Kidney failure threat

Rare genetic disorder linked to protein discovered at Washington University

A protein that helps keep immune system cells from mistakenly swallowing and destroying healthy cells has been linked to an inherited disorder with symptoms similar to severe food poisoning, according to researchers at the Washington University School of Medicine and the University of Newcastle in the United Kingdom.

The results make it possible to genetically screen patients for one form of atypical hemolytic uremic syndrome (atypical HUS), a rare but potentially life-threatening condition linked to excessive blood clots and kidney failure. Normal HUS, often in the headlines because of food-related outbreaks, is caused by consumption of a toxic form of the bacteria E. coli and includes an additional symptom, bloody diarrhea.

John Atkinson, M.D., the Samuel Grant Professor of Medicine at the Washington University
John Atkinson, M.D., the Samuel Grant Professor of Medicine at the Washington University

“Based on what we’ve discovered, atypical HUS patients would be susceptible to more damage anytime they have tissue injury,” says John Atkinson, M.D., the Samuel Grant Professor of Medicine at Washington University. “In a heart attack, for example, these people might get 20 to 30 percent more tissue damage. There are new drugs coming on the market that may help us limit this damage.”

The new study, published in the Proceedings of the National Academy of the Sciences, links atypical HUS to membrane cofactor protein (MCP), a protein Atkinson’s laboratory discovered in 1985.

“In most situations, when you find a new protein, you just genetically disable or remove the protein in the mouse,” Atkinson says. “That can’t be done here because in the mouse, this protein is only expressed on the head of sperm, while in humans it’s found throughout the body. So we didn’t have a model to look at and were trying to find the first human deficiencies of this, not knowing where or how to look.”

The answer came in an e-mail from Timothy Goodship, M.D., a nephrologist at the University of Newcastle. Goodship’s group was studying a registry of families where more than one member had atypical HUS, and had learned that mutations in three families were linked to an area in human DNA where Atkinson’s group had found the gene for MCP.

Red blood cells damaged by inflammation caused by food poisoning.
Red blood cells damaged by inflammation caused by food poisoning.

“It turned out that a mutation in two of the families was a mutation that we’d already made trying to figure out how the protein worked,” Atkinson says. “So in a matter of minutes I knew that these were unlikely to be just the random genetic variations that we all have.”

Atkinson and Goodship put together a theory about what happens in atypical HUS and developed recommendations for clinicians. From Atkinson’s research, they knew that MCP deactivates C3, a protein that coats cells to make it easier for immune system cells known as macrophages to operate. Invading cells lack MCP and therefore do not have this protection, so the macrophages swallow and destroy them. Atkinson compares MCP’s role to that of a sentry protecting the castle — a healthy cell — from excessive damage.

“This is a way that our cells can protect themselves from being damaged too much at an inflammatory site or at an infection site,” Atkinson explains. “You’re going to let some damage occur to get over the infection or injury, but you’d like to minimize that damage.”

In atypical HUS, MCP either is missing or is present in levels too low to prevent collateral damage from immune system responses. This doesn’t present a problem until a patient’s immune system is sufficiently provoked by an infection or an injury.

“The bloodstream and, for some reason, the kidney take the brunt of the out-of-control immune response,” Atkinson says.

Kidney transplants, which provide patients with kidney cells with normal MCP levels, have in some cases relieved the most life-threatening symptoms of atypical HUS. Patients with the condition may be treatable with new drugs currently in development that block excessive inflammation just as MCP does.

Richards A, Kemp EJ, Liszewski MK, Goodship JA, Lampe AK, Decorte R, Muslumanoglu MH, Kavukcu S, Filler G, Pirson Y, Wen LS, Atkinson JP, Goodship THJ. Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. Proceedings of the National Academy of the Sciences, 100: 12966-12971; published online on October 17, 2003; 10.1073/pnas.2135497100.

This research was funded by the Medical Research Council Training Fellowship, the National Kidney Research Fund, and the National Institutes of Health.