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1 Department of Physiology, Human Molecular and Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
2 Department of Medicine, University of Washington, Seattle, Washington, USA
3 Broad Institute, Cambridge, Massachusetts, USA; Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
* To whom correspondence should be addressed. E-mail: mmichalk{at}mcw.edu.
A single point mutation in a novel immune-associated nucleotide gene 5 (Ian5) coincides with severe T-cell lymphopenia in BB rats. We used a transgenic rescue approach in lymphopenic BB-derived congenic F344.lyp/lyp rats to determine if this mutation is responsible for lymphopenia and to establish the functional importance of this novel gene. A 150 kb P1 artificial chromosome (PAC) transgene harboring a wild-type allele of the rat Ian5 gene restored Ian5 transcript and protein levels, completely rescuing the T-cell lymphopenia in the F344.lyp/lyp rats. This successful complementation provides direct functional evidence that the Ian5 gene product is essential for maintaining normal T-cell levels. It also demonstrates that transgenic rescue in the rat is a practical and definitive method for revealing the function of a novel gene.
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