A Comprehensive In Silico Analysis of the Functional and Structural Impact of Nonsynonymous SNPs in the ABCA1 Transporter Gene

Overview

Journal Cholesterol

Date 2014 Sep 13

PMID 25215231

Citations 8

Authors

Francisco R Marin-Martin

Cristina Soler-Rivas

Roberto Martin-Hernandez

Arantxa Rodriguez-Casado

Affiliations

Soon will be listed here.

Abstract

Disease phenotypes and defects in function can be traced to nonsynonymous single nucleotide polymorphisms (nsSNPs), which are important indicators of action sites and effective potential therapeutic approaches. Identification of deleterious nsSNPs is crucial to characterize the genetic basis of diseases, assess individual susceptibility to disease, determinate molecular and therapeutic targets, and predict clinical phenotypes. In this study using PolyPhen2 and MutPred in silico algorithms, we analyzed the genetic variations that can alter the expression and function of the ABCA1 gene that causes the allelic disorders familial hypoalphalipoproteinemia and Tangier disease. Predictions were validated with published results from in vitro, in vivo, and human studies. Out of a total of 233 nsSNPs, 80 (34.33%) were found deleterious by both methods. Among these 80 deleterious nsSNPs found, 29 (12.44%) rare variants resulted highly deleterious with a probability >0.8. We have observed that mostly variants with verified functional effect in experimental studies are correctly predicted as damage variants by MutPred and PolyPhen2 tools. Still, the controversial results of experimental approaches correspond to nsSNPs predicted as neutral by both methods, or contradictory predictions are obtained for them. A total of seventeen nsSNPs were predicted as deleterious by PolyPhen2, which resulted neutral by MutPred. Otherwise, forty two nsSNPs were predicted as deleterious by MutPred, which resulted neutral by PolyPhen2.

Citing Articles

Impact of highly deleterious non-synonymous polymorphisms on GRIN2A protein's structure and function.

Ahammad I, Jamal T, Bhattacharjee A, Chowdhury Z, Rahman S, Hassan M PLoS One. 2023; 18(6):e0286917.

PMID: 37319252 PMC: 10270607. DOI: 10.1371/journal.pone.0286917.

Insilico prediction and functional analysis of nonsynonymous SNPs in human CTLA4 gene.

Irfan M, Iqbal T, Hashmi S, Ghani U, Bhatti A Sci Rep. 2022; 12(1):20441.

PMID: 36443461 PMC: 9705290. DOI: 10.1038/s41598-022-24699-0.

A comprehensive in silico investigation into the nsSNPs of Drd2 gene predicts significant functional consequences in dopamine signaling and pharmacotherapy.

Lira S, Ahammad I Sci Rep. 2021; 11(1):23212.

PMID: 34853389 PMC: 8636637. DOI: 10.1038/s41598-021-02715-z.

Computational SNP Analysis and Molecular Simulation Revealed the Most Deleterious Missense Variants in the NBD1 Domain of Human ABCA1 Transporter.

Dash R, Ali M, Rana M, Munni Y, Barua L, Jahan I Int J Mol Sci. 2020; 21(20).

PMID: 33066695 PMC: 7589834. DOI: 10.3390/ijms21207606.

In silico analysis on the functional and structural impact of Rad50 mutations involved in DNA strand break repair.

Remali J, Aizat W, Ng C, Lim Y, Mohamed-Hussein Z, Fazry S PeerJ. 2020; 8:e9197.

PMID: 32509463 PMC: 7247530. DOI: 10.7717/peerj.9197.

References

Ho Hong S, Rhyne J, Zeller K, Miller M . ABCA1(Alabama): a novel variant associated with HDL deficiency and premature coronary artery disease. Atherosclerosis. 2002; 164(2):245-50. DOI: 10.1016/s0021-9150(02)00106-5. View

Frikke-Schmidt R, Sing C, Nordestgaard B, Tybjaerg-Hansen A . Gender- and age-specific contributions of additional DNA sequence variation in the 5' regulatory region of the APOE gene to prediction of measures of lipid metabolism. Hum Genet. 2004; 115(4):331-45. DOI: 10.1007/s00439-004-1165-z. View

Wellington C, Yang Y, Zhou S, Clee S, Tan B, Hirano K . Truncation mutations in ABCA1 suppress normal upregulation of full-length ABCA1 by 9-cis-retinoic acid and 22-R-hydroxycholesterol. J Lipid Res. 2002; 43(11):1939-49. DOI: 10.1194/jlr.m200277-jlr200. View

Schaefer E, Zech L, Schwartz D, BREWER Jr H . Coronary heart disease prevalence and other clinical features in familial high-density lipoprotein deficiency (Tangier disease). Ann Intern Med. 1980; 93(2):261-6. DOI: 10.7326/0003-4819-93-2-261. View

Sorrenson B, Suetani R, Williams M, Bickley V, George P, Jones G . Functional rescue of mutant ABCA1 proteins by sodium 4-phenylbutyrate. J Lipid Res. 2012; 54(1):55-62. PMC: 3520540. DOI: 10.1194/jlr.M027193. View

Sundar P, Feingold E, Minster R, DeKosky S, Kamboh M . Gender-specific association of ATP-binding cassette transporter 1 (ABCA1) polymorphisms with the risk of late-onset Alzheimer's disease. Neurobiol Aging. 2006; 28(6):856-62. DOI: 10.1016/j.neurobiolaging.2006.04.005. View

Fitzgerald M, Mendez A, Moore K, Andersson L, Panjeton H, Freeman M . ATP-binding cassette transporter A1 contains an NH2-terminal signal anchor sequence that translocates the protein's first hydrophilic domain to the exoplasmic space. J Biol Chem. 2001; 276(18):15137-45. DOI: 10.1074/jbc.m100474200. View

Walter M, Kerber S, Fechtrup C, Seedorf U, Breithardt G, Assmann G . Characterization of atherosclerosis in a patient with familial high-density lipoprotein deficiency. Atherosclerosis. 1994; 110(2):203-8. DOI: 10.1016/0021-9150(94)90205-4. View

Wavrant-De Vrieze F, Compton D, Womick M, Arepalli S, Adighibe O, Li L . ABCA1 polymorphisms and Alzheimer's disease. Neurosci Lett. 2007; 416(2):180-3. PMC: 1945126. DOI: 10.1016/j.neulet.2007.02.010. View

10.

Slatter T, Williams M, Frikke-Schmidt R, Tybjaerg-Hansen A, Morison I, McCormick S . Promoter haplotype of a new ABCA1 mutant influences expression of familial hypoalphalipoproteinemia. Atherosclerosis. 2005; 187(2):393-400. DOI: 10.1016/j.atherosclerosis.2005.09.019. View

11.

Jensen M, Pai J, Mukamal K, Overvad K, Rimm E . Common genetic variation in the ATP-binding cassette transporter A1, plasma lipids, and risk of coronary heart disease. Atherosclerosis. 2007; 195(1):e172-80. DOI: 10.1016/j.atherosclerosis.2007.01.025. View

12.

Kolovou V, Marvaki A, Karakosta A, Vasilopoulos G, Kalogiani A, Mavrogeni S . Association of gender, ABCA1 gene polymorphisms and lipid profile in Greek young nurses. Lipids Health Dis. 2012; 11:62. PMC: 3391977. DOI: 10.1186/1476-511X-11-62. View

13.

Brunham L, Kruit J, Iqbal J, Fievet C, Timmins J, Pape T . Intestinal ABCA1 directly contributes to HDL biogenesis in vivo. J Clin Invest. 2006; 116(4):1052-62. PMC: 1401485. DOI: 10.1172/JCI27352. View

14.

Brunham L, Singaraja R, Duong M, Timmins J, Fievet C, Bissada N . Tissue-specific roles of ABCA1 influence susceptibility to atherosclerosis. Arterioscler Thromb Vasc Biol. 2009; 29(4):548-54. DOI: 10.1161/ATVBAHA.108.182303. View

15.

Lawn R, Wade D, Garvin M, Wang X, Schwartz K, Porter J . The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway. J Clin Invest. 1999; 104(8):R25-31. PMC: 481052. DOI: 10.1172/JCI8119. View

16.

Albrecht C, Baynes K, Sardini A, Schepelmann S, Eden E, Davies S . Two novel missense mutations in ABCA1 result in altered trafficking and cause severe autosomal recessive HDL deficiency. Biochim Biophys Acta. 2004; 1689(1):47-57. DOI: 10.1016/j.bbadis.2004.01.007. View

17.

Remaley A, Neufeld E, BREWER Jr H . Regulation and intracellular trafficking of the ABCA1 transporter. J Lipid Res. 2001; 42(9):1339-45. View

18.

Fitz N, Cronican A, Saleem M, Fauq A, Chapman R, Lefterov I . Abca1 deficiency affects Alzheimer's disease-like phenotype in human ApoE4 but not in ApoE3-targeted replacement mice. J Neurosci. 2012; 32(38):13125-36. PMC: 3646580. DOI: 10.1523/JNEUROSCI.1937-12.2012. View

19.

Nishida Y, Hirano K, Tsukamoto K, Nagano M, Ikegami C, Roomp K . Expression and functional analyses of novel mutations of ATP-binding cassette transporter-1 in Japanese patients with high-density lipoprotein deficiency. Biochem Biophys Res Commun. 2002; 290(2):713-21. DOI: 10.1006/bbrc.2001.6219. View

20.

Wang S, Gulshan K, Brubaker G, Hazen S, Smith J . ABCA1 mediates unfolding of apolipoprotein AI N terminus on the cell surface before lipidation and release of nascent high-density lipoprotein. Arterioscler Thromb Vasc Biol. 2013; 33(6):1197-205. PMC: 3701943. DOI: 10.1161/ATVBAHA.112.301195. View