Ashley Turner, Biology
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TREX1 is a gene responsible for encoding a 3'-to-5' DNA exonuclease in human cells. Under normal conditions TREX1 removes bases from the free 3' end to enhance DNA damage and prevent DNA end reannealing and rapid repair. Mutations in TREX1, which result in the absence of the 3'-to-5' DNA exonuclease and the intracellular accumulation of unneeded DNA and RNA, have been shown to trigger immune dysfunction leading to diseases such as systemic lupus erythematosus (SLE) and Aicardi-Goutières Syndrome (AGS). The goal of this study is to determine the potential impact of a TREX1 missense mutation with uncertain clinical significance (VUS). This study relies heavily upon the evolutionary relatedness between humans (Homo sapiens) and nematodes (Caenorhabditis elegans) to examine conservation of TREX1 VUS across species. Thirty TREX1 variants associated with SLE and AGS were screened and analyzed for conservation in the TREX1 nematode ortholog W02F12.4. These variants included those with pathogenic, likely pathogenic, likely benign, and uncertain clinical significance. Variant location and conservation along the W02F12.4 gene was identified for all screened variants. Out of the 30 screened variants, two were found to be conserved in both TREX1 and W02F12.4. These mutations were c.197A>G (p.Lys66Arg) and c.226G>T (p.Ala76Ser), both of which have uncertain clinical significance. Patient variant c.226G>T (p.Ala76Ser) was selected for further investigation due to its proximity with a likely pathogenic and pathogenic variant. PolyPhen-2 analysis predicted this VUS to be probably damaging with scores of 0.982 (HumDiv) and 0.953 (HumVar). DNA primers have been designed in preparation for the amplification of the specific VUS region within W02F12.4 using polymerase chain reaction. Future experiments including RNA guide design and microinjection and use of CRISPR-Cas9 reagents for gene editing of W02F12.4 to generate this VUS C. elegans model. This will allow us to support or refute the potential pathogenicity of c.226G>T (p.Ala76Ser) in vivo through phenotypic changes we observe in the mutant nematode compared to wildtype. This will help provide important insight into the structure and function of autoimmune-associated TREX1 VUS being identified in patients.
student research, biology
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Peters, Jordan, "An Exploration of TREX1 Variants of Uncertain Significance and Their Potential Impact on Autoimmunity in Systemic Lupus Erythematosus and Aicardi-Goutieres Syndrome" (2022). JSU Student Symposium 2022. 48.