Search for a genetic cause of variably protease-sensitive prionopathy
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Variably protease-sensitive prionopathy (VPSPr) is a rare, atypical subtype of prion disease currently classified as sporadic. We performed exome sequencing and targeted sequencing of PRNP non-coding regions on genomic DNA from autopsy-confirmed VPSPr patients (N=67) in order to search for a possible genetic cause. Our search identified no potentially causal variants for VPSPr. The common polymorphism PRNP M129V was the largest genetic risk factor for VPSPr, with an odds ratio of 7.0. Other variants in and near PRNP exhibited association to VPSPr risk only in proportion to their linkage disequilibrium with M129V, and upstream expression quantitative trait loci showed no evidence of independent association to VPSPr risk. We cannot rule out the possibility of causal variants hiding in genomic regions or classes of genetic variation that our search did not canvas. Nevertheless, our data support the classification of VPSPr as a sporadic prion disease.
Author Summary
Prion disease is caused by misfolding of the prion protein (PrP), and can be either sporadic genetic, or acquired. Acquired cases arising from infection through dietary or medical routes are exceedingly rare today (<1% of cases). Sporadic cases occur apparently at random, without any major genetic risk factors, and are not passed down to subsequent generations. All cases of genetic prion disease to date have been traced to DNA changes that alter the amino acid sequence of PrP, and children of people with genetic prion disease are at 50/50 risk of inheriting these autosomal dominant DNA changes. Variably protease sensitive prionopathy, or VPSPr, is a rare and unusual subtype of prion disease, classified as sporadic because there are no changes in PrP’s amino acid sequence. Here we performed DNA sequencing on 67 VPSPr cases to determine whether a genetic variant outside of the PrP amino acid sequence might cause the disease. We found no DNA changes that could potentially cause VPSPr. While it is difficult to prove the negative — a causal genetic change could still exist in some part of the genome where we did not search — our data support the notion that VPSPr is truly sporadic in nature, and that risk of VPSPr is not transmitted in families.