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(Investigative Ophthalmology and Visual Science. 2008;49:1525-1532.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.07-1033
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Mutation in a Novel Connexin-like Gene (Gjf1) in the Mouse Affects Early Lens Development and Causes a Variable Small-Eye Phenotype

Oliver Puk,1 Jana Löster,1 Claudia Dalke,1 Dian Soewarto,2 Helmut Fuchs,2 Birgit Budde,3,4 Peter Nürnberg,3,4 Eckhard Wolf,5 Martin Hrabé de Angelis,2,6 and Jochen Graw1,7

From the Institutes of 1Developmental Genetics and 2Experimental Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; the 3Institute of Molecular Genetics, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany; 5Lehrstuhl für Molekulare Tierzucht und Biotechnologie, Ludwig-Maximilians-Universität, München, Germany; and the Institutes of 6Experimental Genetics and 7Genetics, Technical University Munich, Center of Life and Food Sciences, Weihenstephan, Germany.

PURPOSE. The purpose of the study was the characterization of the novel small-eye mutant Aey12 in the mouse.

METHODS. The eyes of the mutants were described morphologically and histologically and by in situ hybridization.

RESULTS. The homozygotes were viable and fully fertile, which identifies Aey12 as a new microphthalmia phenotype in the mouse, different from Maf or Pax6 mutants. Histologic analysis indicated the presence of the lens vesicle; however, the primary fiber cells did not elongate properly. Genome-wide linkage analysis mapped the mutation to the proximal region of chromosome 10 between the markers D10Mit206 and D10Mit189. Among the positional candidate genes, one EST (expressed sequence tag), D230044M03Rik, encodes a connexin-like protein. A G->T point mutation was identified at cDNA position 96, resulting in an R32Q amino acid exchange in a transmembrane domain. The mutation leads to a loss of an SsiI restriction site, which is present in five wild-type mouse strains (102, C3H, C57BL/6, DBA, and JF1). The gene is expressed in the posterior part of the lens vesicle, where the primary fiber elongation starts. In the mutants, the expression pattern of Pax6, Prox1, Six3, and Crygd are modified, but not the pattern of Pax2.

CONCLUSIONS. The mutated mouse gene belongs to the family of connexin-encoding genes (gene symbols Gja–Gje). Together with its rat and human homologues, it defines a new subgroup, referred to as Gjf1. The mouse mutant described herein offers a new functional candidate gene for microphthalmia-related disorders at the corresponding locus on human chromosome 6, area q24.






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