Year: 2023
Type: article
Study design: Observational Study
Abstract: Background and Objectives Sporadic Creutzfeldt-Jakob disease (sCJD) has established genetic risk factors, but, in contrast to genetic and acquired CJD, the initial trigger for misfolded prion aggregation and spread is not known. In this study, we tested the hypotheses that pathologic somatic variants in the prion gene PRNP are increased in sCJD, potentially leading to the seeding of misfolded prion protein. Methods High-depth amplicon-based short read sequencing of the PRNP coding region was performed on postmortem brain tissue from patients with a clinical and neuropathologic diagnosis of sCJD (n = 142), Alzheimer disease (AD) (n = 51) and controls with no clinical or neuropathologic diagnosis of a neurodegenerative disease (n = 71). Each DNA sample was sequenced twice, including independent PCR amplification, library preparation, and sequencing. We used RePlow to call somatic variants with high sensitivity and specificity and optimal sequence kernel association test to compare variant burden between groups. Results Two sCJD cases had somatic (variant allele frequency 0.5–1%) PRNP variants not previously identified, but with high in silico predicated pathogenicity. However, the pathogenicity of these variants is uncertain, as both located in the octapeptide repeat region where no point variations have previously been associated with sCJD. There was no overall difference in burden somatic PRNP in sCJD compared with controls and a lower burden compared with Alzheimer disease. Discussion Somatic variants in PRNP are unlikely to play a major role in sCJD but may contribute to the disease mechanism in a minority of cases.
Source: Neurology Genetics
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,300
Funders: Wellcome Trust, Alzheimer's Society, National Institute for Health and Care Research, Leverhulme Trust, Department of Health and Social Care, University of Edinburgh, Medical Research Council, Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, NIHR Cambridge Biomedical Research Centre
Awards: G139696651, G191149831, Nuclear genomic control of mitochondrial DNA heteroplasmy in humans: population genetics & disease, G2246497895, Genetic factors modulating the expression of mitochondrial disease., ReComp: sustained value extraction from analytics by recurring selective re-computation, G347399793, G370598735, G3758191533, G4335143496, Stratifying patients with Leber Hereditary Optic Neuropathy (LHON) for idebenone therapy using mitochondrial DNA analysis, High-throughput Genomics and Transcriptomics of the Human Developmental Biology Resource, Mechanisms of oxygen toxicity in the context of mitochondrial dysfunction, Investigation of the function of the ER/mitochondria contact sites in cell physiology and disease, MRC Strategic Award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases, Newcastle University Single Cell Functional Genomics Unit (NUSCU), G6641991021, G71761217, G724433139, G7492172941, NIHR Senior Investigator Award, Mitochondrial genomics in human health and diseases.
(How variation in nuclear and mitochondrial DNA causes rare mitochondrial diseases and common late-onset human disorders), NIHR Senior Investigator Award, G7826725679, G8403700937, NIHR Senior Investigator Award, G8877123792
OpenAlex ID: W4317469281