A Copine family member, Cpne8, is a candidate quantitative trait gene for prion disease incubation time in mouse

Abstract

Prion disease incubation time in mice is determined by many factors including genetic background. The prion gene itself plays a major role in incubation time; however, other genes are also known to be important. Whilst quantitative trait loci (QTL) studies have identified multiple loci across the genome, these regions are often large, and with the exception of Hectd2 on Mmu19, no quantitative trait genes or nucleotides for prion disease incubation time have been demonstrated. In this study, we use the Northport heterogeneous stock of mice to reduce the size of a previously identified QTL on Mmu15 from approximately 25 to 1.2 cM. We further characterised the genes in this region and identify Cpne8, a member of the copine family, as the most promising candidate gene. We also show that Cpne8 mRNA is upregulated at the terminal stage of disease, supporting a role in prion disease. Applying these techniques to other loci will facilitate the identification of key pathways in prion disease pathogenesis.Electronic supplementary materialThe online version of this article (doi:10.1007/s10048-009-0219-8) contains supplementary material, which is available to authorized users.

Effect of fixation on brain and lymphoreticular vCJD prions and bioassay of key positive specimens from a retrospective vCJD prevalence study

“…Modelling cannot estimate the number of sub-clinically infected carriers, and the discrepancy between numbers of clinical cases and prevalence estimates from 512 JDF Wadsworth et al population screening remains unexplained [16][17][18][19]. Incubation periods in human prion infections, even in the absence of a species barrier, may exceed five decades [6,20,21], and multiple genetic loci in addition to the PrP gene are known to influence prion incubation periods in mice [22][23][24][25] and susceptibility in humans [26,27]. Asymptomatically infected carriers appear to have transmitted vCJD prion infection and disease to others via blood transfusion [28][29][30] or blood products [31].…”

Rare structural genetic variation in human prion diseases

“…These included PRNP, RARB-THRB, STMN2, HECTD2, SPRN, ZBTB38-RASA, BACE, MTMR7, NPAS2, PLCD, CPNE8, SOD1, STCH and CTSD [2,3,19,21,22,29,30,36]. No CNV overlapping these genes was found in more than one individual in a case or control group (table 1 supplementary).…”

“…Several large-scale association studies have reported a role for large CNVs in susceptibility to several human conditions including idiopathic epilepsy, attention deficit hyperactivity disorder, schizophrenia, bipolar disorder, mental retardation, autism, and Alzheimer's disease [1,6,13,14,25,26,40] [2,3,19,21,22,29,30,36]. As a generalisation, few common structural genetic variations are risk factors in common diseases [10], whereas several rare CNVs, including whole or partial gene deletions and/or duplications are known to be major risk factors and/or dominantly inherited disease causing mutations in neurodegenerative diseases [1,13,14,25,26,35,40].…”

The Retinoic Acid Receptor Beta (Rarb) Region of Mmu14 Is Associated with Prion Disease Incubation Time in Mouse

“…PCR and sequencing reactions were carried out as previously described [17] and run either on a MegaBACE1000 (Amersham Biosciences) or 3730 capillary sequencer (Applied Biosystems).…”