DOI

10.17077/etd.33unz31i

Document Type

Dissertation

Date of Degree

Summer 2017

Degree Name

PhD (Doctor of Philosophy)

Degree In

Genetics

First Advisor

Sheffield, Val C.

First Committee Member

Seo, Seongjin

Second Committee Member

Mullins, Robert F.

Third Committee Member

Smith, Richard J.H.

Fourth Committee Member

Kwitek, Anne E.

Fifth Committee Member

Stamnes, Mark A.

Abstract

The primary cilium is vital for the health and well being of the organism. Diseases of the cilia, referred to as ciliopathies, present with overlapping phenotypes due to a protein defect in the same organelle. Three such disorders are Nephronophthisis (NPHP), Bardet-Biedl Syndrome (BBS), and Senior-Loken Syndrome (SLS). Mutations in serologically defined colon cancer antigen 8(SDCCAG8 [MIM 613524]) have been associated with all of these disorders (BBS16, NPHP10, SLSN7). Little is known about the role of SDCCAG8 in ciliary function, and the mechanisms through which SDCCAG8 leads to ciliopathy phenotypes are potentially novel and may identify therapeutic targets for treating clia related disorders. My work aimed at elucidating these mechanisms utilizing in vitro and in vivo models to identify specific interactors of SDCCAG8. Here, we show an interaction with the multi-aminoacyl tRNA synthetase complex (MSC) and more specifically, with the aminoacyl interacting multifunctional protein 2 (AIMP2). We also determined that the interaction between these genes is dependent on the N-terminus of AIMP2 and a region in the C-terminus of SDCCAG8. Further work characterized the importance of SDCCAG8 in AIMP2 nuclear localization. Loss of SDCCAG8 results in increased AIMP2 nuclear localization and downstream upregulation of p53. We also characterized an Sdccag8 mouse model and assessed its utility as a ciliopathy model. We performed a phenotypic characterization of this model and identified a genomic deletion encompassing a neighboring gene, Akt3. Due to this finding, we suggest that individuals interested in this mouse model proceed with caution. In addition, we used this model to identify a potential modifier locus of lethality. Overall, the work presented in this thesis advances the understanding of the biology of SDCCAG8 and its role in the cell.

Keywords

BBS, Ciliopathy, NPHP, SDCCAG8

Pages

xvii, 132 pages

Bibliography

Includes bibliographical references (pages 117-132).

Copyright

Copyright © 2017 Katie Weihbrecht

Included in

Genetics Commons

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