Mutations and polymorphisms at 25 different sites of the PRNP coding region have been identified (10 of them by this group). In 1995, two new mutations causing familial Creutzfeldt-Jakob disease (CJD) (R3-4 deletion and a point substitution at codon 219) and two new alleles associated with fatal familial insomnia (FFI) (178N+129M+delR3/4 and 200K+129M) were discovered and corresponding phenotypes characterized. In FFI and familial CJD, clinically and pathologically distinct syndromes both linked to the 178N mutation, phenotypic expression is dependent on a polymorphism at codon 129: the 178N+129M allele is responsible for FFI, whereas 178N+129V causes CJD. The fact that an unique allele, 178N+129M+delR3-4, produced typical features of FFI confirms that the 178N+129M alleles are specific for FFI. Homozygosity for either amino acid at position 129 has been identified as a predisposing factor in iatrogenic CJD. Homozygosity for valine at 129th residue may control susceptibility to kuru. In familial CJD, homozygosity for the 129th amino acid has an aggravating effect. The PrP gene in five species of primates used in studies of experimental transmission, shows 95 to 99% sequence homology with the coding region of the human PRNP gene which may explain the varying success in transmitting human disease. DNA polymorphisms at two positions in rhesus monkeys may play an important role in determining sensitivity to an experimental infection. A polymorphism in the apolipoprotein E gene controlling the age of onset in sporadic Alzheimer's disease does not influence the age of onset or the rate of progression in CJD; conversely, codon 129 polymorphism in the PRNP gene does not influence phenotypic expression of other neurological disorders. The gene location for very-early-onset Alzheimer's disease with rapid progression and myoclonus in a Finnish family has been assigned by linkage analysis to chromosome 14q. Apolipoprotein H (Apo H) was shown to be involved in CNS autoimmune disease and its expression increases with aging; we have identified several unknown species of ApoH cDNA in human brain libraries and are currently selecting clones for sequencing analysis. Studies of Viliuisk encephalomyelitis (VE) have been significantly intensified. A variety of laboratory animals have been inoculated with materials from patients with acute and subacute VE in order to isolate and study the infectious agent.
