Neuropathologically directed profiling of PRNP somatic and germline variants in sporadic human prion disease.
PRNP
Creutzfeldt–Jakob disease
Genetics
Prion disease
Somatic mutation
Journal
Acta neuropathologica
ISSN: 1432-0533
Titre abrégé: Acta Neuropathol
Pays: Germany
ID NLM: 0412041
Informations de publication
Date de publication:
24 Jul 2024
24 Jul 2024
Historique:
received:
21
06
2024
accepted:
20
07
2024
revised:
19
07
2024
medline:
26
7
2024
pubmed:
26
7
2024
entrez:
24
7
2024
Statut:
epublish
Résumé
Creutzfeldt-Jakob Disease (CJD), the most common human prion disease, is associated with pathologic misfolding of the prion protein (PrP), encoded by the PRNP gene. Of human prion disease cases, < 1% were transmitted by misfolded PrP, ~ 15% are inherited, and ~ 85% are sporadic (sCJD). While familial cases are inherited through germline mutations in PRNP, the cause of sCJD is unknown. Somatic mutations have been hypothesized as a cause of sCJD, and recent studies have revealed that somatic mutations accumulate in neurons during aging. To investigate the hypothesis that somatic mutations in PRNP may underlie sCJD, we performed deep DNA sequencing of PRNP in 205 sCJD cases and 170 age-matched non-disease controls. We included 5 cases of Heidenhain variant sporadic CJD (H-sCJD), where visual symptomatology and neuropathology implicate localized initiation of prion formation, and examined multiple regions across the brain including in the affected occipital cortex. We employed Multiple Independent Primer PCR Sequencing (MIPP-Seq) with a median depth of > 5000× across the PRNP coding region and analyzed for variants using MosaicHunter. An allele mixing experiment showed positive detection of variants in bulk DNA at a variant allele fraction (VAF) as low as 0.2%. We observed multiple polymorphic germline variants among individuals in our cohort. However, we did not identify bona fide somatic variants in sCJD, including across multiple affected regions in H-sCJD, nor in control individuals. Beyond our stringent variant-identification pipeline, we also analyzed VAFs from raw sequencing data, and observed no evidence of prion disease enrichment for the known germline pathogenic variants P102L, D178N, and E200K. The lack of PRNP pathogenic somatic mutations in H-sCJD or the broader cohort of sCJD suggests that clonal somatic mutations may not play a major role in sporadic prion disease. With H-sCJD representing a localized presentation of neurodegeneration, this serves as a test of the potential role of clonal somatic mutations in genes known to cause familial neurodegeneration.
Identifiants
pubmed: 39048735
doi: 10.1007/s00401-024-02774-2
pii: 10.1007/s00401-024-02774-2
doi:
Substances chimiques
Prion Proteins
0
PRNP protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
10Subventions
Organisme : NCEZID CDC HHS
ID : CK000309
Pays : United States
Organisme : NINDS NIH HHS
ID : NS074317
Pays : United States
Organisme : NINDS NIH HHS
ID : NS103848
Pays : United States
Organisme : NIA NIH HHS
ID : AG086138
Pays : United States
Organisme : NIA NIH HHS
ID : AG082346
Pays : United States
Organisme : NIA NIH HHS
ID : AG065502
Pays : United States
Organisme : NIA NIH HHS
ID : HL007627
Pays : United States
Organisme : NIA NIH HHS
ID : AG079857
Pays : United States
Organisme : Doris Duke Charitable Foundation
ID : 2021183
Pays : United States
Organisme : BrightFocus Foundation
ID : A20201292F
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Abascal F, Harvey LMR, Mitchell E, Lawson ARJ, Lensing SV, Ellis P et al (2021) Somatic mutation landscapes at single-molecule resolution. Nature 593:405–410. https://doi.org/10.1038/s41586-021-03477-4
doi: 10.1038/s41586-021-03477-4
pubmed: 33911282
Appleby BS, Appleby KK, Crain BJ, Onyike CU, Wallin MT, Rabins PV (2009) Characteristics of established and proposed sporadic Creutzfeldt–Jakob disease variants. Arch Neurol 66:208–215. https://doi.org/10.1001/archneurol.2008.533
doi: 10.1001/archneurol.2008.533
pubmed: 19204157
Appleby BS, Appleby KK, Rabins PV (2007) Does the presentation of Creutzfeldt–Jakob disease vary by age or presumed etiology? A meta-analysis of the past 10 years. J Neuropsychiatry Clin Neurosci 19:428–435. https://doi.org/10.1176/jnp.2007.19.4.428
doi: 10.1176/jnp.2007.19.4.428
pubmed: 18070846
Azevedo FAC, Carvalho LRB, Grinberg LT, Farfel JM, Ferretti REL, Leite REP et al (2009) Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J Comp Neurol 513:532–541. https://doi.org/10.1002/cne.21974
doi: 10.1002/cne.21974
pubmed: 19226510
Bae JH, Liu R, Roberts E, Nguyen E, Tabrizi S, Rhoades J et al (2023) Single duplex DNA sequencing with CODEC detects mutations with high sensitivity. Nat Genet 55:871–879. https://doi.org/10.1038/s41588-023-01376-0
doi: 10.1038/s41588-023-01376-0
pubmed: 37106072
pmcid: 10181940
Baiardi S, Capellari S, Ladogana A, Strumia S, Santangelo M, Pocchiari M et al (2016) Revisiting the Heidenhain variant of Creutzfeldt–Jakob disease: evidence for prion type variability influencing clinical course and laboratory findings. J Alzheimers Dis 50:465–476. https://doi.org/10.3233/JAD-150668
doi: 10.3233/JAD-150668
pubmed: 26682685
Baldassari S, Ribierre T, Marsan E, Adle-Biassette H, Ferrand-Sorbets S, Bulteau C et al (2019) Dissecting the genetic basis of focal cortical dysplasia: a large cohort study. Acta Neuropathol 138:885–900. https://doi.org/10.1007/s00401-019-02061-5
doi: 10.1007/s00401-019-02061-5
pubmed: 31444548
pmcid: 6851393
Beck JA, Poulter M, Campbell TA, Adamson G, Uphill JB, Guerreiro R et al (2010) PRNP allelic series from 19 years of prion protein gene sequencing at the MRC prion unit. Hum Mutat 31:E1551–E1563. https://doi.org/10.1002/humu.21281
doi: 10.1002/humu.21281
pubmed: 20583301
Beck JA, Poulter M, Campbell TA, Uphill JB, Adamson G, Geddes JF et al (2004) Somatic and germline mosaicism in sporadic early-onset Alzheimer’s disease. Hum Mol Genet 13:1219–1224. https://doi.org/10.1093/hmg/ddh134
doi: 10.1093/hmg/ddh134
pubmed: 15115757
Bizzotto S, Dou Y, Ganz J, Doan RN, Kwon M, Bohrson CL et al (2021) Landmarks of human embryonic development inscribed in somatic mutations. Science 371:1249–1253. https://doi.org/10.1126/science.abe1544
doi: 10.1126/science.abe1544
pubmed: 33737485
pmcid: 8170505
Büeler H, Aguzzi A, Sailer A, Greiner RA, Autenried P, Aguet M et al (1993) Mice devoid of PrP are resistant to scrapie. Cell 73:1339–1347. https://doi.org/10.1016/0092-8674(93)90360-3
doi: 10.1016/0092-8674(93)90360-3
pubmed: 8100741
Chen S, Francioli LC, Goodrich JK, Collins RL, Kanai M, Wang Q et al (2024) A genomic mutational constraint map using variation in 76,156 human genomes. Nature 625:92–100. https://doi.org/10.1038/s41586-023-06045-0
doi: 10.1038/s41586-023-06045-0
pubmed: 38057664
Collinge J (2016) Mammalian prions and their wider relevance in neurodegenerative diseases. Nature 539:217–226. https://doi.org/10.1038/nature20415
doi: 10.1038/nature20415
pubmed: 27830781
Collinge J, Palmer MS, Dryden AJ (1991) Genetic predisposition to iatrogenic Creutzfeldt–Jakob disease. Lancet 337:1441–1442. https://doi.org/10.1016/0140-6736(91)93128-v
doi: 10.1016/0140-6736(91)93128-v
pubmed: 1675319
Cooper SA, Murray KL, Heath CA, Will RG, Knight RSG (2005) Isolated visual symptoms at onset in sporadic Creutzfeldt–Jakob disease: the clinical phenotype of the “Heidenhain variant.” Br J Ophthalmol 89:1341–1342. https://doi.org/10.1136/bjo.2005.074856
doi: 10.1136/bjo.2005.074856
pubmed: 16170128
pmcid: 1772891
Cracco L, Appleby BS, Gambetti P (2018) Fatal familial insomnia and sporadic fatal insomnia. Handb Clin Neurol 153:271–299. https://doi.org/10.1016/B978-0-444-63945-5.00015-5
doi: 10.1016/B978-0-444-63945-5.00015-5
pubmed: 29887141
Deleault NR, Harris BT, Rees JR, Supattapone S (2007) Formation of native prions from minimal components in vitro. Proc Natl Acad Sci U S A 104:9741–9746. https://doi.org/10.1073/pnas.0702662104
doi: 10.1073/pnas.0702662104
pubmed: 17535913
pmcid: 1887554
DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C et al (2011) A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 43:491–498. https://doi.org/10.1038/ng.806
doi: 10.1038/ng.806
pubmed: 21478889
pmcid: 3083463
D’Gama AM, Geng Y, Couto JA, Martin B, Boyle EA, LaCoursiere CM et al (2015) Mammalian target of rapamycin pathway mutations cause hemimegalencephaly and focal cortical dysplasia. Ann Neurol 77:720–725. https://doi.org/10.1002/ana.24357
doi: 10.1002/ana.24357
pubmed: 25599672
pmcid: 4471336
D’Gama AM, Woodworth MB, Hossain AA, Bizzotto S, Hatem NE, LaCoursiere CM et al (2017) Somatic mutations activating the mTOR pathway in dorsal telencephalic progenitors cause a continuum of cortical dysplasias. Cell Rep 21:3754–3766. https://doi.org/10.1016/j.celrep.2017.11.106
doi: 10.1016/j.celrep.2017.11.106
pubmed: 29281825
pmcid: 5752134
Doan RN, Miller MB, Kim SN, Rodin RE, Ganz J, Bizzotto S et al (2021) MIPP-Seq: ultra-sensitive rapid detection and validation of low-frequency mosaic mutations. BMC Med Genomics 14:47. https://doi.org/10.1186/s12920-021-00893-3
doi: 10.1186/s12920-021-00893-3
pubmed: 33579278
pmcid: 7881461
Edgar RC (2010) Search and clustering orders of magnitude faster than BLAST. Bioinformatics 26:2460–2461. https://doi.org/10.1093/bioinformatics/btq461
doi: 10.1093/bioinformatics/btq461
pubmed: 20709691
Faucheux BA, Privat N, Brandel J-P, Sazdovitch V, Laplanche J-L, Maurage C-A et al (2009) Loss of cerebellar granule neurons is associated with punctate but not with large focal deposits of prion protein in Creutzfeldt–Jakob disease. J Neuropathol Exp Neurol 68:892–901. https://doi.org/10.1097/NEN.0b013e3181af7f23
doi: 10.1097/NEN.0b013e3181af7f23
pubmed: 19606064
Foutz A, Appleby BS, Hamlin C, Liu X, Yang S, Cohen Y et al (2017) Diagnostic and prognostic value of human prion detection in cerebrospinal fluid. Ann Neurol 81:79–92. https://doi.org/10.1002/ana.24833
doi: 10.1002/ana.24833
pubmed: 27893164
pmcid: 5266667
Frontzek K, Carta M, Losa M, Epskamp M, Meisl G, Anane A et al (2020) Autoantibodies against the prion protein in individuals with PRNP mutations. Neurology 95:e2028–e2037. https://doi.org/10.1212/WNL.0000000000009183
doi: 10.1212/WNL.0000000000009183
pubmed: 32098855
pmcid: 7682844
Gajdusek DC, Zigas V (1959) Kuru; clinical, pathological and epidemiological study of an acute progressive degenerative disease of the central nervous system among natives of the Eastern Highlands of New Guinea. Am J Med 26:442–469. https://doi.org/10.1016/0002-9343(59)90251-7
doi: 10.1016/0002-9343(59)90251-7
pubmed: 13626997
Gambetti P, Parchi P, Petersen RB, Chen SG, Lugaresi E (1995) Fatal familial insomnia and familial Creutzfeldt–Jakob disease: clinical, pathological and molecular features. Brain Pathol 5:43–51. https://doi.org/10.1111/j.1750-3639.1995.tb00576.x
doi: 10.1111/j.1750-3639.1995.tb00576.x
pubmed: 7767490
Garraway LA, Lander ES (2013) Lessons from the cancer genome. Cell 153:17–37. https://doi.org/10.1016/j.cell.2013.03.002
doi: 10.1016/j.cell.2013.03.002
pubmed: 23540688
Genovese G, Kähler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF et al (2014) Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 371:2477–2487. https://doi.org/10.1056/NEJMoa1409405
doi: 10.1056/NEJMoa1409405
pubmed: 25426838
pmcid: 4290021
Goldfarb LG, Brown P, Little BW, Cervenáková L, Kenney K, Gibbs CJ Jr et al (1993) A new (two-repeat) octapeptide coding insert mutation in Creutzfeldt–Jakob disease. Neurology 43:2392–2394. https://doi.org/10.1212/wnl.43.11.2392
doi: 10.1212/wnl.43.11.2392
pubmed: 8232966
Goldgaber D, Goldfarb LG, Brown P, Asher DM, Brown WT, Lin S et al (1989) Mutations in familial Creutzfeldt–Jakob disease and Gerstmann–Sträussler–Scheinker’s syndrome. Exp Neurol 106:204–206. https://doi.org/10.1016/0014-4886(89)90095-2
doi: 10.1016/0014-4886(89)90095-2
pubmed: 2572450
Guha T, Malkin D (2017) Inherited TP53 mutations and the Li–Fraumeni syndrome. Cold Spring Harb Perspect Med 7:a026187. https://doi.org/10.1101/cshperspect.a026187
doi: 10.1101/cshperspect.a026187
pubmed: 28270529
pmcid: 5378014
Hsiao K, Baker HF, Crow TJ, Poulter M, Owen F, Terwilliger JD et al (1989) Linkage of a prion protein missense variant to Gerstmann–Sträussler syndrome. Nature 338:342–345. https://doi.org/10.1038/338342a0
doi: 10.1038/338342a0
pubmed: 2564168
Hsiao KK, Scott M, Foster D, Groth DF, DeArmond SJ, Prusiner SB (1990) Spontaneous neurodegeneration in transgenic mice with mutant prion protein. Science 250:1587–1590. https://doi.org/10.1126/science.1980379
doi: 10.1126/science.1980379
pubmed: 1980379
Huang AY, Zhang Z, Ye AY, Dou Y, Yan L, Yang X et al (2017) MosaicHunter: accurate detection of postzygotic single-nucleotide mosaicism through next-generation sequencing of unpaired, trio, and paired samples. Nucleic Acids Res 45:e76. https://doi.org/10.1093/nar/gkx024
doi: 10.1093/nar/gkx024
pubmed: 28132024
pmcid: 5449543
Jones E, Hummerich H, Viré E, Uphill J, Dimitriadis A, Speedy H et al (2020) Identification of novel risk loci and causal insights for sporadic Creutzfeldt–Jakob disease: a genome-wide association study. Lancet Neurol 19:840–848. https://doi.org/10.1016/S1474-4422(20)30273-8
doi: 10.1016/S1474-4422(20)30273-8
pubmed: 32949544
pmcid: 8220892
Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q et al (2020) The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581:434–443. https://doi.org/10.1038/s41586-020-2308-7
doi: 10.1038/s41586-020-2308-7
pubmed: 32461654
pmcid: 7334197
Keogh MJ, Wei W, Aryaman J, Walker L, van den Ameele J, Coxhead J et al (2018) High prevalence of focal and multi-focal somatic genetic variants in the human brain. Nat Commun 9:4257. https://doi.org/10.1038/s41467-018-06331-w
doi: 10.1038/s41467-018-06331-w
pubmed: 30323172
pmcid: 6189186
Khoshkhoo S, Wang Y, Chahine Y, Erson-Omay EZ, Robert SM, Kiziltug E et al (2023) Contribution of somatic Ras/Raf/mitogen-activated protein kinase variants in the hippocampus in drug-resistant mesial temporal lobe epilepsy. JAMA Neurol 80:578–587. https://doi.org/10.1001/jamaneurol.2023.0473
doi: 10.1001/jamaneurol.2023.0473
pubmed: 37126322
pmcid: 10152377
Kim CC, Haldiman T, Langeveld J, Kong QQ, Safar JG (2013) Coexistence and evolution of prions by natural selection. Prion 7:10. https://doi.org/10.4161/pri.24863
doi: 10.4161/pri.24863
Kim C, Haldiman T, Cohen Y, Chen W, Blevins J, Sy M-S et al (2011) Protease-sensitive conformers in broad spectrum of distinct PrPSc structures in sporadic Creutzfeldt–Jakob disease are indicator of progression rate. PLoS Pathog 7:e1002242. https://doi.org/10.1371/journal.ppat.1002242
doi: 10.1371/journal.ppat.1002242
pubmed: 21931554
pmcid: 3169556
Kim C, Haldiman T, Surewicz K, Cohen Y, Chen W, Blevins J et al (2012) Small protease sensitive oligomers of PrPSc in distinct human prions determine conversion rate of PrP(C). PLoS Pathog 8:e1002835. https://doi.org/10.1371/journal.ppat.1002835
doi: 10.1371/journal.ppat.1002835
pubmed: 22876179
pmcid: 3410855
Kim C, Xiao X, Chen S, Haldiman T, Smirnovas V, Kofskey D et al (2018) Artificial strain of human prions created in vitro. Nat Commun 9:2166. https://doi.org/10.1038/s41467-018-04584-z
doi: 10.1038/s41467-018-04584-z
pubmed: 29867164
pmcid: 5986862
Kim J, Park SM, Koh HY, Ko A, Kang H-C, Chang WS et al (2023) Threshold of somatic mosaicism disrupting the brain function. bioRxiv. https://doi.org/10.1101/2023.12.30.573716
doi: 10.1101/2023.12.30.573716
pubmed: 38529510
pmcid: 10962739
Kobayashi A, Teruya K, Matsuura Y, Shirai T, Nakamura Y, Yamada M et al (2015) The influence of PRNP polymorphisms on human prion disease susceptibility: an update. Acta Neuropathol 130:159–170. https://doi.org/10.1007/s00401-015-1447-7
doi: 10.1007/s00401-015-1447-7
pubmed: 26022925
Kroll F, Dimitriadis A, Campbell T, Darwent L, Collinge J, Mead S et al (2022) Prion protein gene mutation detection using long-read nanopore sequencing. Sci Rep 12:8284. https://doi.org/10.1038/s41598-022-12130-7
doi: 10.1038/s41598-022-12130-7
pubmed: 35585119
pmcid: 9117325
Li H, Durbin R (2010) Fast and accurate long-read alignment with Burrows–Wheeler transform. Bioinformatics 26:589–595. https://doi.org/10.1093/bioinformatics/btp698
doi: 10.1093/bioinformatics/btp698
pubmed: 20080505
pmcid: 2828108
Liu MH, Costa B, Choi U, Bandler RC, Lassen E, Grońska-Pęski M et al (2023) Single-strand mismatch and damage patterns revealed by single-molecule DNA sequencing. bioRxiv. https://doi.org/10.1101/2023.02.19.526140
doi: 10.1101/2023.02.19.526140
pubmed: 38405786
pmcid: 10888964
Lloyd SE, Mead S, Collinge J (2013) Genetics of prion diseases. Curr Opin Genet Dev 23:345–351. https://doi.org/10.1016/j.gde.2013.02.012
doi: 10.1016/j.gde.2013.02.012
pubmed: 23518043
pmcid: 3705206
Lodato MA, Rodin RE, Bohrson CL, Coulter ME, Barton AR, Kwon M et al (2018) Aging and neurodegeneration are associated with increased mutations in single human neurons. Science 359:555–559. https://doi.org/10.1126/science.aao4426
doi: 10.1126/science.aao4426
pubmed: 29217584
Lodato MA, Woodworth MB, Lee S, Evrony GD, Mehta BK, Karger A et al (2015) Somatic mutation in single human neurons tracks developmental and transcriptional history. Science 350:94–98. https://doi.org/10.1126/science.aab1785
doi: 10.1126/science.aab1785
pubmed: 26430121
pmcid: 4664477
Luquette LJ, Miller MB, Zhou Z, Bohrson CL, Zhao Y, Jin H et al (2022) Single-cell genome sequencing of human neurons identifies somatic point mutation and indel enrichment in regulatory elements. Nat Genet 54:1564–1571. https://doi.org/10.1038/s41588-022-01180-2
doi: 10.1038/s41588-022-01180-2
pubmed: 36163278
pmcid: 9833626
Martincorena I, Fowler JC, Wabik A, Lawson ARJ, Abascal F, Hall MWJ et al (2018) Somatic mutant clones colonize the human esophagus with age. Science 362:911–917. https://doi.org/10.1126/science.aau3879
doi: 10.1126/science.aau3879
pubmed: 30337457
pmcid: 6298579
Martin FJ, Amode MR, Aneja A, Austine-Orimoloye O, Azov AG, Barnes I et al (2023) Ensembl 2023. Nucleic Acids Res 51:D933–D941. https://doi.org/10.1093/nar/gkac958
doi: 10.1093/nar/gkac958
pubmed: 36318249
Masters CL, Richardson EP (1978) Subacute Spongiform Encephalopathy (Creutzfeldt–Jakob Disease): the nature and progression of spongiform change. Brain 101:333–344. https://doi.org/10.1093/brain/101.2.333
doi: 10.1093/brain/101.2.333
pubmed: 352478
Mead S, Lloyd S, Collinge J (2019) Genetic factors in mammalian prion diseases. Annu Rev Genet 53:117–147. https://doi.org/10.1146/annurev-genet-120213-092352
doi: 10.1146/annurev-genet-120213-092352
pubmed: 31537104
Mead S, Poulter M, Beck J, Webb TEF, Campbell TA, Linehan JM et al (2006) Inherited prion disease with six octapeptide repeat insertional mutation–molecular analysis of phenotypic heterogeneity. Brain 129:2297–2317. https://doi.org/10.1093/brain/awl226
doi: 10.1093/brain/awl226
pubmed: 16923955
Mead S, Poulter M, Uphill J, Beck J, Whitfield J, Webb TEF et al (2009) Genetic risk factors for variant Creutzfeldt–Jakob disease: a genome-wide association study. Lancet Neurol 8:57–66. https://doi.org/10.1016/S1474-4422(08)70265-5
doi: 10.1016/S1474-4422(08)70265-5
pubmed: 19081515
pmcid: 2643048
Mead S, Uphill J, Beck J, Poulter M, Campbell T, Lowe J et al (2012) Genome-wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP. Hum Mol Genet 21:1897–1906. https://doi.org/10.1093/hmg/ddr607
doi: 10.1093/hmg/ddr607
pubmed: 22210626
Mead S, Whitfield J, Poulter M, Shah P, Uphill J, Campbell T et al (2009) A novel protective prion protein variant that colocalizes with kuru exposure. N Engl J Med 361:2056–2065. https://doi.org/10.1056/NEJMoa0809716
doi: 10.1056/NEJMoa0809716
pubmed: 19923577
Medori R, Tritschler HJ, LeBlanc A, Villare F, Manetto V, Chen HY et al (1992) Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene. N Engl J Med 326:444–449. https://doi.org/10.1056/NEJM199202133260704
doi: 10.1056/NEJM199202133260704
pubmed: 1346338
pmcid: 6151859
Meyer M, Kircher M (2010) Illumina sequencing library preparation for highly multiplexed target capture and sequencing. Cold Spring Harb Protoc. https://doi.org/10.1101/pdb.prot5448
doi: 10.1101/pdb.prot5448
pubmed: 20516186
Miller MB, Geoghegan JC, Supattapone S (2011) Dissociation of infectivity from seeding ability in prions with alternate docking mechanism. PLoS Pathog 7:e1002128. https://doi.org/10.1371/journal.ppat.1002128
doi: 10.1371/journal.ppat.1002128
pubmed: 21779169
pmcid: 3136465
Miller MB, Huang AY, Kim J, Zhou Z, Kirkham SL, Maury EA et al (2022) Somatic genomic changes in single Alzheimer’s disease neurons. Nature 604:714–722. https://doi.org/10.1038/s41586-022-04640-1
doi: 10.1038/s41586-022-04640-1
pubmed: 35444284
pmcid: 9357465
Minikel EV, Vallabh SM, Lek M, Estrada K, Samocha KE, Sathirapongsasuti JF et al (2016) Quantifying prion disease penetrance using large population control cohorts. Sci Transl Med 8:322ra9. https://doi.org/10.1126/scitranslmed.aad5169
doi: 10.1126/scitranslmed.aad5169
pubmed: 26791950
pmcid: 4774245
Minikel EV, Zhao HT, Le J, O’Moore J, Pitstick R, Graffam S et al (2020) Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints. Nucleic Acids Res 48:10615–10631. https://doi.org/10.1093/nar/gkaa616
doi: 10.1093/nar/gkaa616
pubmed: 32776089
pmcid: 7641729
Murley AG, Nie Y, Golder Z, Keogh MJ, Smith C, Ironside JW et al (2023) High-depth PRNP sequencing in brains with sporadic Creutzfeldt–Jakob disease. Neurol Genet 9:e200054. https://doi.org/10.1212/NXG.0000000000200054
doi: 10.1212/NXG.0000000000200054
pubmed: 36686280
pmcid: 9853313
Nicolas G, Acuña-Hidalgo R, Keogh MJ, Quenez O, Steehouwer M, Lelieveld S et al (2018) Somatic variants in autosomal dominant genes are a rare cause of sporadic Alzheimer’s disease. Alzheimers Dement 14:1632–1639. https://doi.org/10.1016/j.jalz.2018.06.3056
doi: 10.1016/j.jalz.2018.06.3056
pubmed: 30114415
Oldoni E, Fumagalli GG, Serpente M, Fenoglio C, Scarioni M, Arighi A et al (2016) PRNP P39L variant is a rare cause of frontotemporal dementia in Italian population. J Alzheimers Dis 50:353–357. https://doi.org/10.3233/JAD-150863
doi: 10.3233/JAD-150863
pubmed: 26757195
Owen F, Poulter M, Shah T, Collinge J, Lofthouse R, Baker H et al (1990) An in-frame insertion in the prion protein gene in familial Creutzfeldt–Jakob disease. Brain Res Mol Brain Res 7:273–276. https://doi.org/10.1016/0169-328x(90)90038-f
doi: 10.1016/0169-328x(90)90038-f
pubmed: 2159587
Palmer MS, Dryden AJ, Hughes JT, Collinge J (1991) Homozygous prion protein genotype predisposes to sporadic Creutzfeldt–Jakob disease. Nature 352:340–342. https://doi.org/10.1038/352340a0
doi: 10.1038/352340a0
pubmed: 1677164
Palmer MS, Mahal SP, Campbell TA, Hill AF, Sidle KC, Laplanche JL et al (1993) Deletions in the prion protein gene are not associated with CJD. Hum Mol Genet 2:541–544. https://doi.org/10.1093/hmg/2.5.541
doi: 10.1093/hmg/2.5.541
pubmed: 8100163
Parchi P, Castellani R, Capellari S, Ghetti B, Young K, Chen SG et al (1996) Molecular basis of phenotypic variability in sporadic Creutzfeldt–Jakob disease. Ann Neurol 39:767–778. https://doi.org/10.1002/ana.410390613
doi: 10.1002/ana.410390613
pubmed: 8651649
Poduri A, Evrony GD, Cai X, Elhosary PC, Beroukhim R, Lehtinen MK et al (2012) Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron 74:41–48. https://doi.org/10.1016/j.neuron.2012.03.010
doi: 10.1016/j.neuron.2012.03.010
pubmed: 22500628
pmcid: 3460551
Rivière J-B, Mirzaa GM, O’Roak BJ, Beddaoui M, Alcantara D, Conway RL et al (2012) De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet 44:934–940. https://doi.org/10.1038/ng.2331
doi: 10.1038/ng.2331
pubmed: 22729224
pmcid: 3408813
Rohland N, Reich D (2012) Cost-effective, high-throughput DNA sequencing libraries for multiplexed target capture. Genome Res 22:939–946. https://doi.org/10.1101/gr.128124.111
doi: 10.1101/gr.128124.111
pubmed: 22267522
pmcid: 3337438
Safar JG, Geschwind MD, Deering C, Didorenko S, Sattavat M, Sanchez H et al (2005) Diagnosis of human prion disease. Proc Natl Acad Sci U S A 102:3501–3506. https://doi.org/10.1073/pnas.0409651102
doi: 10.1073/pnas.0409651102
pubmed: 15741275
pmcid: 552933
Safar J, Wille H, Itri V, Groth D, Serban H, Torchia M et al (1998) Eight prion strains have PrP(Sc) molecules with different conformations. Nat Med 4:1157–1165. https://doi.org/10.1038/2654
doi: 10.1038/2654
pubmed: 9771749
Sala Frigerio C, Lau P, Troakes C, Deramecourt V, Gele P, Van Loo P et al (2015) On the identification of low allele frequency mosaic mutations in the brains of Alzheimer’s disease patients. Alzheimers Dement 11:1265–1276. https://doi.org/10.1016/j.jalz.2015.02.007
doi: 10.1016/j.jalz.2015.02.007
pubmed: 25937274
Samocha KE, Robinson EB, Sanders SJ, Stevens C, Sabo A, McGrath LM et al (2014) A framework for the interpretation of de novo mutation in human disease. Nat Genet 46:944–950. https://doi.org/10.1038/ng.3050
doi: 10.1038/ng.3050
pubmed: 25086666
pmcid: 4222185
Silveira JR, Raymond GJ, Hughson AG, Race RE, Sim VL, Hayes SF et al (2005) The most infectious prion protein particles. Nature 437:257–261. https://doi.org/10.1038/nature03989
doi: 10.1038/nature03989
pubmed: 16148934
pmcid: 1513539
Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW (2013) Cancer genome landscapes. Science 339:1546–1558. https://doi.org/10.1126/science.1235122
doi: 10.1126/science.1235122
pubmed: 23539594
pmcid: 3749880
Wang F, Wang X, Yuan C-G, Ma J (2010) Generating a prion with bacterially expressed recombinant prion protein. Science 327:1132–1135. https://doi.org/10.1126/science.1183748
doi: 10.1126/science.1183748
pubmed: 20110469
pmcid: 2893558
Watson N, Brandel J-P, Green A, Hermann P, Ladogana A, Lindsay T et al (2021) The importance of ongoing international surveillance for Creutzfeldt–Jakob disease. Nat Rev Neurol 17:362–379. https://doi.org/10.1038/s41582-021-00488-7
doi: 10.1038/s41582-021-00488-7
pubmed: 33972773
pmcid: 8109225
Wei W, Keogh MJ, Aryaman J, Golder Z, Kullar PJ, Wilson I et al (2019) Frequency and signature of somatic variants in 1461 human brain exomes. Genet Med 21:904–912. https://doi.org/10.1038/s41436-018-0274-3
doi: 10.1038/s41436-018-0274-3
pubmed: 30214067
Werner B, Case J, Williams MJ, Chkhaidze K, Temko D, Fernández-Mateos J et al (2020) Measuring single cell divisions in human tissues from multi-region sequencing data. Nat Commun 11:1035. https://doi.org/10.1038/s41467-020-14844-6
doi: 10.1038/s41467-020-14844-6
pubmed: 32098957
pmcid: 7042311
Won S-Y, Kim Y-C, Jeong B-H (2023) Elevated E200K somatic mutation of the prion protein gene (PRNP) in the brain tissues of patients with sporadic Creutzfeldt–Jakob disease (CJD). Int J Mol Sci 24:14831. https://doi.org/10.3390/ijms241914831
doi: 10.3390/ijms241914831
pubmed: 37834279
pmcid: 10573534
Zanusso G, Liu D, Ferrari S, Hegyi I, Yin X, Aguzzi A et al (1998) Prion protein expression in different species: analysis with a panel of new mAbs. Proc Natl Acad Sci U S A 95:8812–8816. https://doi.org/10.1073/pnas.95.15.8812
doi: 10.1073/pnas.95.15.8812
pubmed: 9671761
pmcid: 21159
Zarranz JJ, Digon A, Atarés B, Rodríguez-Martínez AB, Arce A, Carrera N et al (2005) Phenotypic variability in familial prion diseases due to the D178N mutation. J Neurol Neurosurg Psychiatry 76:1491–1496. https://doi.org/10.1136/jnnp.2004.056606
doi: 10.1136/jnnp.2004.056606
pubmed: 16227536
pmcid: 1739400
Zerr I, Ladogana A, Mead S, Hermann P, Forloni G, Appleby BS (2024) Creutzfeldt–Jakob disease and other prion diseases. Nat Rev Dis Primers 10:14. https://doi.org/10.1038/s41572-024-00497-y
doi: 10.1038/s41572-024-00497-y
pubmed: 38424082