title: Duplication of amyloid precursor protein (APP), but not prion protein (PRNP) gene is a significant cause of early onset dementia in a large UK series.
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.
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: McNaughton
authors.forename: William
authors.initials: W
authors.lastname: Knight
authors.forename: Rita
authors.initials: R
authors.lastname: Guerreiro
authors.forename: Natalie
authors.initials: N
authors.lastname: Ryan
authors.forename: Jessica
authors.initials: J
authors.lastname: Lowe
authors.forename: Mark
authors.initials: M
authors.lastname: Poulter
authors.forename: David J
authors.initials: DJ
authors.lastname: Nicholl
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Tamas
authors.initials: T
authors.lastname: Revesz
authors.forename: James
authors.initials: J
authors.lastname: Lowe
authors.forename: Martin
authors.initials: M
authors.lastname: Rossor
authors.forename: John
authors.initials: J
authors.lastname: Collinge
authors.forename: Simon
authors.initials: S
authors.lastname: Mead
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D015984:Causality; D005260:Female; D020440:Gene Duplication / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology* / Q000235:genetics*; D006801:Humans; D008297:Male; D015995:Prevalence; D011328:Prions / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D006113:United Kingdom / Q000453:epidemiology
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D011328:Prions