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Polymorphism discovered years ago is linked to multiple sclerosis
Mutation causes altered expression of the CD45 protein on surfaces of immune cells
Edward R. Winstead

A genetic mutation identified ten years ago in healthy individuals has been linked to an increased risk for developing multiple sclerosis. Researchers in Germany discovered abnormal proteins on the surface of white blood cells, or lymphocytes, in a patient with multiple sclerosis (MS). Lymphocytes are immune cells, and MS is widely believed to involve a breakdown in the body's normal immune response.

The mutation, or polymorphism, in a gene called PTPRC appears to alter the expression of CD45 proteins on lymphocytes. Why this alteration might increase the risk of developing MS is not known. But because of its location on lymphocytes, CD45 has been suspected by some researchers to play a role in MS.

The PTPRC polymorphism is a point mutation—a difference in a single unit of DNA—not previously associated with disease. A decade after it was first reported, the polymorphism was rediscovered during a study of cell surface proteins led by Bernhard Hemmer, of Philipps University, in Marburg, Germany. Hemmer's group traced the origin of the abnormal protein in the MS patient to the polymorphism.

The patient is one of eight siblings, four of which have an inherited form of MS. An analysis of the gene and the disease in three German families with a high incidence of MS revealed that the polymorphism is a risk factor for the disease. (A similar study of an American family did not find a significant association between the mutation and risk for MS.) The polymorphism was present in apparently unaffected family members, although some of these individuals may go on to develop the disease.

The researchers emphasize that PTPRC is just one piece of the puzzle. "There are at least 20 to 30 genes—and maybe more—that regulate susceptibility to multiple sclerosis," says Norbert Sommer, of the Department of Neurology, Philipps University. "The point we want to make is that this finding is not the solution to MS. That is absolutely clear." The study appears in Nature Genetics.

Nonetheless, the strategy of working backward from the altered expression of CD45 to the polymorphism seems to have worked in this case. A series of genome scans in recent years have largely been unsuccessful in identifying genes for MS, according to Sommer. "Unfortunately," he says, "the really interesting hotspots in the genome have not been identified, and no single gene to our knowledge has been associated with MS."

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Jacobsen, M. et al. A point mutation in PTPRC is associated with the development of multiple sclerosis. Nat Genet 26, 495-499 (December 2000).

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