A novel mechanism of phenotypic heterogeneity demonstrated by the effect of a polymorphism on a pathogenic mutation in the PRNP (prion protein gene)

Robert B. Petersen, Lev G. Goldfarb, Massimo Tabaton, Paul Brown, Lucia Monari, Pietro Cortelli, Pasquale Montagna, Lucila Autilio-Gambetti, D. Carleton Gajdusek, Elio Lugaresi, Pierluigi Gambeffi

Research output: Contribution to journalArticlepeer-review

Abstract

Fatal familial insomnia (FFI) is a subacute dementing illness originally described in 1986. The phenotypic characteristics of this disease include progressive untreatable insomnia, dysautonomia, endocrine and motor disorders, preferential hypometabolism in the thalamus as determined by PET scanning, and selective thalamic atrophy. These characteristics readily distinguish FFI from other previously described neurodegenerative conditions. Recently, FFI was shown to be linked to a mutation in the prion protein gene (PRNP) at codon 178, which results in the substitution of asparagine for aspartic acid. As such, FFI represents the most recent addition to the growing family of prion protein-related diseases. The mutation that results in FFI had previously been linked to a subtype of familial Creutzfeld-Jakob disease (178Asn CJD). The genotypic basis for the difference between FFI and 178AsnCJD lies in a polymorphism at codon 129 of the mutant prion protein gene: 129Met 178Asn results in FFI, 129Val 178Asn in CJD. The finding that the combination of a polymorphism and a single pathogenic mutation result in two distinct conditions represents a singnificant advance in our understanding of phenotypic variability.

Original languageEnglish
Pages (from-to)99-103
Number of pages5
JournalMolecular Neurobiology
Volume8
Issue number2-3
DOIs
Publication statusPublished - Apr 1994

Keywords

  • Creutzfeldt-Jakob disease
  • dementia
  • Fatal familial insomnia
  • mutation
  • phenotype
  • polymorphism
  • prion
  • PRNP

ASJC Scopus subject areas

  • Neuroscience(all)
  • Physiology
  • Cellular and Molecular Neuroscience

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