title: HECTD2 is associated with susceptibility to mouse and human prion disease.
abstract: Prion diseases are fatal transmissible neurodegenerative disorders, which include Scrapie, Bovine Spongiform Encephalopathy (BSE), Creutzfeldt-Jakob Disease (CJD), and kuru. They are characterised by a prolonged clinically silent incubation period, variation in which is determined by many factors, including genetic background. We have used a heterogeneous stock of mice to identify Hectd2, an E3 ubiquitin ligase, as a quantitative trait gene for prion disease incubation time in mice. Further, we report an association between HECTD2 haplotypes and susceptibility to the acquired human prion diseases, vCJD and kuru. We report a genotype-associated differential expression of Hectd2 mRNA in mouse brains and human lymphocytes and a significant up-regulation of transcript in mice at the terminal stage of prion disease. Although the substrate of HECTD2 is unknown, these data highlight the importance of proteosome-directed protein degradation in neurodegeneration. This is the first demonstration of a mouse quantitative trait gene that also influences susceptibility to human prion diseases. Characterisation of such genes is key to understanding human risk and the molecular basis of incubation periods.
authors.affiliation: MRC Prion Unit, University College London Institute of Neurology, London, United Kingdom.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Lloyd
authors.forename: Emma G
authors.initials: EG
authors.lastname: Maytham
authors.forename: Hirva
authors.initials: H
authors.lastname: Pota
authors.forename: Julia
authors.initials: J
authors.lastname: Grizenkova
authors.forename: Eleni
authors.initials: E
authors.lastname: Molou
authors.forename: James
authors.initials: J
authors.lastname: Uphill
authors.forename: Holger
authors.initials: H
authors.lastname: Hummerich
authors.forename: Jerome
authors.initials: J
authors.lastname: Whitfield
authors.forename: Michael P
authors.initials: MP
authors.lastname: Alpers
authors.forename: Simon
authors.initials: S
authors.lastname: Mead
authors.forename: John
authors.initials: J
authors.lastname: Collinge
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017096:Prion Diseases / Q000235:genetics* / Q000378:metabolism / Q000662:veterinary*; D040641:Quantitative Trait Loci; D012376:Rodent Diseases / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D044767:Ubiquitin-Protein Ligases