Transgenic rescue demonstrates involvement of the Ian5 gene in T cell development in the rat

• Published in: Physiological genomics 2004-10, Vol.19 (2), p.228-232
• Main Authors: Michalkiewicz, Mieczyslaw, Michalkiewicz, Teresa, Ettinger, Ruth A, Rutledge, Elizabeth A, Fuller, Jessica M, Moralejo, Daniel H, Van Yserloo, Brian, MacMurray, Armand J, Kwitek, Anne E, Jacob, Howard J, Lander, Eric S, Lernmark, Ake
• Format: Article
• Language: English
• Subjects: Animals; Genetic Complementation Test; GTP-Binding Proteins - genetics; GTP-Binding Proteins - metabolism; GTP-Binding Proteins - physiology; Lung - chemistry; Lung - pathology; Lymph Nodes - chemistry; Lymph Nodes - pathology; Lymphopenia - genetics; Lymphopenia - metabolism; Lymphopenia - pathology; Mutation - genetics; Mutation - physiology; Rats; Rats, Inbred BB; Rats, Inbred F344; Rats, Sprague-Dawley; RNA, Messenger - genetics; RNA, Messenger - metabolism; Spleen - chemistry; Spleen - pathology; T-Lymphocytes - metabolism; Thymus Gland - chemistry; Thymus Gland - pathology; Transgenes - genetics; Transgenes - physiology
• ISSN: 1094-8341; 1531-2267
• DOI: 10.1152/physiolgenomics.00126.2004

1 Department of Physiology, Human Molecular and Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226 2 Department of Medicine, University of Washington, Seattle, Washington 98195 3 Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02138 4 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 5 Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115 6 Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02141 ABSTRACT 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 whether 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. diabetes; lymphopenia; apoptosis