Genetic Risk Factors of Creutzfeldt-Jakob Disease in the Population of Newborns in Slovakia

Abstract

The most frequent human prion disease is Creutzfeldt–Jakob disease (CJD). It occurs as sporadic (sCJD), genetic (gCJD), iatrogenic (iCJD) form and as variant CJD. The genetic form represents about 10–15% of confirmed cases worldwide, in Slovakia as much as 65–75%. Focal accumulation of gCJD was confirmed in Orava region. The most common point mutation of the prion protein gene (PRNP) is E200K. CJD has a long asymptomatic phase and it is not known when the carriers of the mutation E200K become infectious. Precautions to prevent iCJD are focused especially on clinical CJD cases, but asymptomatic CJD-specific mutation carriers cannot be excluded, and represent a potential genetic CJD-risk group. The aim of this study was to determine the occurrence, frequency and geographic distribution of the E200K mutation among the newborns, comparing the areas of focal accumulation of gCJD with extra-focal ones, as well as distribution of the polymorphism M129V of the PRNP gene. A total of 2915 samples of dry blood spots from anonymous newborns were analyzed. We used RealTime PCR method to determine the presence of the E200K mutation and the M129V polymorphism. Genetic testing revealed 13 carriers of the E200K mutation. Investigation of the M129V polymorphism affirmed higher representation of methionine homozygotes (48% MM, 44% MV, 8% VV). Achieved results fully confirmed our previous observations concerning both the specific and nonspecific genetic CJD risk among the Slovak general population. The 48% of methionine homozygotes and 4 carriers of the E200K mutation among 1000 live-born children in Slovakia underline the benefits of genetic testing.

Effects of the pathological E200K mutation on human prion protein: A computational screening and molecular dynamics approach

“…In this research, we used SIFT, Polyphen‐2, I‐Mutant 3.0, SNPs&GO, and PhD‐SNP to analyze E200K, revealing this mutation's impact on prion illness. First, the information on human PRNP nsSNP (E200K) as deleterious nsSNP was collected from published articles 14,26,38,39 . Then the amino acid sequence of the human prion protein was extracted from the UniProt database (UniProt ID: P04156).…”

“…First, the information on human PRNP nsSNP (E200K) as deleterious nsSNP was collected from published articles. 14,26,38,39 Then the amino acid sequence of the human prion protein was extracted from the UniProt database (UniProt ID: P04156). The NMR structure of the PRNP was obtained from Brookhaven Protein Data Bank (PDB ID: 1HJM), the NMR structure of the human prion protein (hPrP) globular domain with residues 121−230 at Ph 7.0.…”

“…12 Then, the SPDB viewer was used to search for missing atoms and perform energy minimization. The modifications of the PDB structure were achieved by Accelrys Discovery Studio 4.1 40 and Pymol. 41 Finally, energetic optimization and MD simulations were performed by GROMACS v5.…”

Effects of the Pathological E200K Mutation on Human Prion Protein: A Computational screening and Molecular Dynamic approach

“…In the rst, the information of human PRNP nsSNP (E200K) as deleterious nsSNP was collected from published articles (14,(36)(37)(38). Then the amino acid sequence of Human Prion protein was extracted from the Uniprot Database (Uniprot ID: P04156).…”

Optimization of the RT-QuIC in prion disease diagnostic

“…The penetrance for the genetic form of prion disease varies between different mutations and geographic and ethnic clusters 110 . For instance, the penetrance for the gCJD with E200K mutation was 67 % in Italian 48 , 59,5 % Slovak 111,112 , and 100 % in the Libyan Jewish population in Israel 113 . The countries where geographic cluster/high incidence of E200K mutation cases was reported are colored in dark blue.…”