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Molecular Neurobiology

, Volume 8, Issue 2–3, pp 99–103 | Cite as

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
Neurodegenerative Diseases Part II: Transmissible Neurodegenerative Disorders (Proceedings of the symposium “Transmissible and Nontransmissible Neurodegenerative Disorders” held in Ocho Rios, Jamaica, February 28–March 5, 1993)

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.

Index Entries

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

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Copyright information

© Humana Press Inc 1994

Authors and Affiliations

  • Robert B. Petersen
    • 1
  • Lev G. Goldfarb
    • 2
  • Massimo Tabaton
    • 1
  • Paul Brown
    • 2
  • Lucia Monari
    • 1
  • Pietro Cortelli
    • 3
  • Pasquale Montagna
    • 3
  • Lucila Autilio-Gambetti
    • 1
  • D. Carleton Gajdusek
    • 2
  • Elio Lugaresi
    • 3
  • Pierluigi Gambeffi
    • 1
  1. 1.Institute of PathologyCase Western Reserve UniversityCleveland
  2. 2.National Institutes of HealthBethesda
  3. 3.Neurological InstituteUniversity of BolognaBolognaItaly

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