Leading the way to a cure


Functional Genomics of SLE-associated SMG7/NMNAT2 Locus

Tsao, Bettty, PhD

University of California, Los Angeles

Genome-wide association studies (GWAS) have greatly expanded our understanding about genetic variants linked to the risk of lupus. However, simply knowing the link between a genetic variant and lupus is just the first part of a story. Far more important, however, is understanding how that genetic variant affects the immune system and results in lupus. 

With this grant, Dr. Tsao and her team will explore the underlying mechanism of the newly identified NMNAT2/SMG7 risk locus, an “address” of two neighboring genes, to better understand its role in lupus. 

The NMNAT2 gene regulates energy metabolism, primarily in the brain, but its role in lupus is unclear. In contrast, SMG7 serves as a “cleaner” in cells, controlling mRNA quality, gene expression and alternative splicing, which are important for the production of autoantibodies in lupus.

Earlier studies showed a link between lupus-associated SMG7variants and reduced expression of SMG7, while decreased SMG7 levels appear to lead to elevated production of antinuclear autoantibodies, the most prevalent autoantibodies in lupus. 

These studies will focus on whether dysfunction in messenger RNA surveillance systems resulting from the lupus-associated SMG7 variants may be a unique mechanism contributing to the development of lupus.

What this study means for people with lupus: Greater understanding of the underlying pathology of lupus—what goes wrong at the cellular and molecular level—will enable the development of treatments that target those abnormalities.

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