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Researchers Discover Mutation Causing Protein Misfolding Remission

Light chain amyloidosis, a deadly protein misfolding disease, is caused by multiple mutations in cells that are intended to protect the body.

Instead, the mutations send misfolded bundles of proteins through the bloodstream, potentially destroying the heart, kidneys, liver or other organs. Mayo Clinic researchers have identified one of these mutations and have shown that the molecule’s shifting position is as important as its unique shape. The findings appear in the current issue of the journal Structure.

“This is a condition that often is misdiagnosed because it could appear as many other common conditions and can affect different organs,” says Marina Ramirez-Alvarado, Ph.D., Mayo Clinic biochemist and senior author of the study. “It can be initially identified by a simple blood test and a fat aspirate analysis. After that, we can only treat symptoms as there is currently no cure.”

About 2,000 patients are diagnosed with amyloidosis annually in the United States. Survival after diagnosis averages about three years. Immunoglobulin molecules made in cells from the bone marrow are subject to mutations that can cause the proteins to misfold. In essence, what should be a set configuration of amino acids becomes chaotic, appearing in models as a twisted ball of “spaghetti” that then accumulates more fibrous threads called fibrils. These misfolded proteins travel in the bloodstream accumulating fibrils that clog osmotic and other filtering processes in the liver, kidneys and heart, ultimately causing other organ-based diseases.

Mayo researchers studied light chains that normally are made in plasma B cells as part of the protective immune mechanism, found in bone marrow. Through a combination of crystallography, nuclear magnetic resonance spectroscopy, and bioinformatics, they were able to determine the surface shape of the molecule involved with one mutation and also deduce that it was constantly shifting its position, from 90 degrees to 180 degrees off the normal position of the comparable functional protein.

Because of the realignment, the protective nature of the molecule is lost and its new molecular contacts promote amyloid formation. This process is what happens in 85 percent of amyloidosis patients. In this specific case, the researchers were able to identify that the mutation called the Tyr-to-His substitution in the reconfiguration at position 87 on the protein was the alteration that promoted fibril development. Researchers say that while this is just one of many possible mutations, it is a beginning towards identifying targets for future drug development in a condition that is otherwise fatal.

Others involved in the study are Elizabeth Baden, Ph.D., and Barbara Owen, Ph.D., Mayo Clinic; Francis Peterson, Ph.D., and Brian Volkman, Ph.D., both of the Medical College of Wisconsin, Milwaukee. The National Institutes of Health and Mayo Clinic supported the research.

About Mayo Clinic
For more than 100 years, millions of people from all walks of life have found answers at Mayo Clinic. These patients tell us they leave Mayo Clinic with peace of mind knowing they received care from the world's leading experts. Mayo Clinic is the first and largest integrated, not-for-profit group practice in the world. At Mayo Clinic, a team of specialists is assembled to take the time to listen, understand and care for patients' health issues and concerns. These teams draw from more than 3,700 physicians and scientists and 50,100 allied staff that work at Mayo Clinic’s campuses in Minnesota, Florida, and Arizona; and community-based providers in more than 70 locations in southern Minnesota, western Wisconsin and northeast Iowa. These locations treat more than half a million people each year. To best serve patients, Mayo Clinic works with many insurance companies, does not require a physician referral in most cases and is an in-network provider for millions of people. To obtain the latest news releases from Mayo Clinic, go to For information about research and education visit ( is available as a resource for your general health information.

Robert Nellis | Newswise Science News
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