identifies Regions Distinct from Pax6 Responsible for Extreme Small-Eye and Belly-Spotting Phenotypes

Jack Favor^*,1, Alan Bradley, Nathalie Conte, Dirk Janik, Walter Pretsch^*, Peter Reitmeir, Michael Rosemann^**, Wolfgang Schmahl, Johannes Wienberg and Irmgard Zaus^*

^* Institute of Human Genetics, Institute of Health Management, ^** Institute of Radiation Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg D-85764, Germany, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom, Lehrstuhl für Allgemeine Pathologie und Neuropathologie, Tierärztliche Fakultät, Ludwig-Maximilians-Universität, München D-80539, Germany and Chrombios GmbH, Raubling D-83064, Germany

¹ Corresponding author: Institute of Human Genetics, Helmholtz Zentrum München German Research Center for Environmental Health, Ingolstädter Lanstrasse 1 D-85764, Neuherberg, Germany.
E-mail: favor{at}helmholtz-muenchen.de

In the mouse Pax6 function is critical in a dose-dependent manner for proper eye development. Pax6 contiguous gene deletions were shown to be homozygous lethal at an early embryonic stage. Heterozygotes express belly spotting and extreme microphthalmia. The eye phenotype is more severe than in heterozygous Pax6 intragenic null mutants, raising the possibility that deletions are functionally different from intragenic null mutations or that a region distinct from Pax6 included in the deletions affects eye phenotype. We recovered and identified the exact regions deleted in three new Pax6 deletions. All are homozygous lethal at an early embryonic stage. None express belly spotting. One expresses extreme microphthalmia and two express the milder eye phenotype similar to Pax6 intragenic null mutants. Analysis of Pax6 expression levels and the major isoforms excluded the hypothesis that the deletions expressing extreme microphthalmia are directly due to the action of Pax6 and functionally different from intragenic null mutations. A region distinct from Pax6 containing eight genes was identified for belly spotting. A second region containing one gene (Rcn1) was identified for the extreme microphthalmia phenotype. Rcn1 is a Ca⁺²-binding protein, resident in the endoplasmic reticulum, participates in the secretory pathway and expressed in the eye. Our results suggest that deletion of Rcn1 directly or indirectly contributes to the eye phenotype in Pax6 contiguous gene deletions.

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