ABCA7 p.Gly1527Ala
| Predicted by SNAP2: | A: N (57%), C: D (59%), D: D (63%), E: D (59%), F: D (75%), H: N (53%), I: D (71%), K: D (59%), L: D (71%), M: D (71%), N: N (57%), P: D (63%), Q: N (53%), R: D (59%), S: N (61%), T: N (53%), V: N (61%), W: D (85%), Y: D (71%), |
| Predicted by PROVEAN: | A: N, C: N, D: N, E: N, F: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N, |
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[hide] The genetics and neuropathology of Alzheimer's dis... Acta Neuropathol. 2012 Sep;124(3):305-23. doi: 10.1007/s00401-012-0996-2. Epub 2012 May 23. Schellenberg GD, Montine TJ
The genetics and neuropathology of Alzheimer's disease.
Acta Neuropathol. 2012 Sep;124(3):305-23. doi: 10.1007/s00401-012-0996-2. Epub 2012 May 23., [PMID:22618995]
Abstract [show]
Here we review the genetic causes and risks for Alzheimer's disease (AD). Early work identified mutations in three genes that cause AD: APP, PSEN1 and PSEN2. Although mutations in these genes are rare causes of AD, their discovery had a major impact on our understanding of molecular mechanisms of AD. Early work also revealed the epsilon4 allele of the APOE as a strong risk factor for AD. Subsequently, SORL1 also was identified as an AD risk gene. More recently, advances in our knowledge of the human genome, made possible by technological advances and methods to analyze genomic data, permit systematic identification of genes that contribute to AD risk. This work, so far accomplished through single nucleotide polymorphism arrays, has revealed nine new genes implicated in AD risk (ABCA7, BIN1, CD33, CD2AP, CLU, CR1, EPHA1, MS4A4E/MS4A6A, and PICALM). We review the relationship between these mutations and genetic variants and the neuropathologic features of AD and related disorders. Together, these discoveries point toward a new era in neurodegenerative disease research that impacts not only AD but also related illnesses that produce cognitive and behavioral deficits.
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No. Sentence Comment
274 This work also reported suggestive results for ABCA7 (5.0 9 10-7 , OR = 1.15, CI = 1.09-1.21) with the peak signal at a non-synonymous SNP that is potentially the pathogenic variant (p.Gly1527Ala).
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ABCA7 p.Gly1527Ala 22618995:274:185
status: NEW[hide] ATP-binding cassette transporter A7 (ABCA7) loss o... J Biol Chem. 2015 Oct 2;290(40):24152-65. doi: 10.1074/jbc.M115.655076. Epub 2015 Aug 10. Satoh K, Abe-Dohmae S, Yokoyama S, St George-Hyslop P, Fraser PE
ATP-binding cassette transporter A7 (ABCA7) loss of function alters Alzheimer amyloid processing.
J Biol Chem. 2015 Oct 2;290(40):24152-65. doi: 10.1074/jbc.M115.655076. Epub 2015 Aug 10., [PMID:26260791]
Abstract [show]
The ATP-binding cassette transporter A7 (ABCA7) has been identified as a susceptibility factor of late onset Alzheimer disease in genome-wide association studies. ABCA7 has been shown to mediate phagocytosis and affect membrane trafficking. The current study examined the impact of ABCA7 loss of function on amyloid precursor protein (APP) processing and generation of amyloid-beta (Abeta). Suppression of endogenous ABCA7 in several different cell lines resulted in increased beta-secretase cleavage and elevated Abeta. ABCA7 knock-out mice displayed an increased production of endogenous murine amyloid Abeta42 species. Crossing ABCA7-deficient animals to an APP transgenic model resulted in significant increases in the soluble Abeta as compared with mice expressing normal levels of ABCA7. Only modest changes in the amount of insoluble Abeta and amyloid plaque densities were observed once the amyloid pathology was well developed, whereas Abeta deposition was enhanced in younger animals. In vitro studies indicated a more rapid endocytosis of APP in ABCA7 knock-out cells that is mechanistically consistent with the increased Abeta production. These in vitro and in vivo findings indicate a direct role of ABCA7 in amyloid processing that may be associated with its primary biological function to regulate endocytic pathways. Several potential loss-of-function ABCA7 mutations and deletions linked to Alzheimer disease that in some instances have a greater impact than apoE allelic variants have recently been identified. A reduction in ABCA7 expression or loss of function would be predicted to increase amyloid production and that may be a contributing factor in the associated Alzheimer disease susceptibility.
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16 The single nucleotide polymorphisms (SNPs) associated with LOAD are distributed in various domains of the ABCA7 gene and include intronic SNPs and a coding sequence causing G1527A substitution.
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ABCA7 p.Gly1527Ala 26260791:16:173
status: NEW