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Novel human ABCC9/SUR2 brain‐expressed transcripts and an eQTL relevant to hippocampal sclerosis of aging
Author(s) -
Nelson Peter T.,
Wang WangXia,
Wilfred Bernard R.,
Wei Angela,
Dimayuga James,
Huang Qingwei,
Ighodaro Eseosa,
Artiushin Sergey,
Fardo David W.
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13202
Subject(s) - biology , untranslated region , expression quantitative trait loci , three prime untranslated region , genetics , human brain , gene , locus (genetics) , single nucleotide polymorphism , allele , rna splicing , hippocampal sclerosis , genotype , rna , neuroscience , temporal lobe , epilepsy
AbstractABCC 9 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 ABCC 9 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 ABCC 9 transcript expression and/or splicing. Rapid amplification of ABCC 9 cDNA ends (3′ RACE ) provided evidence of novel 3′ UTR portions of ABCC 9 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 ABCC 9 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 . Micro RNA transfection experiments yielded results compatible with the hypothesis that miR‐30c causes down‐regulation of SUR 2 transcripts with the longer 3′ UTR . Thus we report evidence of complex ABCC 9 genetic regulation in brain, which may be of direct relevance to human disease.ABCC9 gene variants are associated with increased risk for hippocampal sclerosis of aging (HS‐Aging – a prevalent brain disease with symptoms that mimic Alzheimer's disease). We describe novel ABCC9 variants in human brain, corresponding to altered 3'UTR length, which could lead to targeting by miR‐30c. We also determined that the HS‐Aging risk mutation is associated with variation in ABCC9 transcript expression.