ABCC9 genetic polymorphisms are associated with increased risk for various human diseases including hippocampal sclerosis of aging. The main goals of this study were 1 > to detect the ABCC9 variants and define the specific 3′ untranslated region (3′UTR) for each variant in human brain, and 2 > to determine whether a polymorphism (rs704180) associated with risk for hippocampal sclerosis of aging pathology is also associated with variation in ABCC9 transcript expression and/or splicing. Rapid amplification of ABCC9 cDNA ends (3′RACE) provided evidence of novel 3′ UTR portions of ABCC9 in human brain. In silico and experimental studies were performed focusing on the single nucleotide polymorphism, rs704180. Analyses from multiple databases, focusing on rs704180 only, indicated that this risk allele is a local expression quantitative trait locus (eQTL). Analyses of RNA from human brains showed increased ABCC9 transcript levels in individuals with the risk genotype, corresponding with enrichment for a shorter 3′ UTR which may be more stable than variants with the longer 3′ UTR. MicroRNA transfection experiments yielded results compatible with the hypothesis that miR‐30c causes down‐regulation of SUR2 transcripts with the longer 3′ UTR. Thus we report evidence of complex ABCC9 genetic regulation in brain, which may be of direct relevance to human disease.

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Published in Journal of Neurochemistry, v. 134, issue 6, p. 1026-1039.

© 2015 International Society for Neurochemistry

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This work was supported by the National Institutes of Health grants [K25 AG043546 to DF, P30 AG028383 to PTN].

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