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Protein Misfolding, Not Mutant Gene, Key To Lethal Sleep Disorder

nifestations of the disease are determined not by the abnormal gene or the sequence of amino acids in the protein, but purely by the abnormal shape taken on by the protein.

This supports the controversial notion, says Mastrianni, that "even in the familial form, it's the prion strain, the precise conformation of the misfolded protein, and not the variation in the gene that ultimately determines the consequences of the disease."

Familial fatal insomnia has been found in only 24 extended families worldwide, but the sporadic version, though still quite rare, may prove somewhat more common, accounting for "most or all cases of pure thalamic dementia," suggest the authors.

Perhaps best known as the cause of "mad cow disease" (bovine spongiform encephalopathy), prions can cause several uncommon human brain disorders such as Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, kuru and FFI, and may even be suspects in more common disorders such as Alzheimer's disease, ALS or Parkinson's disease.

The different prion disorders all result from gross irregularities in the folding of a particular protein, the normal function of which is not known. The initial folding error may be induced by a genetic mutation or may occur spontaneously. It then spreads via protein-to-protein contact, with the misshapen version somehow inducing normal proteins to take on the new, indigestible structure.

The first SFI patient was a previously healthy 44-year-old California man who developed increasing trouble falling asleep. His personal physician initially dismissed his complaints, saying they were "all in his head," but after about four months of sleeping an average of one hour per night the patient began to have trouble walking, lost weight and produced tears excessively (consistent w
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Contact: John Easton
jeaston@mcis.bsd.uchicago.edu
773-702-6241
University of Chicago Medical Center
27-May-1999


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