Does PRNP gene control the clinical and pathological phenotype of human spongiform transmissible encephalopathies?

Background: Human spongiform transmissible encephalopathies (TSE) are a gro up of neurodegenerative diseases caused by a transmissible not yet recogniz ed agent; their distinctive neuropathological features are astrocytosis, sp ongiform lesions of the neuropil, neuronal loss and occasionally amyloid pl aques in the cortical and sub-cortical gray matter. TSE are biochemically c haracterized by the deposition in the nervous system of an amyloid-type pro tein, PrPres derived from the post-translational modification of a normal p rotein, PrPsen. The expression of this protein is controlled by the PRNP ge ne mapped on chromosome 20 in man. A number of point mutations of the PRNP gene have been described in the familial forms of these TSE. Some of these mutations have been associated with differences in the phenotypic expressio n of the disease. Material and methods: This study was designed to verify w hether it was possible to identify a selective phenotype depending upon a g iven PRNP modified genotye; for this purpose, a group of familial TSE cases (CJD 210(ILE), CJD 201(LYS), FFI 178(ASN)) were selected and their neuropa thological profiles have been compared with those of a large series of spor adic CJD cases. Results: No significant differences were found between the topography and severity of lesions in the cerebral cortex, cerebellum, hipp ocampus, basal ganglia and thalamus between the two groups. Two differences were found: the clinical duration of the disease which appeared significan tly (p = 0.02) shorter in the 210(ILE)-mutated cases compared to that of no n-mutated sporadic cases. The highly selective vulnerability of thalamus in FFI showing a severe pathology especially in its dorso-medial part in comp arison with that of the sporadic CJD cases. Conclusion: The results of this Study confirm that the different polymorphism at codon 129 of the PRNP gen e, which could be involved in the structural "domains" of human PrP, might modulate the pathological phenotype of TSE.