Abstract
Amyloid precursor protein gene (APP) duplications have been identified in screens of selected probands with early onset familial Alzheimer's disease (FAD). A causal role for copy number variation (CNV) in the prion protein gene (PRNP) in prion dementias is not known. We aimed to determine the prevalence of copy number variation in APP and PRNP in a large referral series, test a screening method for detection of the same, and expand knowledge of clinical phenotype. We used a 3-tiered screening assay for APP and PRNP duplication (exonic real-time quantitative polymerase chain reaction [exon-qPCR], fluorescent microsatellite quantitative PCR [fm-q-PCR], and Illumina array [Illumina Inc., San Diego, CA, USA]) for analysis of a heterogeneous referral series comprising 1531 probands. Five of 1531 probands screened showed APP duplication, a similar prevalence to APP missense mutation. Real-time quantitative PCR and fluorescent microsatellite quantitative PCR were similar individually but are theoretically complementary; we used Illumina arrays as our reference assay. Two of 5 probands were from an autosomal dominant early onset Alzheimer's disease (familial Alzheimer's disease) pedigree. One extensive, noncontiguous duplication on chromosome 21 was consistent with an unbalanced translocation not including the Down's syndrome critical region. Seizures were prominent in the other typical APP duplications. A range of imaging, neuropsychological, cerebrospinal fluid, and pathological findings are reported that extend the known phenotype. APP but not PRNP duplication is a significant cause of early onset dementia in the UK. The recognized phenotype may be expanded to include the possibility of early seizures and apparently sporadic disease which, in part, may be due to different mutational mechanisms. The pros and cons of our screening method are discussed.
Highlights
With the development of experimental therapeutics targeting amyloid- in Alzheimer’s disease (AD)
Using exon-qPCR, comparison was made between the amplification of Amyloid precursor protein gene (APP) or prion protein gene (PRNP) and an internal reference marker (APP-GRN and PRNP-APP respectively)
Twenty-one samples from the AD cohort and 19 samples from the prion disease cohort were considered as potential copy number variation (CNV) based on whether ⌬Ct value was greater than 2 standard deviations (2 SDs) from the mean
Summary
A Finnish family with autosomal dominant early-onset AD and prominent cerebral amyloid angiopathy (CAA) where no causative mutation was identified (Remes et al, 2004) has subsequently been screened, and found to harbor an APPdup (Rovelet-Lecrux et al, 2007). While these studies uncovered an important mutational mechanism at APP, several questions remain about the frequency of these mutations in larger, less selected APP patient cohorts in different countries and the associated phenotypic spectrum. As we are aware, PRNP CNV in human prion disease has been explored in only 1 series (Collins et al, 2010)
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