Molecular genetics of human prion diseases in Germany

Abstract

Human prion diseases may be acquired as infectious diseases, they may be inherited in an autosomal dominant fashion or occur sporadically. Mutations and polymorphisms in the sequence of the coding region of the prion protein gene (PRNP) have been established as an important factor in all of these three types of prion diseases. Therefore, a total of 578 patients with suspect prion diseases referred to the German Creutzfeldt-Jakob disease (CJD) surveillance unit over a period of 4.5 years have been examined for mutations and polymorphisms in the coding region of PRNP. We found 40 cases with a missense mutation previously reported as pathogenic. Amongst these, the aspartate to asparagine change at codon 178 (D178N) was the most common mutation. All of these cases carried the D178N mutation in coupling with methionine at codon 129, resulting in the typical fatal familial insomnia (FFI) genotype. Most cases with pathogenic mutations were not found in the group of clinically "probable" cases according to established clinical criteria, supporting the notion that inherited prion diseases often exhibit atypical features. Two novel missense mutations (T188R and P238S) and several silent polymorphisms were found, demonstrating the quality of our screening procedure based on a modified version of the single-stranded conformational polymorphism technique. In "definite" CJD cases with no pathogenic mutation, the patients clinically classified as "probable" were mostly homozygous for methionine at the common polymorphism at codon 129, whereas there was a marked over-representation of patients homozygous for valine amongst those clinically classified as "possible". This large study on suspect cases of human prion diseases in Germany clearly shows that PRNP genetics is essential for a comprehensive analysis of prion diseases.

Prion disease genetics

“…In Germany, Windl found 40 cases of IPD from 578 suspect prion disease cases referred to a surveillance unit. 10 In total, 13/40 cases were found to have D178N, 8/40 had E200K, 7/40 had P102L, 6/40 had V210I (c.628G4A) and 5/40 had OPRI. In France, however, Laplanche did not detect any D178N cases out of 57, but 8/57 had E200K.…”

“…9,10 There are three types of pathogenic PRNP mutation: point mutations leading to an amino-acid substitution or premature stop codon, and insertion of additional octapeptide repeats (OPRI) (Figure 1). Over 30 different mutations have been described: some are typically associated with particular clinical categories of prion disease; others are associated with a spectrum of clinical phenotypes, often with striking phenotypic variability.…”

MRI and clinical syndrome in dura materrelated Creutzfeldt-Jakob disease

“…Analysis of the prion protein gene (PRNP) was performed after isolation of genomic DNA from blood according to standard methods [17]. PRNP mutations were excluded in all but one patient by full PRNP sequencing (case 9).…”

Human Prion disease with a T188K mutation in Chinese: a case report

“…In addition to T188K mutation, two other mutations, T188A and T188R, have been described to be linked with genetic CJD [4,5]. The T188A patient is an 82-year old Australian woman, who suffered from sCJD-like symptoms and died 4 months later.…”