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 - PubMed (original) (raw)

. 2012 Feb;33(2):426.e13-21.

doi: 10.1016/j.neurobiolaging.2010.10.010. Epub 2010 Dec 28.

William Knight, Rita Guerreiro, Natalie Ryan, Jessica Lowe, Mark Poulter, David J Nicholl, John Hardy, Tamas Revesz, James Lowe, Martin Rossor, John Collinge, Simon Mead

Affiliations

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

Daniel McNaughton et al. Neurobiol Aging. 2012 Feb.

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.

Copyright © 2012 Elsevier Inc. All rights reserved.

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Figures

Fig. 1

Fig. 1

Chr21 diagram showing _APP_dup regions with respect to genes. APP duplications in 5 probands. Single nucleotide polymorphism (SNP) start and end positions for these duplications are included in the supplementary data. Black horizontal bars indicate the extent of heterozygous duplications. Minimal sizes (in parenthesis) of previously reported duplications are indicated by gray horizontal bars and the intervals of the duplication boundaries by dotted lines. Gene content excludes pseudogenes and open reading frames. The transcription start site of genes are indicated by vertical bars. Proband 1 has a partial duplication of NCAM2 and proband 2 has a full duplication of this gene.

Fig. 2

Fig. 2

Magnetic resonance imaging (MRI) scans from _APP_dup patients. (A) Proband 1 showing extensive white matter abnormalities, microbleeds, (Aii) and an amygdala hemorrhage (Ai, arrow), and (B) proband 2 (aged 47) showing white matter abnormalities on T2 weighted scans (Bii) and hippocampal atrophy (Bi).

Fig. 3

Fig. 3

Pedigrees from 5 families. Filled symbols denote affected or probably affected individuals, “S” denotes patient with seizures but not clearly a progressive neurodegenerative disease; see Table 1

Fig. 4

Fig. 4

Pathology of proband 4. Amyloid pathology is shown by immunohistochemistry for amyoid beta protein in frontal cortex (a) and temporal cortex (b). Several different patterns of cortical amyloid deposition were seen including diffuse subpial, diffuse, and neuritic plaques and diffuse “clouds” in the entorhinal region. Severe and widespread cerebral amyloid angiopathy was present involving vessels in the spinal (c), cerebral (d), and cerebellar (e) meninges. Rare cerebellar amyloid plaques were noted. Tau pathology was widespread in the temporal cortex (g) mainly in the form of nonplaque neuritic deposition but also including plaque neurites and tangles. Plaque, tangle, and nonplaque neuritic tau deposition were found to affect the cerebral cortex in a wide distribution extending beyond the superior temporal gyrus and heavily involving the occipital cortex amounting to Braak stage VI. Tau staining was prominent in the substantia nigra (f) as both tangle and neuritic deposition. An unusual feature was strong focal glial tau deposition in the white matter in coils and fine neurites (not illustrated). Alpha synuclein staining showed no pathological deposition either in the cortex or subcortical regions including the substantia nigra (not illustrated).

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