International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 61 - ENU MUTAGENESIS IDENTIFIES A RECESSIVE MUTATION IN A DNAJ PROTEIN THAT RESULTS IN RETARDED GROWTH AND POLYDACTYLY

Webb T 1, McKie L 1, West K 1, Peters J 2, Cross SH 1, Jackson I 1

1 MRC Human Genetics Unit, Edinburgh, United Kingdom and 2 MRC Mammalian Genetics Unit, Harwell, United Kingdom

Chromosomal deletions can be used in mutagenesis stategies that screen for recessive phenotypes. Several mouse chromosomal deletions are available which remove the Pax6 gene and result in the small-eye phenotype. The Pax6Sey-1H deletion spans 3Mb and includes about 15 genes. We have used this deletion in an ENU mutagenesis screen for phenotypes revealed when hemizygous with the deletion. We have found one mutation from 233 pedigrees tested. The mutation is lethal against the Pax6Sey-1H deletion. Mice heterozygous for the mutation are phenotypically normal. When homozygous the mutation is generally recessive lethal by E14, and embryos have retarded growth as early as E9. However, some mice are born which are small and have extra digits on one or both hind limbs. Sequencing of the genes in the deletion interval identified a splice site mutation in a novel member of the Dnaj family of molecular chaperones. The mutation causes the in frame skipping of exon 4, leading to an mRNA that encodes a protein with an internal 23 amino acid deletion. We have expressed wild type and mutant proteins in E. coli for further studies. Expression in mammalian cells is underway.

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