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Neurogenetics

Human prion diseases are transmissible, neurodegenerative illnesses such as Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker syndrome (GSS). The biochemical hallmark of these diseases is an accumulation of an abnormal form of the cellular prion protein (PrP) in the central nervous system. Almost all GSS cases and between 5 to 15% of CJD cases are familial and all of these inherited cases show a mutation in the PrP gene. The appearence of a prion disease in cattle, bovine spongiform encephalopathy (BSE), has caused considerable worry about the potential transmission of the animal disease to humans. As part of an European effort to monitor the incidence and the potential causes of human prion diseases we examined the PrP gene of German patients that were referred to us as potential CJD cases.
Following the extraction of genomic DNA and amplification of the PrP gene by means of the polymerase chain reaction (PCR) the screening for known and unknown mutations was performed by non-radioactive single-strand conformational polymorphism. The exact nature of detected mutations was determined by sequencing of the PCR product or by cleavage with suited restriction endonucleases.
In this way several CJD and GSS patients carrying a mutated PrP allele were detected. One patient showed a large insert of 24 basepair repeats in the N-terminal half of the protein, the others had point mutations at either the position 102 (proline to leucine) or 178 (aspartic acid to asparagine). One of the cases with a 178 mutation is of particular historical interest as this patient was described by Jakob and represented for a long time the prototypical inherited form of CJD. Most patients with verified mutations had a known familial history of the disease as well as a peculiar disease course. In non-familial CJD the common polymorphism at amino acid position 129 of PrP (methionine or valine) seems to influence incidence and pathological phenotype of the disease. Homozygotes for methionine are significantly overrepresented in our patient sample compared to the normal German population. On the other hand CJD patients carrying a valine allele mostly show the distinct and rather rare deposition of PrP in amyloid plaques.



Headings
prion diseases
cellular prion protein (PrP)
Creutzfeldt-Jakob disease (CJD)
Gerstmann-Sträussler-Scheinker syndrome (GSS)

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