Down syndrome is caused by a genomic imbalance of human chromosome 21 which is mainly observed as trisomy 21. The regions on human chromosome 21 are syntenically conserved in three regions on mouse chromosomes 10, 16 and 17. Ts65Dn mice, the most widely used model for Down syndrome, are trisomic for approximately 56.5% of the human chromosome 21 syntenic region on mouse chromosome 16. To generate a more complete trisomic mouse model of Down syndrome, we have established a 22.9 Mb duplication spanning the entire human chromosome 21 syntenic region on mouse chromosome 16 in mice using Cre/loxP-mediated long-range chromosome engineering. The presence of the intact duplication in mice was confirmed by fluorescent in situ hybridization and BAC-based array comparative genomic hybridization. The expression levels of the genes within the duplication interval reflect gene-dosage effects in the mutant mice. The cardiovascular and gastrointestinal phenotypes of the mouse model were similar to those of patients with Down syndrome. This new mouse model represents a powerful tool to further understand the molecular and cellular mechanisms of Down syndrome.

Mammalian cells have established mechanisms to reduce the abundance of mRNAs that harbor a nonsense codon and prematurely terminate translation. In the case of the human triosephosphate isomerase (TPI gene), nonsense codons located less than 50 to 55 bp upstream of intron 6, the 3-most intron, fail to mediate mRNA decay. With the aim of understanding the feature(s) of TPI intron 6 that confer function in positioning the boundary between nonsense codons that do and do not mediate decay, the effects of deleting or duplicating introns have been assessed. The results demonstrate that TPI intron 6 functions to position the boundary because it is the 3-most intron. Since decay takes place after pre-mRNA splicing, it is conceivable that removal of the 3-most intron from pre-mRNA "marks" the 3-most exon-exon junction of product mRNA so that only nonsense codons located more than 50 to 55 nucleotides upstream of the "mark" mediate mRNA decay. Decay may be elicited by the failure of translating ribosomes to translate sufficiently close to the mark or, more likely, the scanning or looping out of some component(s) of the translation termination complex to the mark. In support of scanning, a nonsense codon does not elicit decay if some of the introns that normally reside downstream of the nonsense codon are deleted so the nonsense codon is located (i) too far away from a downstream intron, suggesting that all exon-exon junctions may be marked, and (ii) too far away from a downstream failsafe sequence that appears to function on behalf of intron 6, i.e., when intron 6 fails to leave a mark. Notably, the proposed scanning complex may have a greater unwinding capability than the complex that scans for a translation initiation codon since a hairpin structure strong enough to block translation initiation when inserted into the 5 untranslated region does not block nonsense-mediated decay when inserted into exon 6 between a nonsense codon residing in exon 6 and intron 6.For all organisms that have been studied, the abundance of mRNAs harboring a nonsense codon generated by either a frameshift or a nonsense mutation is generally no more than 20 to 25% of normal (for reviews, see references 22, 23, 30, and 36). In the case of mammalian cells, exceptions to this generalization arise when nonsense codon recognition is prevented by inhibitors of translation such as (i) a suppressor tRNA (3, 21), (ii) ribosome-binding drugs, including anisomysin, cycloheximide, emetine, puromycin, or pactamycin (8, 26, 34); (iii) a secondary structure within the 5Ј untranslated region that blocks translation initiation (3); or (iv) polio virus infection, which inactivates cap-dependent translation (8). Exceptions also arise for nonsense codons followed by an in-frame translation reinitiation site (47) or residing within the distal end of the translational reading frame (reviewed in references 22 and 23).For mRNA encoding human triosephosphate isomerase (TPI), the boundary between distal nonsense codons that do and do not reduce mRNA abundance resides bet...