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Rare Mutations Linked to Meningitis
By Nancy Touchette

A new study suggests that rare mutations in a single gene can increase a person’s risk for developing meningitis and shock. Most people are exposed to the bacterium that causes meningitis at some point in their lives, though they may never know they’re infected. A small fraction of these will develop meningitis, septic shock and death within a matter of hours.

N. meningitidis

The research adds to a growing body of data that says a person’s genome is critical in determining the course of infectious disease. Genes may explain why some people escape bacterial infections without any symptoms at all, while others succumb rapidly.

“This study makes significant progress in understanding some of the factors that make a host susceptible to disease,” says Ian Feavers of the National Institute for Biological Standards and Control, the United Kingdom. “Virulent organisms can be carried by healthy people without causing disease. But when they do cause disease, why is that?”

The bacterium Neisseria meningitidis, commonly called meningococcus, causes the disease. It colonizes the nose and throat, where it is normally kept in check by the immune system and lives without causing any harm.

Researchers have known that people with immune deficiencies are at risk for the more severe forms of meningococcal disease. But even people with healthy immune systems can become ill.

In the new study, Bruce Beutler of the Scripps Research Institute in La Jolla, California, and his colleagues detected rare mutations in a gene called toll-like receptor 4 among two hundred patients with the disease. A significant percentage had a mutation in the gene, but most did not have the same mutation.

“This is just one of many influential genes that are likely to affect susceptibility to meningococcal disease,” says Beutler. “What we may be seeing is a cumulative effect of many rare mutations that collectively account for a fair fraction of cases.”

In the new study, the same gene was sequenced in 237 patients and 421 healthy individuals. To find susceptibility genes, researchers typically look for variations in the genome but do not sequence one entire gene per person in a study.

They found only one mutation in people without disease, but eleven different mutations in those with severe meningococcal disease. A common mutation found in both controls and patients was not associated with disease.

“If we had used the standard methods for looking for mutations, we would have found nothing,” says Martin L. Hibberd, now at the Genome Institute of Singapore and a co-author of the study. “If a mutation is deleterious, it is less likely to be carried from generation to generation. So it is important to begin to seek out these rarer mutations.”

The toll-like receptor 4 belongs to a family of proteins that form part of the innate immune response, the first line of defense against invading pathogens. Toll receptors were first found in fruit flies, where they play a role in the development of the embryo.

Lipopolysaccharides, the sugar molecules that coat the outside surface of meningococcal bacteria are recognized by special receptors on human macrophages.

The toll-like receptor 4 sits on the surface of cells called macrophages. The receptor detects certain invaders by binding to sugar molecules on their outside surface. This binding sends a signal to the macrophage that a pathogen is present, causing the macrophage to unleash a host of chemicals that destroys the invader.

In fact, the devastating effects of meningococcal disease may be caused more by the response to the organism than to the bacteria itself.

“It’s the overproduction of cytokines and other molecules that triggers septic shock,” says Beutler. “A low response causes local inflammation that kills the bacteria. But a high response is counterproductive.”

If menigococcus enters the bloodstream, sepsis, characterized by fever, chills, rash and muscle pain can develop rapidly. In extreme cases, meningococcus interferes with blood clotting, triggering shock, or extremely low blood pressure, and even death. Meningitis occurs when the organism infects the lining of the brain.

See related GNN articles
»DNA Melting Map: Finding Rare Mutations for Common Diseases
»Sore Throat or Toxic Shock: It's In Your Genes

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I. Smirnova et al. Assay of locus-specific genetic load implicates rare toll-like receptor 4 mutations in meningococcal susceptibility. Proc. Natl. Acad. Sci. USA 100, 6075-80 (May 13, 2003).

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