Investigating rare genetic variants in a human enzyme

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Our genome is like a parts-list for all of the molecular machines that make us human. Choose any two people on earth, and their DNA will be 99.9% identical- but in the context of our vast amounts of DNA, 0.1% equates to about 10,000 differences in the makeup of each individual’s machinery. These variations make us unique at the molecular level- but in some cases, they can also cause genetic disease.

Though there are thousands of rare genetic diseases, most of them are not completely understood. Genetic variants are categorized as pathogenic (or likely pathogenic), benign (or likely benign), or when predictions fail, a “variant of uncertain significance”, or VUS. There are hundreds of thousands of VUS’s, each from a real patient with symptoms that have not been definitively linked to an underlying genetic cause.

In our lab, we try to make a small impact by studying one protein, linked to one disease, at a time. We create and compare the activities of “normal” and “mutant” versions of the protein with the goal of providing insight into the true impact of each VUS. This summer our focus was on Lactate Dehydrogenase (LDHA), the enzyme responsible for generating the lactic acid that is essential to humans’ ability to maintain intense levels of exercise. Students were able to express and purify 8 different variants of the protein.


Funding from DePauw University Faculty Development Funds.

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