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ABCA7

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ABCA7
Identifiers
AliasesABCA7, ABCA-SSN, ABCX, AD9, ATP binding cassette subfamily A member 7
External IDsOMIM: 605414; MGI: 1351646; HomoloGene: 22783; GeneCards: ABCA7; OMA:ABCA7 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

10347

27403

Ensembl

ENSG00000064687

ENSMUSG00000035722

UniProt

Q8IZY2

Q91V24

RefSeq (mRNA)

NM_019112
NM_033308

NM_013850
NM_001347081

RefSeq (protein)

NP_061985

NP_001334010
NP_038878

Location (UCSC)Chr 19: 1.04 – 1.07 MbChr 10: 79.83 – 79.85 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

ATP-binding cassette sub-family A member 7 is a protein that in humans is encoded by the ABCA7 gene.[5]

Function

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The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies: ABC1, MDR/TAP, CFTR/MRP, ALD (adrenoleukodystrophy), OABP, GCN20, and White. This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. This full transporter has been detected predominantly in myelo-lymphatic tissues with the highest expression in peripheral leukocytes, thymus, spleen, and bone marrow. The function of this protein is not yet known; however, the expression pattern suggests a role in lipid homeostasis in cells of the immune system. Alternative splicing of this gene results in two transcript variants.[5]

Lack of ABCA7 gene exhibits phenotypes in mice, such as moderate decrease in plasma HDL and adipose tissues only in female, while release of cellular cholesterol and phospholipid is not impaired.[6] Accordingly, decrease in plasma lectin level was also reported.[7] Reduction of CD3 or CD1d may lead to dysfunction of T cells by deletion of ABCA7.[8][9]

On the other hand, transfected and expressed ABCA7, but not endogenous ABCA7, mediates release of cell phospholipid and cholesterol to generate HDL-like particles but contain less cholesterol than those generated by ABCA1. [10] [7] ABCA7-generated HDL is smaller and appears as a single peak in a molecular sieve HPLC analysis in comparison to HDL generated by ABCA1 that shows twin peaks of small and poor in cholesterol and large and rich in cholesterol. [11] [12] ABCA7 mRNA generates full length cDNA and a spliced form of cDNA, and only the former is capable of generating HDL when transfected.[13]

ABCA7 was shown associated with cellular phagocytotic activity.[14][15] The promoter of ABCA7 contains sterol regulatory element (SRE) so that ABCA7 is down-regulated by cell cholesterol through sterol regulatory element binding protein (SREBP) 2.[14] Therefore, ABCA7 expression and phagocytosis are up-regulated by use of HMG-reductase inhibitors (statins).[16] In addition, ABCA7 is stabilized like ABCA1 by helical apolipoproteins such as apoA-I,[17][18][19] and phagocytosis is accordingly increased in such a condition.[19]

In summary, ABCA7 is a substantially related protein to ABCA1 but it does not mediate cell cholesterol release by generation of HDL unless it is externally transfected and expressed in vitro. ABCA7 is shown associated with cellular phagocytotic function in vivo and in vitro, and expression of the ABCA7 gene is regulated by cell cholesterol mainly through the SRE/SREBP system in a negative feed-back fashion in contrast to positive feedback by the LXR/RXR system for ABCA1.[20] ABCA7 thus links cholesterol metabolism to host defense system.

Clinical significance

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In 2011, two genome-wide association studies (GWAS) identified ABCA7 as a new susceptibility locus for late-onset Alzheimer's disease.[21][22] The finding was also confirmed by other meta-analysis investigations later.[23][24] Such association of ABCA7 variants was reported on more specific findings of the disease such as memory decline and incident mild cognitive impairment [25] or cortical and hippocampal atrophy.[26][27]

Protein-disrupting variants in ABCA7 have been shown to predispose to Alzheimer's disease.[28] The Icelandic database of Decode Genetics has shown a doubled probability of developing Alzheimer's disease when inactive variants of the ABCA7 gene are present.[29]

By using the knock-out mice, ABCA7 was indicated involved in generation and processing of amyloid β (Aβ) peptides. In the brain of the amyloid precursor protein transgenic mice, deletion of ABCA7 resulted in accumulation of Aβ40 and Aβ42 in the early stage [30] apparently by accelerating Aβ production.[30][31] More rapid endocytosis of amyloid precursor protein was observed in primary microglia from ABCA7 deficient mice.[30] Roles of ABCA7 are also implicated for microglial phagocytotic function [32] and immune responses.[33][12] Although the direct target of ABCA7 function is unclear, the findings are so far mechanistically consistent with the increased Aβ production.

The data can be summarized as 1) loss of function of ABCA7 is associated with a risk for late onset Alzheimer's disease, 2) one of its molecular backgrounds can be enhanced production/decreased processing of Aβ peptides, and 3) ABCA7 is at least shown to increase phagocytosis including that of microglia. Since ABCA7 gene is down-regulated by cell cholesterol via the SRE/SREBP system,[14] the data accumulated are consistent with clinical implication that use of statins, HMG-CoA reductase inhibitors, reduces risk for Alzheimer's disease.[34]

See also

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Notes

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000064687 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000035722 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b "Entrez Gene: ABCA7 ATP-binding cassette, sub-family A (ABC1), member 7".
  6. ^ Kim WS, Fitzgerald ML, Kang K, Okuhira K, Bell SA, Manning JJ, et al. (February 2005). "Abca7 null mice retain normal macrophage phosphatidylcholine and cholesterol efflux activity despite alterations in adipose mass and serum cholesterol levels". The Journal of Biological Chemistry. 280 (5): 3989–3995. doi:10.1074/jbc.M412602200. PMID 15550377.
  7. ^ a b Bhatia S, Fu Y, Hsiao JT, Halliday GM, Kim WS (December 2017). "Deletion of Alzheimer's Disease Risk Gene ABCA7 Alters White Adipose Tissue Development and Leptin Levels". Journal of Alzheimer's Disease Reports. 1 (1): 237–247. doi:10.3233/ADR-170029. PMC 6159609. PMID 30480241.
  8. ^ Meurs I, Calpe-Berdiel L, Habets KL, Zhao Y, Korporaal SJ, Mommaas AM, et al. (2012). "Effects of deletion of macrophage ABCA7 on lipid metabolism and the development of atherosclerosis in the presence and absence of ABCA1". PLOS ONE. 7 (3): e30984. Bibcode:2012PLoSO...730984M. doi:10.1371/journal.pone.0030984. PMC 3293875. PMID 22403608.
  9. ^ Nowyhed HN, Chandra S, Kiosses W, Marcovecchio P, Andary F, Zhao M, et al. (January 2017). "ATP Binding Cassette Transporter ABCA7 Regulates NKT Cell Development and Function by Controlling CD1d Expression and Lipid Raft Content". Scientific Reports. 7: 40273. Bibcode:2017NatSR...740273N. doi:10.1038/srep40273. PMC 5238393. PMID 28091533.
  10. ^ Kim WS, Fitzgerald ML, Kang K, Okuhira K, Bell SA, Manning JJ, et al. (February 2005). "Abca7 null mice retain normal macrophage phosphatidylcholine and cholesterol efflux activity despite alterations in adipose mass and serum cholesterol levels". The Journal of Biological Chemistry. 280 (5): 3989–3995. doi:10.1074/jbc.M412602200. PMID 15550377. S2CID 24263492.
  11. ^ Meurs I, Calpe-Berdiel L, Habets KL, Zhao Y, Korporaal SJ, Mommaas AM, et al. (2012). "Effects of deletion of macrophage ABCA7 on lipid metabolism and the development of atherosclerosis in the presence and absence of ABCA1". PLOS ONE. 7 (3): e30984. Bibcode:2012PLoSO...730984M. doi:10.1371/journal.pone.0030984. PMC 3293875. PMID 22403608.
  12. ^ a b Nowyhed HN, Chandra S, Kiosses W, Marcovecchio P, Andary F, Zhao M, et al. (January 2017). "ATP Binding Cassette Transporter ABCA7 Regulates NKT Cell Development and Function by Controlling CD1d Expression and Lipid Raft Content". Scientific Reports. 7: 40273. Bibcode:2017NatSR...740273N. doi:10.1038/srep40273. PMC 5238393. PMID 28091533.
  13. ^ Ikeda Y, Abe-Dohmae S, Munehira Y, Aoki R, Kawamoto S, Furuya A, et al. (November 2003). "Posttranscriptional regulation of human ABCA7 and its function for the apoA-I-dependent lipid release". Biochemical and Biophysical Research Communications. 311 (2): 313–318. doi:10.1016/j.bbrc.2003.10.002. PMID 14592415.
  14. ^ a b c Iwamoto N, Abe-Dohmae S, Sato R, Yokoyama S (September 2006). "ABCA7 expression is regulated by cellular cholesterol through the SREBP2 pathway and associated with phagocytosis". Journal of Lipid Research. 47 (9): 1915–1927. doi:10.1194/jlr.M600127-JLR200. PMID 16788211. S2CID 23145752.
  15. ^ Jehle AW, Gardai SJ, Li S, Linsel-Nitschke P, Morimoto K, Janssen WJ, et al. (August 2006). "ATP-binding cassette transporter A7 enhances phagocytosis of apoptotic cells and associated ERK signaling in macrophages". The Journal of Cell Biology. 174 (4): 547–556. doi:10.1083/jcb.200601030. PMC 2064260. PMID 16908670.
  16. ^ Tanaka N, Abe-Dohmae S, Iwamoto N, Fitzgerald ML, Yokoyama S (August 2011). "HMG-CoA reductase inhibitors enhance phagocytosis by upregulating ATP-binding cassette transporter A7". Atherosclerosis. 217 (2): 407–414. doi:10.1016/j.atherosclerosis.2011.06.031. PMC 3150192. PMID 21762915.
  17. ^ Arakawa R, Yokoyama S (June 2002). "Helical apolipoproteins stabilize ATP-binding cassette transporter A1 by protecting it from thiol protease-mediated degradation". The Journal of Biological Chemistry. 277 (25): 22426–22429. doi:10.1074/jbc.M202996200. PMID 11950847. S2CID 27052533.
  18. ^ Lu R, Arakawa R, Ito-Osumi C, Iwamoto N, Yokoyama S (October 2008). "ApoA-I facilitates ABCA1 recycle/accumulation to cell surface by inhibiting its intracellular degradation and increases HDL generation". Arteriosclerosis, Thrombosis, and Vascular Biology. 28 (10): 1820–1824. doi:10.1161/ATVBAHA.108.169482. PMID 18617649. S2CID 13492156.
  19. ^ a b Tanaka N, Abe-Dohmae S, Iwamoto N, Fitzgerald ML, Yokoyama S (September 2010). "Helical apolipoproteins of high-density lipoprotein enhance phagocytosis by stabilizing ATP-binding cassette transporter A7". Journal of Lipid Research. 51 (9): 2591–2599. doi:10.1194/jlr.M006049. PMC 2918442. PMID 20495215.
  20. ^ Costet P, Luo Y, Wang N, Tall AR (September 2000). "Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor". The Journal of Biological Chemistry. 275 (36): 28240–28245. doi:10.1074/jbc.M003337200. PMID 10858438.
  21. ^ Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, et al. (May 2011). "Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease". Nature Genetics. 43 (5): 429–435. doi:10.1038/ng.803. PMC 3084173. PMID 21460840.
  22. ^ Naj AC, Jun G, Beecham GW, Wang LS, Vardarajan BN, Buros J, et al. (May 2011). "Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease". Nature Genetics. 43 (5): 436–441. doi:10.1038/ng.801. PMC 3090745. PMID 21460841.
  23. ^ Reitz C, Jun G, Naj A, Rajbhandary R, Vardarajan BN, Wang LS, et al. (April 2013). "Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E ϵ4, and the risk of late-onset Alzheimer disease in African Americans". JAMA. 309 (14): 1483–1492. doi:10.1001/jama.2013.2973. PMC 3667653. PMID 23571587.
  24. ^ Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al. (December 2013). "Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease". Nature Genetics. 45 (12): 1452–1458. doi:10.1038/ng.2802. PMC 3896259. PMID 24162737.
  25. ^ Carrasquillo MM, Crook JE, Pedraza O, Thomas CS, Pankratz VS, Allen M, et al. (January 2015). "Late-onset Alzheimer's risk variants in memory decline, incident mild cognitive impairment, and Alzheimer's disease". Neurobiology of Aging. 36 (1): 60–67. doi:10.1016/j.neurobiolaging.2014.07.042. PMC 4268433. PMID 25189118.
  26. ^ Ramirez LM, Goukasian N, Porat S, Hwang KS, Eastman JA, Hurtz S, et al. (March 2016). "Common variants in ABCA7 and MS4A6A are associated with cortical and hippocampal atrophy". Neurobiology of Aging. 39: 82–89. doi:10.1016/j.neurobiolaging.2015.10.037. PMID 26923404. S2CID 195675085.
  27. ^ Schott JM, Crutch SJ, Carrasquillo MM, Uphill J, Shakespeare TJ, Ryan NS, et al. (August 2016). "Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease". Alzheimer's & Dementia. 12 (8): 862–871. doi:10.1016/j.jalz.2016.01.010. PMC 4982482. PMID 26993346.
  28. ^ Chen JA, Wang Q, Davis-Turak J, Li Y, Karydas AM, Hsu SC, et al. (April 2015). "A multiancestral genome-wide exome array study of Alzheimer disease, frontotemporal dementia, and progressive supranuclear palsy". JAMA Neurology. 72 (4): 414–422. doi:10.1001/jamaneurol.2014.4040. PMC 4397175. PMID 25706306.
  29. ^ Steinberg S, Stefansson H, Jonsson T, Johannsdottir H, Ingason A, Helgason H, et al. (May 2015). "Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease". Nature Genetics. 47 (5): 445–447. doi:10.1038/ng.3246. hdl:11250/296499. PMID 25807283. S2CID 205349727.
  30. ^ a b c Satoh K, Abe-Dohmae S, Yokoyama S, St George-Hyslop P, Fraser PE (October 2015). "ATP-binding cassette transporter A7 (ABCA7) loss of function alters Alzheimer amyloid processing". The Journal of Biological Chemistry. 290 (40): 24152–24165. doi:10.1074/jbc.M115.655076. PMC 4591804. PMID 26260791.
  31. ^ Sakae N, Liu CC, Shinohara M, Frisch-Daiello J, Ma L, Yamazaki Y, et al. (March 2016). "ABCA7 Deficiency Accelerates Amyloid-β Generation and Alzheimer's Neuronal Pathology". The Journal of Neuroscience. 36 (13): 3848–3859. doi:10.1523/JNEUROSCI.3757-15.2016. PMC 4812140. PMID 27030769.
  32. ^ Fu Y, Hsiao JH, Paxinos G, Halliday GM, Kim WS (September 2016). "ABCA7 Mediates Phagocytic Clearance of Amyloid-β in the Brain". Journal of Alzheimer's Disease. 54 (2): 569–584. doi:10.3233/JAD-160456. PMID 27472885.
  33. ^ Aikawa T, Ren Y, Yamazaki Y, Tachibana M, Johnson MR, Anderson CT, et al. (November 2019). "ABCA7 haplodeficiency disturbs microglial immune responses in the mouse brain". Proceedings of the National Academy of Sciences of the United States of America. 116 (47): 23790–23796. Bibcode:2019PNAS..11623790A. doi:10.1073/pnas.1908529116. PMC 6876254. PMID 31690660.
  34. ^ Zissimopoulos JM, Barthold D, Brinton RD, Joyce G (February 2017). "Sex and Race Differences in the Association Between Statin Use and the Incidence of Alzheimer Disease". JAMA Neurology. 74 (2): 225–232. doi:10.1001/jamaneurol.2016.3783. PMC 5646357. PMID 27942728.

Further reading

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This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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