Genetic Variations in ABCA7 Can Increase Secreted Levels of Amyloid-β₄₀ and Amyloid-β₄₂ Peptides and ABCA7 Transcription in Cell Culture Models

[Journal of Alzheimer Disease, 53(3)2016, 875-892, DOI 10.3233/JAD-150965]

https://content.iospress.com/articles/journal-of-alzheimers-disease/jad150965

In this paper it was stated that the major and minor allele of SNP rs3752246 were C and G, respectively. While Naj et al. Nat Genet 43:436-441, 2011 and Hollingworth et al. Nat Genet 43:429-435, 2011 both stated that the C>G mutation at rs3752246 leads to a glycine to alanine substitution, it is actually a major-G allele and a minor-C allele at this site that creates the missense mutation of Glycine to Alanine (https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=3752246). It follows that the allele labeled ‘Ala1527’ in the paper is actually the major-G allele (GGT) encoding glycine and the allele labeled ‘Gly1527’ is actually the minor-C allele (GCT) encoding alanine (see Erratum Table 1).

Please note important changes to the abstract and introduction stemming from these revelations (Erratum Table 2). Figures 1 and 2 of Bamji-Mirza et al. 2016 are not affected by this labeling issue. The labeling in Figs. 3, 4, 5 & 6 require modification such that Fig. 3A and all subsequent figures should read Minor-C allele (ABCA7/Ala1527) and Major-G allele (ABCA7/Gly1527). The data from Figs. 3, 4 and 5 thus show that the Major-G allele is the risk allele conferring AD phenotypes. Data from Fig. 6 now show that increase in BACE1 activity and Aβ levels observed with HMA treatment of ABCA/Ala1527-expresing cells is not due to removal of the putative myristoylation site. Cellular treatment with HMA is non-specific and may alter other cellular mechanisms for the observed that requires further investigation. However, Fig. 7 provides amino acid-based evidence that expression of an ABCA7 peptide containing Glycine is larger (heavier) than an ABCA7 peptide containing Alanine, suggesting a difference in protein modification, as evidenced by western blot and mass spectrometry.