Vol 8. Issue 20 / June 30, 2008

Study of Disease-Causing Mutations Uncovers Surprising Pattern

By Mark Schrope

A new Scripps Research Institute survey of genetic mutations definitively tied to diseases has revealed clustering in a specific region of an important class of enzymes. The pattern was so clear it suggests that other mutations contributing to a wide range of diseases are likely to be tied to the region. New searches focused there may lead to a wealth of new targets for drug treatments.

The location of the cluster revealed through the study is outside the range where mutation searches typically focus, so the research also challenges a foundational assumption of these past studies, suggesting that new broader strategies may be needed.

The work, led by Nicholas Schork, a professor in the Department of Molecular and Experimental Medicine at Scripps Research, and the director of research for Scripps Genomic Medicine, a collaborative program of Scripps Research and Scripps Health, was reported on June 25 in the Early Edition of the Proceedings of the National Academy of Sciences.

One of the most promising means for identifying and understanding the genetic foundations of certain diseases is to search for single-letter alterations in the genetic code of disease sufferers. Known as single nucleotide polymorphisms, or SNPs, these mutations can be important targets for drugs aimed at treating a particular disease.

The problem is that people suffering from a disease may have countless SNPs, so separating those that cause problems from those that are benign remains exceedingly challenging. Researchers have, however, been able to identify SNPs that cause certain hereditary diseases because family members suffering from a disease will share the same mutations, making them easier to identify through comparison against healthy people.

The Scripps Research team's study focused on an analysis of a subset of these known disease-causing SNPs that are associated with a critical group of enzymes called protein kinases. These widespread enzymes regulate many cellular activities and are definitively tied to a wide range of developmental and metabolic diseases such as diabetes, as well as certain forms of cancer. The group's goal was to determine if the disease-causing SNPs affected random locations in the kinases, or if these SNPs instead led to alterations clustered in a particular region of the enzymes. What they found was more than a little surprising.

Rethinking Disease Mutations

The group's initial hypothesis was that the SNPs would map to alterations in the kinases' core region, responsible for performing the enzymes' most critical function—phosphorylation, or attaching phosphates and oxygen groups to targeted proteins. The assumption was that for a mutation to cause disease, it would most likely have some impact that blocks the enzyme from performing its main job.

The researchers found that while benign SNPs were tied to a random array of locations on the kinases, those linked to diseases were in fact clustered in a specific kinase region. However, that region was not within the expected critical core, but rather a side area associated with that core. 

Rather than completely block the main phosphorylation activity, changes in this side region often simply handicap that activity, perhaps causing the kinase to bind less effectively with target proteins, or less reliably phosphorylate them.  "You might hinder the activity, but with enough function leftover to keep you alive, " says the report's first author, Scripps Research scientist Ali Torkamani, "even with severe biological deficits because of it."

Based on the results, Torkamani and Schork now believe that mutations that more completely block phosphorylation by the enzymes are simply fatal. "In hindsight, this actually makes more sense," says Torkamani.

Schork says that, based on the team's results, researchers looking for disease-causing genes may be able to more easily pinpoint the important ones by looking for mutations that affect the protein kinase side chain they identified. "Now, of course, the chase is on," says Schork, "There's no disease I can think of where the kinases have no impact."

Accurate identification of important SNPs can be a critical tool in fighting a disease, because researchers can then search for new drugs that prevent or mitigate the impacts of a mutation. Such targeted drug discovery work may lead to new drugs that help large pools of disease sufferers that carry the same or similar mutations. But disease-causing SNPs may only affect a limited number of people or even a single patient, and researchers one day hope to be able to tailor drugs for a particular patient's troublesome SNPs through personalized medicine.

The Schork team's work also suggests that some past SNP studies may have been at least partially misguided. Many studies aimed at finding disease culprits have used what is known as a sequence conservation approach. This calls for limiting searches to mutations tied to specific biological components such as proteins that both perform important functions and have been conserved through evolution. This would mean that the genes coding for a particular protein are found in more or less the same form in simpler organisms. The reasoning is that evolutionary conservation of a protein typically means that its function is critical to life, and as such would seem a logical place to start in a search for mutations that cause life-threatening diseases.

But the region of the kinases where the Schork group found clustering is not one that has been conserved, reinforcing the idea that mutations that block absolutely critical functions simply lead to death, while those that cause disease may just handicap.  "That kind of flies in the face of a lot of thinking about the functionality of elements in the genome," says Schork.

Though the Scripps Research team's work was tied to a particular group of proteins and enzymes, the findings suggest that in other areas as well, disease-causing mutations are more likely to occur in less critical regions, or at least that they can occur in those regions. If so, this would mean that either a changed or expanded focus in SNP surveys is warranted.

In addition to Torkamani and Schork, authors on the paper, titled "Congenital disease SNPs target lineage specific structural elements in protein kinases," were Natarajan Kannan and Susan Taylor, from the University of California, San Diego. See

The work was supported by various grants from the National Institutes of Health, as well as by Scripps Genomic Medicine, the Dickinson Family Fellowship (awarded to Torkamani), and the University of California, San Diego.


Send comments to: mikaono[at]scripps.edu




A new study led by Professor Nicholas Schork has revealed an unexpected clustering of single nucleotide polymorphisms (SNPs), genetic mutations that could provide important targets for drug development. Photo by Dana Neibert.