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DNA repair defects as a mechanism contributing to the development of lupus.

Xu, Jiadi
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1367938177

Abstract Details

2013, MS, University of Cincinnati, Medicine: Molecular and Developmental Biology.
Lupus system erythematosus (SLE) is chronic autoimmune that is characterized by chronic inflammation and the production of anti-nuclear auto-antibodies together with a strong environmental and genetic components. The pathogenesis of SLE is not completely understood. Genetic, epigenetic and environmental factors are components. For clues to how genetic components contribute to SLE development, we use the exome sequencing and genome wide association study (GWAS) designs to reveal the genetics of SLE. There is evidence that defective DNA repair is one of the causative factors that associated with SLE. SLE patients are usually photosensitive to sunlight and frequently develop malar and vasculitic rashes. Studies of lymphocytes and fibroblasts in SLE patients have shown increased sensitivity to ionizing radiation and ultraviolet light. Ionizing radiation is known to cause both single and double stranded DNA breaks. Recently, there are studies showing that there are both single and double strand DNA break repair defects in pediatric SLE patients. Also, studies have shown that DNA damage in cells caused by etoposide response to interferon (IFN) signaling. IFN is well known to the initiating pathogenic factor of human SLE. Hence, we hypothesized that DNA repair defect after radiation caused by specific variants found in SLE patients is a potential cause of disease pathogenesis through the IFN induced SLE. From GWAS study of SLE, over 50 genetic variants have been associated with SLE, some of the genes are important in DNA repair pathway such as TREX1, BRCC1, BRCC3 and BRCC4. Currently, we found RAD51B as a new SLE susceptibility gene in our African American GWAS data. In addition, from our exome sequencing project, we found one family that has two potentially dysfunctional variants of RAD51B. The coincidence that we found variants in same DNA repair gene by using two different genetic methods suggests that DNA repair pathway is playing an important role in SLE. In addition, from another pediatric lupus trio, we found a de novo variant in RAD54B in the child. Child shows DNA repair defect after ionizing radiation by clonogenic survival assay and neutral comet assay. We developed the lymphoblastoid cell lines (LCLs) of this particular trio as the standard model. We transduced a wild type vector of RAD54B cDNA into the mutant cells and show that this procedure complements the DNA repair deficiency. Our data are consistent with the phenotype that this de novo variant in a DNA repair gene affects DNA repair efficiency in SLE patients, which also leads us to hypothesize that de novo variants contribute to an important proportion of pediatric SLE. Collectively, our work uncovers the previously unappreciated mechanism how genetic components in DNA repair pathways are associated with SLE. We not only demonstrate the genetic variants by both exome sequencing and GWAS studies, but also study the biological function of variants by developing a model system in LCLs, identifying a new potential mechanism of pathogenesis and opening a window for a new approach to clinical treatment.
John Harley, M.D. Ph.D. (Committee Chair)
Paul Andreassen, Ph.D. (Committee Member)
Kenneth M. Kaufman, Ph.D. (Committee Member)
53 p.
Genetics
lupus; DNA repair; exome sequencing;

Recommended Citations

Citations

  • Xu, J. (2013). DNA repair defects as a mechanism contributing to the development of lupus. [Master's thesis, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1367938177

    APA Style (7th edition)

  • Xu, Jiadi. DNA repair defects as a mechanism contributing to the development of lupus. 2013. University of Cincinnati, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1367938177.

    MLA Style (8th edition)

  • Xu, Jiadi. "DNA repair defects as a mechanism contributing to the development of lupus." Master's thesis, University of Cincinnati, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1367938177

    Chicago Manual of Style (17th edition)

ucin1367938177
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This open access ETD is published by University of Cincinnati and OhioLINK.