Characterization of Prion Disease Associated with a Two-Octapeptide Repeat Insertion
Genetic prion disease accounts for 10–15% of prion disease. While insertion of four or more octapeptide repeats are clearly pathogenic, smaller repeat insertions have an unclear pathogenicity. The goal of this case series was to provide an insight into the characteristics of the 2-octapeptide repeat...
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MDPI AG
2021-09-01
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| Online Access: | https://www.mdpi.com/1999-4915/13/9/1794 |
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| author | Nicholas Brennecke Ignazio Cali Tze How Mok Helen Speedy Genomics England Research Consortium Laszlo L. P. Hosszu Christiane Stehmann Laura Cracco Gianfranco Puoti Thomas W. Prior Mark L. Cohen Steven J. Collins Simon Mead Brian S. Appleby |
| author_facet | Nicholas Brennecke Ignazio Cali Tze How Mok Helen Speedy Genomics England Research Consortium Laszlo L. P. Hosszu Christiane Stehmann Laura Cracco Gianfranco Puoti Thomas W. Prior Mark L. Cohen Steven J. Collins Simon Mead Brian S. Appleby |
| author_sort | Nicholas Brennecke |
| collection | DOAJ |
| description | Genetic prion disease accounts for 10–15% of prion disease. While insertion of four or more octapeptide repeats are clearly pathogenic, smaller repeat insertions have an unclear pathogenicity. The goal of this case series was to provide an insight into the characteristics of the 2-octapeptide repeat genetic variant and to provide insight into the risk for Creutzfeldt–Jakob disease in asymptomatic carriers. 2-octapeptide repeat insertion prion disease cases were collected from the National Prion Disease Pathology Surveillance Center (US), the National Prion Clinic (UK), and the National Creutzfeldt–Jakob Disease Registry (Australia). Three largescale population genetic databases were queried for the 2-octapeptide repeat insertion allele. Eight cases of 2-octapeptide repeat insertion were identified. The cases were indistinguishable from the sporadic Creutzfeldt–Jakob cases of the same molecular subtype. Western blot characterization of the prion protein in the absence of enzymatic digestion with proteinase K revealed that 2-octapeptide repeat insertion and sporadic Creutzfeldt–Jakob disease have distinct prion protein profiles. Interrogation of large-scale population datasets suggested the variant is of very low penetrance. The 2-octapeptide repeat insertion is at most a low-risk genetic variant. Predictive genetic testing for asymptomatic blood relatives is not likely to be justified given the low risk. |
| first_indexed | 2024-03-10T07:08:59Z |
| format | Article |
| id | doaj.art-c04a6d71b61f49a99831430bef4d4116 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-10T07:08:59Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-c04a6d71b61f49a99831430bef4d41162023-11-22T15:38:05ZengMDPI AGViruses1999-49152021-09-01139179410.3390/v13091794Characterization of Prion Disease Associated with a Two-Octapeptide Repeat InsertionNicholas Brennecke0Ignazio Cali1Tze How Mok2Helen Speedy3Genomics England Research Consortium4Laszlo L. P. Hosszu5Christiane Stehmann6Laura Cracco7Gianfranco Puoti8Thomas W. Prior9Mark L. Cohen10Steven J. Collins11Simon Mead12Brian S. Appleby13Department of Neurology, Case Western Reserve University & University Hospitals Cleveland Medical, Cleveland, OH 44106, USADepartment of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USAMRC Prion Unit at University College London, Institute of Prion Diseases, London W1W 7FF, UKMRC Prion Unit at University College London, Institute of Prion Diseases, London W1W 7FF, UKGenomics England Limited of Dawson Hall, Charterhouse Square, London EC1M 6BQ, UKMRC Prion Unit at University College London, Institute of Prion Diseases, London W1W 7FF, UKAustralian National Creutzfeldt-Jakob Disease Registry, The Florey Institute, The University of Melbourne, Melbourne, VIC 3010, AustraliaDepartment of Pathology and Laboratory Medicine, School of Medicine, Indiana University, Indianapolis, IN 46202, USADepartment of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 81100 Caserta, ItalyCenter for Human Genetics Laboratory, Case Western Reserve University & University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USADepartment of Neurology, Case Western Reserve University & University Hospitals Cleveland Medical, Cleveland, OH 44106, USAAustralian National Creutzfeldt-Jakob Disease Registry, The Florey Institute, The University of Melbourne, Melbourne, VIC 3010, AustraliaMRC Prion Unit at University College London, Institute of Prion Diseases, London W1W 7FF, UKDepartment of Neurology, Case Western Reserve University & University Hospitals Cleveland Medical, Cleveland, OH 44106, USAGenetic prion disease accounts for 10–15% of prion disease. While insertion of four or more octapeptide repeats are clearly pathogenic, smaller repeat insertions have an unclear pathogenicity. The goal of this case series was to provide an insight into the characteristics of the 2-octapeptide repeat genetic variant and to provide insight into the risk for Creutzfeldt–Jakob disease in asymptomatic carriers. 2-octapeptide repeat insertion prion disease cases were collected from the National Prion Disease Pathology Surveillance Center (US), the National Prion Clinic (UK), and the National Creutzfeldt–Jakob Disease Registry (Australia). Three largescale population genetic databases were queried for the 2-octapeptide repeat insertion allele. Eight cases of 2-octapeptide repeat insertion were identified. The cases were indistinguishable from the sporadic Creutzfeldt–Jakob cases of the same molecular subtype. Western blot characterization of the prion protein in the absence of enzymatic digestion with proteinase K revealed that 2-octapeptide repeat insertion and sporadic Creutzfeldt–Jakob disease have distinct prion protein profiles. Interrogation of large-scale population datasets suggested the variant is of very low penetrance. The 2-octapeptide repeat insertion is at most a low-risk genetic variant. Predictive genetic testing for asymptomatic blood relatives is not likely to be justified given the low risk.https://www.mdpi.com/1999-4915/13/9/1794prion diseaseCreutzfeldt-Jakob diseasegenetic Creutzfeldt-Jakob diseasegeneticsoctapeptide repeat insertion |
| spellingShingle | Nicholas Brennecke Ignazio Cali Tze How Mok Helen Speedy Genomics England Research Consortium Laszlo L. P. Hosszu Christiane Stehmann Laura Cracco Gianfranco Puoti Thomas W. Prior Mark L. Cohen Steven J. Collins Simon Mead Brian S. Appleby Characterization of Prion Disease Associated with a Two-Octapeptide Repeat Insertion Viruses prion disease Creutzfeldt-Jakob disease genetic Creutzfeldt-Jakob disease genetics octapeptide repeat insertion |
| title | Characterization of Prion Disease Associated with a Two-Octapeptide Repeat Insertion |
| title_full | Characterization of Prion Disease Associated with a Two-Octapeptide Repeat Insertion |
| title_fullStr | Characterization of Prion Disease Associated with a Two-Octapeptide Repeat Insertion |
| title_full_unstemmed | Characterization of Prion Disease Associated with a Two-Octapeptide Repeat Insertion |
| title_short | Characterization of Prion Disease Associated with a Two-Octapeptide Repeat Insertion |
| title_sort | characterization of prion disease associated with a two octapeptide repeat insertion |
| topic | prion disease Creutzfeldt-Jakob disease genetic Creutzfeldt-Jakob disease genetics octapeptide repeat insertion |
| url | https://www.mdpi.com/1999-4915/13/9/1794 |
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