High-Depth PRNP Sequencing in Brains With Sporadic Creutzfeldt-Jakob Disease
| Autor: | Alexander G. Murley, Yu Nie, Zoe Golder, Michael John Keogh, Colin Smith, James W. Ironside, Patrick F. Chinnery |
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| Přispěvatelé: | Murley, Alexander G [0000-0003-0813-0670], Apollo - University of Cambridge Repository |
| Rok vydání: | 2023 |
| Předmět: |
2 Aetiology
Aging Prevention FOS: Clinical medicine Human Genome Neurosciences Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Transmissible Spongiform Encephalopathy (TSE) FOS: Health sciences Neurodegenerative Alzheimer's Disease 3105 Genetics Brain Disorders Rare Diseases Infectious Diseases Emerging Infectious Diseases FOS: Biological sciences Neurological Acquired Cognitive Impairment Genetics 2.1 Biological and endogenous factors Dementia Neurology (clinical) Genetics (clinical) 31 Biological Sciences |
| Popis: | Background and ObjectivesSporadic 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 genePRNPare increased in sCJD, potentially leading to the seeding of misfolded prion protein.MethodsHigh-depth amplicon-based short read sequencing of thePRNPcoding 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.ResultsTwo sCJD cases had somatic (variant allele frequency 0.5–1%)PRNPvariants 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 somaticPRNPin sCJD compared with controls and a lower burden compared with Alzheimer disease.DiscussionSomatic variants inPRNPare unlikely to play a major role in sCJD but may contribute to the disease mechanism in a minority of cases. |
| Databáze: | OpenAIRE |
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