Fatal Familial Insomnia and Familial Creutzfeldt-Jakob Disease: Different Prion Proteins Determined by a DNA Polymorphism

Fatal familial insomnia and a subtype of Creutzfeldt-Jakob disease, two clinically and pathologically distinct diseases, are linked to the same mutation at codon 178 (Asp-178 → Asn) but segregate with different genotypes determined by this mutation and the methionine-valine polymorphism at codon 129...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 91; no. 7; pp. 2839 - 2842
Main Authors:	Monari, Lucia, Chen, Shu G., Brown, Paul, Parchi, Piero, Petersen, Robert B., Mikol, Jacqueline, Gray, Franscoise, Cortelli, Pietro, Montagna, Pasquale, Ghetti, Bernardino, Goldfarb, Lev G., Gajdusek, D. Carleton, Lugaresi, Elio, Gambetti, Pierluigi, Autilio-Gambetti, Lucila
Format:	Journal Article Conference Proceeding
Language:	English
Published:	Washington, DC National Academy of Sciences of the United States of America 29-03-1994 National Acad Sciences National Academy of Sciences
Subjects:	Biological and medical sciences Brain Central nervous system diseases Codon Codons Creutzfeldt Jakob syndrome Creutzfeldt-Jakob disease Creutzfeldt-Jakob Syndrome - genetics Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Deoxyribonucleic acid Disease DNA Endopeptidase K fatal familial insomnia genes Genetic mutation Humans Insomnia man Medical research Medical sciences Nervous system diseases Neurology Pathology Peptide Fragments - chemistry Phenotype polymorphism Polymorphism, Genetic Prion diseases Prion Diseases - genetics prion protein Prions Prions - chemistry Prions - drug effects Prions - genetics Protein isoforms Proteins PrPSc Proteins Serine Endopeptidases - metabolism Sleep Initiation and Maintenance Disorders - genetics Human Nervous system diseases Molecular form Genetic inheritance Family study Sleep disorder Cerebral disorder Genetic disease Infection Proteins Etiology Insomnia Viral disease Central nervous system disease Prion Mutation Creutzfeldt Jakob disease Polymorphism
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Summary:	Fatal familial insomnia and a subtype of Creutzfeldt-Jakob disease, two clinically and pathologically distinct diseases, are linked to the same mutation at codon 178 (Asp-178 → Asn) but segregate with different genotypes determined by this mutation and the methionine-valine polymorphism at codon 129 of the prion protein gene. The abnormal isoforms of the prion protein in these two diseases were found to differ both in the relative abundance of glycosylated forms and in the size of the protease-resistant fragments. The size difference was consistent with a different protease cleavage site, suggesting a different conformation of the protease-resistant prion protein present in the two diseases. These differences are likely to be responsible for the type and location of the lesions that characterize these two diseases. Therefore, the combination of the mutation at codon 178 and the polymorphism at codon 129 determines the disease phenotype by producing two altered conformations of the prion protein.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.91.7.2839