Genotype–Phenotype Relationships: Fatal Familial Insomnia and Creutzfeldt–Jakob Disease

Lev G Goldfarb, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA

Published online: January 2006

DOI: 10.1038/npg.els.0006037

Some of the thousands of DNA polymorphisms identified in the coding regions of human genes affect functional characteristics of the encoded proteins and may predispose an individual to complex trait disorders such as diabetes, asthma, atherosclerosis and Parkinson disease. ‘Nonpathogenic’ DNA polymorphisms can modify the phenotypic expression of Mendelian disorders; a striking example of such influence is a DNA variation identified at codon 129 of the PRNP (prion protein) gene that determines the phenotypic expression of two separate disorders.

Keywords: DNA polymorphism; PRNP gene; prion; transmissible spongiform encephalopathy; fatal familial insomnia; Creutzfeldt–Jakob disease; genotype–phenotype correlation

Figure 1. Effects of various PRNP genotypes on disease phenotype. (a, b) The D178N mutation and 129M polymorphic variant on the pathogenic chromosome (D178N,129M) correspond to a major phenotype of fatal familial insomnia. The amino acid at position 129 of the normal chromosome determines the topography and type of lesion: the loss of neurons and gliosis in the thalamus are characteristic of the D178N,129M/178D,129M genotype, whereas much more intense spongiform degeneration in the cerebral cortex is present in individuals with the D178N,129M/178D,129V genotype. (c, d) The mutant D178N,129V allele causes severe and diffuse spongiform degeneration in the cerebral cortex typical of familial Creutzfeld–Jakob disease and very mild spongiform change in the thalamus. No significant contribution from the normal chromosome has been identified so far. (e) Loss of neurons and gliosis in the dorsomedial thalamic nucleus in an individual with the D178N,129M/178D,129M FFI genotype. (f) Spongiform degeneration and neuronal loss in the cerebral cortex of an individual with the D178N, 129V/178D, 129V fCJD genotype.
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 References
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 Further Reading
    book Brown P (1994) "Transmissible human spongiform encephalopathy (infectious cerebral amyloidosis): Creutzfeldt–Jakob Disease, Gerstmann–Sträussler–Scheinker syndrome, and Kuru". Calne DB (ed.) Neurodegenerative Diseases, pp. 839–876. Philadelphia, PA: WB Saunders.
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    Goldfarb LG, Brown P, Haltia M, et al. (1992) Creutzfeldt–Jakob disease cosegregates with the codon 178Asn PRNP mutation in families of European origin. Annals of Neurology 31: 274–281.
    Hsiao KK, Groth D, Scott M, et al. (1994) Serial transmission in rodents of neurodegeneration from transgenic mice expressing mutant prion protein. Proceedings of the National Academy of Sciences of the United States of America 91: 9126–9130.
    Lugaresi E, Tobler I, Gambetti P and Montagna P (1998) The pathophysiology of fatal familial insomnia. Brain Pathology 8: 521–526.
    Medori R, Tritschler HJ, LeBlanc A, et al. (1992) Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene. New England Journal of Medicine 326: 444–449.
    Petersen RB, Parchi P, Richardson SL, Urig CB and Gambetti P (1996) Effect of the D178N mutation and the codon 129 polymorphism on the metabolism of the prion protein. Journal of Biological Chemistry 271: 12661–12668.
    book Prusiner SB (ed.) (1999) Prion Biology and Diseases Cold Spring Harbor Laboratory Press, NY: Cold Spring Harbor Laboratory Press.
    Telling GC, Haga T, Torchia M, et al. (1996) Interactions between wild-type and mutant prion proteins modulate neurodegeneration in transgenic mice. Genes and Development 10: 1736–1750.
    Telling GC, Scott M, Mastriani J, et al. (1995) Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein. Cell 53: 79–90.
 Web Links
    ePath Prion protein (p27-30) (PRNP); LocusID: 5621. LocusLink http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=5621
    ePath Prion protein (p27-30) (PRNP); MIM number: 176640. OMIM http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?176640

Related Sub-Topics:

Prion Diseases | Molecular Genetics of Common and Complex Disease | Specific Genetic Disorders | Mutational Mechanisms of Genetic Disease | Inter-Individual Variation and Polymorphism | Proteins: Structure, Function, Metabolism
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Article Title: Genotype–Phenotype Relationships: Fatal Familial Insomnia and Creutzfeldt–Jakob Disease
 
How to Cite close
Goldfarb, Lev G(Jan 2006) Genotype–Phenotype Relationships: Fatal Familial Insomnia and Creutzfeldt–Jakob Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0006037]