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Genetics of Prion Disease

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Prions and Diseases

Abstract

The Prion Diseases (PrDs) are rare transmissible neurodegenerative diseases that result from the accumulation of a misfolded isoform (PrPSc) of the normal cellular form of the prion protein (PrPC), a naturally occurring surface membrane glycoprotein highly concentrated in neurons. Although the vast majority of PrDs are sporadic in nature, roughly 15 % are attributed to an autosomal dominant mutation of the prion protein gene (PRNP). More than 50 PRNP variants that result in single amino acid substitutions, variably lengthed insertions, deletions, or truncations at multiple positions within the prion protein (PrP), have been reported. Genotype-phenotype correlations are based primarily on the underlying histopathology that classify the disease as Creutzfeldt-Jakob disease (CJD), Gerstmann Sträussler Scheinker disease (GSS), or fatal familial insomnia (FFI). Some, but not all have demonstrated transmissibility to susceptible experimental hosts. Whereas some variants, such as the common polymorphic codon 129, affect risk to sporadic PrD, most are causal. Variable penetrance among some PRNP variants is notable, leading to define the variant as risk-associated or causal. This chapter reviews these issues that define the current state of understanding of the complex genetics of PrD, with special focus on the most common PRNP variants linked to genetic PrD.

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  1. Department of Neurology, Center for Comprehensive Care and Research on Memory Disorders, Behavioral Neurology and Neuropsychiatry, Committee on Neurobiology, University of Chicago, Chicago, IL, USA

    James A. Mastrianni

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  1. Departments of Pathology and Neurology, National Prion Disease Pathology Surveillance Center, National Center for Regenerative Medicine Case Western Reserve University, School of Medicine, Cleveland, OH, USA

    Wen-Quan Zou

  2. Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    Pierluigi Gambetti

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Mastrianni, J.A. (2023). Genetics of Prion Disease. In: Zou, WQ., Gambetti, P. (eds) Prions and Diseases. Springer, Cham. https://doi.org/10.1007/978-3-031-20565-1_19

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