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ORIGINAL RESEARCH ARTICLE

The Tetratricopeptide Repeat Domain 7 Gene Is Mutated in Flaky Skin Mice: A Model for Psoriasis, Autoimmunity, and Anemia

Cynthia Helms^*, Stephen Pelsue, Li Cao^*, Erika Lamb, Brett Loffredo, Patricia Taillon-Miller^*, Brooke Herrin^*, Lisa M. Burzenski, Bruce Gott, Bonnie L. Lyons, Deana Keppler^*, Leonard D. Shultz and Anne M. Bowcock^*,,1

^* Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110; Department of Applied Medical Sciences, University of Southern Maine, Portland, Maine 04103; Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110; and The Jackson Laboratory, Bar Harbor, Maine 04609

To whom requests for reprints should be addressed at ¹ Department of Genetics, Washington University School of Medicine, 4566 Scott Avenue, St. Louis, MO 63110. E-mail: bowcock{at}genetics.wustl.edu

The flaky skin (fsn) mutation in mice causes pleiotropic abnormalities including psoriasiform dermatitis, anemia, hyper-IgE, and anti-dsDNA autoantibodies resembling those detected in systemic lupus erythematosus. The fsn mutation was mapped to an interval of 3.9 kb on chromosome 17 between D17Mit130 and D17Mit162. Resequencing of known and predicted exons and regulatory sequences from this region in fsn/fsn and wild-type mice indicated that the mutation is due to the insertion of an endogenous retrovirus (early transposon class) into intron 14 of the Tetratricopeptide repeat (TPR) domain 7 (Ttc7) gene. The insertion leads to reduced levels of wild-type Ttc7 transcripts in fsn mice and the insertion of an additional exon derived from the retrovirus into the majority of Ttc7 mRNAs. This disrupts one of the TPRs within TTC7 and may affect its interaction with an as-yet unidentified protein partner. The Ttc7 is expressed in multiple types of tissue including skin, kidney, spleen, and thymus, but is most abundant in germinal center B cells and hematopoietic stem cells, suggesting an important role in the development of immune system cells. Its role in immunologic and hematologic disorders should be further investigated.

Key Words: flaky skin mutation • fsn • Ttc7 gene • psoriasis • autoimmunity • anemia

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