Abstract
Background PION (Pigeon homologue protein), located on chromosome 7q11.23, encodes gSAP (gamma-secretase activating protein), which is cleaved to form a 16 kDa Cterminal fragment (gSAP-16K) that interacts with gamma-secretase to facilitate the cleavage of amyloid precursor protein-beta-C-terminal fragment (APP-betaCTF), releasing the neurotoxic peptide A-beta [He G, et al, Nature 2010]. The study by He G, el al. also demonstrated that partial siRNA-mediated inhibition of gSAP expression in N2a cells reduces A-beta production, suggesting that gSAP-16K modulates APP-beta-CTF cleavage in a dose-dependent manner. Taken together, these observations suggest that levels of PION gene expression in human brain may also affect levels of A-beta production and thereby influence the risk of developing Alzheimer’s disease. The goal of the present study is to quantify variation of PION mRNA expression in human prefrontal cortex and identify haplotypes and/or combinations of genotypes that predict high- or low-levels of mRNA expression. Methods Sixty-four independent frozen sections of prefrontal cortex (Han Chinese autopsy samples; Brodmann area 46) were obtained from the China Brain Bank Center (Wuhan, China). Genomic DNA and total RNA were isolated using standard techniques. A common SNP, rs2037753 (heterozygosity = 0.422), located within exon 16 of PION mRNA was chosen as am olecular marker to distinguish mRNAs derived from each autosomal allele. SNaPShot © -based AEI assays were carried out as previously described [Lim JE,Molecular Psychiatry, 2007]. Analysis of population distributions of log2AEI ratios was carried out using a mathematical model developed in-house. Levels of PION mRNA relative to mRNA encoding the house-keeping gene GAPDH were quantified by real-time PCR (calculated as ΔCt). Genomewide genotyping of all the above samples was carried out using HumanOmni1-Qad arras (Illumina) arrays. SNPs with genotypes that correlate with relative expression of PION mRNA were identified by linear regression analysis for SNPs within a 205,650 base pair region of chromosome 7 centered on PION. Results
Highlights
PION (Pigeon homologue protein), located on chromosome 7q11.23, encodes gSAP, which is cleaved to form a 16 kDa Cterminal fragment that interacts with gamma-secretase to facilitate the cleavage of amyloid precursor protein-beta-C-terminal fragment (APP-betaCTF), releasing the neurotoxic peptide A-beta [He G, et al, Nature 2010]
Mathematical modeling of the log2AEI population distributions predicted that PION mRNA expression is controlled by three cis-acting regulatory elements, one of which is in partial linkage disequilibrium with the marker SNP
Scanning SNPs in the region of the PION gene for correlations with mRNA expression revealed a single SNP, rs10271991, that is highly correlated with mRNA expression (r2 = 23.5; P =0.0001)
Summary
PION (Pigeon homologue protein), located on chromosome 7q11.23, encodes gSAP (gamma-secretase activating protein), which is cleaved to form a 16 kDa Cterminal fragment (gSAP-16K) that interacts with gamma-secretase to facilitate the cleavage of amyloid precursor protein-beta-C-terminal fragment (APP-betaCTF), releasing the neurotoxic peptide A-beta [He G, et al, Nature 2010]. The goal of the present study is to quantify variation of PION mRNA expression in human prefrontal cortex and identify haplotypes and/or combinations of genotypes that predict high- or low-levels of mRNA expression
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