Characterizing a Novel Gene, Mosaic, and Its Role in Mediating a Multisystem Autoimmunity

Alice Chan¹, Emily Brown², Oded Foreman³, Anita Oberbauer⁴, Angela Hughes⁵, Shelly Burton⁶, Hong-Erh Liang⁷, Mark Anderson⁸ and Danika Bannasch⁹, ¹Pediatric Rheumatology, University of California San Francisco, San Francisco, CA, ²Population Health and Reproduction, School of Veterinary Medicine, University of California Davis, Davis, CA, ³Genentech, Inc, South San Francisco, CA, ⁴Department of Animal Science, School of Veterinary Medicine, University of California Davis, Davis, CA, ⁵Mars Veterinary, Gaithersburg, MD, ⁶Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PE, Canada, ⁷Medicine, University of California San Francisco, San Francisco, CA, ⁸Diabetes Center, University of California San Francisco, San Francisco, CA, ⁹Department of Population Health and Reproduction, School of Veterinary Medicine, University of California Davis, Davis, CA

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: autoimmunity and immunology, T-Regulatory Cells

Session Information

Date: Tuesday, November 10, 2015

Title: T cell Biology and Targets in Autoimmune Disease Poster II

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: A novel candidate gene, Mosaic (Multi-Organ System Autoimmunity in Canines), was identified as the culprit causing an early and severe multiorgan autoimmunity in a purebred canine population. This unique dog breed develops early onset Addison’s disease, arthritis, autoimmune cytopenias, hepatitis and uveitis. Little is known about the function of this gene. It is conserved across all known vertebrae species including humans and mice. The affected dogs possess a single point mutation resulting in an amino acid change of a proline to leucine residue in a highly conserved region. This gene is expressed in immune cells with particularly high abundance in T regulatory (Treg) cells. Thus, we hypothesized that the deficiency in Mosaicdisrupts normal Treg cell function in maintaining immune tolerance and leads to multiorgan autoimmunity.

Methods: The cDNA for Mosaicwas cloned into an expression vector and transfected into 293 cells to assess cellular localization. A knockout mouse was generated carrying a reporter cassette allowing tracing of the endogenous gene expression pattern. Heterozygous knockout mice were used for flow cytometry to identify immune subsets that expressed this gene.

Results: Wild-type and mutant Mosaicshowed nuclear localization by immunohistochemistry and western blotting in transfected cells. Heterozygous knockout mice were assessed by flow cytometry and showed expression in multiple immune cell lineages including high expression in Treg cells and activated T cells.

Conclusion: Mosaic was identified as the causal gene mediating a multi-organ system autoimmunity in a unique breed of dogs. This protein is localized to the nucleus suggesting a role in modifying gene expression and is expressed in multiple immune cell subsets. Further characterization of these mice will shed light on the role of this novel gene in mediating early-onset and severe multi-organ autoimmunity.

Disclosure: A. Chan, None; E. Brown, None; O. Foreman, None; A. Oberbauer, None; A. Hughes, None; S. Burton, None; H. E. Liang, None; M. Anderson, None; D. Bannasch, None.

To cite this abstract in AMA style:

Chan A, Brown E, Foreman O, Oberbauer A, Hughes A, Burton S, Liang HE, Anderson M, Bannasch D. Characterizing a Novel Gene, Mosaic, and Its Role in Mediating a Multisystem Autoimmunity [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/characterizing-a-novel-gene-mosaic-and-its-role-in-mediating-a-multisystem-autoimmunity/. Accessed .

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