Characterization of the biological role of the ciliopathy gene serologically defined colon cancer antigen 8 (SDCCAG8)

Imagine you have a disease that is causing your kidneys to fail. Imagine you’re progressively losing your vision. You’re severely obese and you often get teased for this. You may struggle with fertility or conditions secondary to your obesity like type II diabetes or high blood pressure. While one of these symptoms alone would be difficult for someone to handle, patients with mutations to a subset of genes known as ciliopathy genes may suffer from all of these debilitating conditions simultaneously. Currently, treatment for disorders of these genes (ciliopathies) are limited, but as biological technology advances, so does our ability to treat these conditions. However, before we can even begin to hope to treat these conditions, we must first understand how these genes affect cellular health and wellness. Current treatment options, such as gene therapy or stem cell replacement therapy, require a deep knowledge of a gene’s function and the pathways it’s involved in in order to safely and effectively treat the disorder.

Here, my work focuses on one such ciliopathy gene, SDCCAG8, which ma y cause two ciliopathies with shared symptoms such as retinal degeneration, cognitive impairment, obesity, and early end stage renal failure. When my research began, very little was known about this gene other than that it has been identified in a small number of patients with a ciliopathy. Using a number of molecular tools, I have studied the role of SDCCAG8 in a dish as well as in a mouse model.

First, I found that SDCCAG8 interacts with an interesting complex of proteins that is necessary for the cell to build proteins. Specifically, SDCCAG8 interacts with AIMP2, which is the bridge protein for this complex, as without it the complex falls apart. Second, I found that the interaction of SDCCAG8 with AIMP2 is important because it affects p53, a protein well known for its regulation of tumor growth. Under normal conditions, AIMP2 helps p53 kill damaged cells and our gene appears to aid in this interaction. Third, we investigated a mouse model lacking expression of SDCCAG8 and while we were able to characterize a number of phenotypes such as extra toes on their back feet, we also saw that the non-traditional genetic approach to knocking the gene out actually caused an additional loss of the gene that is located right next to SDCCAG8 on the chromosome. This means that this specific mouse model may not be the best mouse model to study SDCCAG8 loss alone. Overall, this work provides a better understanding of SDCCAG8 and will help us begin to better understand the gene. Understanding the gene will help lead to better treatment options for patients with mutations in this gene.