New genetic tool could identify drug targets for diseases associated with metabolic dysfunction

 There’s a glaring gap in our knowledge of cell metabolism: in many cases, we still don’t know exactly how nutrients are transported into the cell. Without that understanding, it’s extremely difficult, if not impossible, to develop treatments for the many diseases linked to the protein transporters that drive metabolism. Now, a new study in Nature Genetics presents a tool to map these metabolic gene functions more precisely. The platform, dubbed GeneMAP, has already identified one key gene-metabolite association at the heart of mitochondrial metabolism.

GeneMAP was developed in the laboratory of Kivanç Birsoy, the Chapman Perelman Associate Professor at Rockefeller, and is available to the public via an online portal.

The platform builds on prior models of gene expression, using existing datasets to determine the function of metabolic genes and link their resulting proteins to candidate metabolites—relying heavily on genome-wide association studies (GWAS) of the complete set of small-molecule chemicals found within human cells. As such, it’s one of the first tools of its kind.

When Artem Khan, a graduate student in Birsoy’s group took GeneMAP for a test drive, the platform quickly highlighted 2,000 gene-metabolite associations, half of which were already supported by published evidence. A promising start, but researchers hoped GeneMAP would be able to discover the functions of proteins not yet matched to any metabolite. They soon got their wish, when GeneMAP identified a connection between the gene known as SLC25A48 and the mitochondria’s ability to transport the essential metabolite choline. Birsoy’s lab in collaboration with Eric Gamazon’s lab at Vanderbilt University subsequently vindicated GeneMAP’s assessment by demonstrating that loss of SLC25A48 reduced choline content by about 50-fold a strong indication that they’d identified a previously unknown mitochondrial transporter protein.

The findings suggest that GeneMAP could become a primary tool for discovering metabolic gene functions, deepening our understanding of metabolism, and giving rise to results that could have clinical implications. Prior work from the Birsoy lab used similar techniques to link a metabolite to a transporter protein implicated in a debilitating disease that causes vision problems, muscle weakness, and difficulties with spatial orientation.

“Many nutrient transporters are associated with neurodegenerative diseases,” Birsoy says. “The more transporters we identify, the more possible treatments we find.”