- Fatal familial insomnia (FFI) is linked to a mutation
at codon 178 of the prion protein gene, coupled with the methionine codon
at position 129, the site of a methionine/valine polymorphism. The D178N
mutation coupled with the 129 valine codon is linked to a subtype of Creutzfeldt-Jakob
disease (CJD178) with a different phenotype. Two protease resistant fragments
of the pathogenic PrP (PrPres), which differ in molecular mass, are associated
with FFI and CJD178, respectively, suggesting that the two PrPres have
different conformations and hence they produce different disease phenotypes.
FFI transmission experiments, which show that the endogenous PrPres recovered
in affected syngenic mice specifically replicates the molecular mass of
the FFI PrPres inoculated and is associated with a phenotype distinct from
that of the CJD178 inoculated mice, support this idea.
The second distinctive feature of the FFI PrPres is the underrepresentation
of the unglycosylated PrPres form. Cell models indicate that the underrepresentation
of this PrPres form results from the PrP dysmetabolism caused by the D178N
mutation and not from the preferential conversion of the glycosylated forms.
Codon 129 on the normal allele further modifies the FFI phenotype determining
patient subpopulations of 129 homozygotes and heterozygotes: disease duration
is generally shorter, insomnia more severe and histopathology more restricted
to the thalamus in the homozygotes than in the heterozygotes. The allelic
origin of PrPres fails to explain this finding since in both cases FFI
PrPres is expressed only by the mutant allele. Despite remarkable advances,
many issues remain unsolved precluding full understanding of the FFI pathogenesis.
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- For a lengthy BBC story on FFI, go to: http://news.bbc.co.uk/hi/english/health/newsid_355000/355297.stm
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