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Molecular insights into an ancient form of Paget’s disease of bone

Shaw, B, Burrell, CL, Green, D, Navarro-Martinez, A, Scott, D, Daroszewska, A, van ’t Hof, R, Smith, L, Hargrave, F, Mistry, S, Bottril, A, Kessler, B, Fisher, R, Singh, A, Dalmay, T, Fraser, WD, King, T, Gonzalez, S and Layfield, R Molecular insights into an ancient form of Paget’s disease of bone. Proceedings of the National Academy of Sciences of USA. ISSN 1091-6490 (Accepted)

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Abstract

Paget’s disease of bone (PDB) is a chronic skeletal disorder that can affect one or several bones in individuals over 55 years of age. PDB like changes have been reported in archaeological remains as old as Roman, although accurate diagnosis and natural history of the disease is lacking. Six skeletons from a collection of 130 excavated at Norton Priory in the North West of England, which dates to medieval times, show atypical and extensive pathological changes resembling contemporary PDB affecting up to 75% of individual skeletons. Disease prevalence in the remaining collection is high, at least 16% of adults, with age at death estimations as low as 35 years. Despite these atypical features, paleoproteomic analysis identified sequestosome 1 (SQSTM1) or p62, a protein central to the pathological milieu of PDB, as one of the few non69 collagenous human sequences preserved in skeletal samples. Targeted proteomic analysis detected >60% of the ancient p62 primary sequence with western blotting indicating p62 abnormalities including in dentition. Direct sequencing of ancient DNA excluded contemporary PDB associated SQSTM1 mutations. Our observations indicate that the ancient p62 protein is likely modified within its C-terminal ubiquitin associated (UBA) domain. Ancient microRNAs were remarkably preserved in an osteosarcoma from a skeleton with extensive disease, with miR-16 expression consistent with that reported in contemporary PDB associated bone tumours. Our work displays the use of proteomics to inform diagnosis of ancient disease such as atypical PDB, which has unusual features presumably potentiated by as yet unidentified environmental or genetic factors.

Item Type: Article
Uncontrolled Keywords: MD Multidisciplinary
Subjects: C Auxiliary Sciences of History > CC Archaeology
G Geography. Anthropology. Recreation > GN Anthropology
R Medicine > R Medicine (General)
Divisions: Natural Sciences and Psychology
Publisher: National Academy of Sciences
Date Deposited: 05 Apr 2019 09:43
Last Modified: 05 Apr 2019 09:47
Editors: Roodman, G
URI: http://researchonline.ljmu.ac.uk/id/eprint/10508

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