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Fig. 2. The openmind phenotype is caused by mutations in the Atr2 gene. (A) Diagram of the domain structure of Atr2. Atr2 has N-terminal homologies to mouse atrophin 1 (Atr1), C. elegans EGL-27, Drosophila Atro and mouse metastasis associated protein 2 (Mta2). Black lines illustrate percent identity to Atr2; only the regions of highest homology are shown. The N terminus of Atr2 includes four domains also found in Mta2; these are the BAH (bromo-adjacent homology), ELM2 (EGL-27 and Mta1 homology 2), SANT (SWI3, ADA2, N-CoR and TFIIIB) and GATA (zinc finger) domains. The C terminus of Atr2 (red oval) is homologous to Atr1. The exon structure of the Atr2 gene is shown with respect to the domain structure of the encoded protein. Exons are numbered from the 5' end of the gene; coding sequences are orange, non-coding sequences white. Positions of the om mutation, insertion alleles and the Atr2S initiation site are indicated. (B) RT-PCR of1200 bases of the amino end of Atr2 from om mutant embryos, and heterozygous and wild-type tissues. The primers amplify two bands from wild-type brain (br.) and testis (tes.), one full-length (right upper arrow) and the other a minor alternatively spliced form lacking exon 5 (right lower arrow). By contrast, shorter fragments amplify from om mutants (left arrows). Brain and testis from heterozygous animals show all transcripts. Mutant and wild-type full length fragments are illustrated. The mutant cDNA has exon 3 spliced to exon 5, whereas wild-type cDNAs always include exon 4. The reading frames of exons 3 and 5 are different, creating a stop codon. (C) The genomic sequence of the 3' end of exon 4 (shaded) and the start of intron 4 is shown. om homozygotes have an ENU-induced single base change of T to A; this mutation destroys the splice donor causing exon 4 to be omitted from the mutant mRNA. (D) Whole-mount in situ hybridization for Atr2 with a 5' probe at E9.5 reveals a dramatic reduction in Atr2 mRNA levels in mutant embryos (right) compared with normal littermates (left). (E) At E9.5, a ßgal-stained compound heterozygote with the Atr2^om/Atr2^PT026 genotype clearly duplicates the om phenotype (see text).

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