Association of the DNASE1L3 rs35677470 polymorphism with systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis: Structural biological insights

Zervou,Maria I.; Andreou,Athena; Matalliotakis,Michail; Spandidos,Demetrios A.; Goulielmos,George N.; Eliopoulos,Elias E.

doi:10.3892/mmr.2020.11547

Association of the DNASE1L3 rs35677470 polymorphism with systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis: Structural biological insights

Authors:
- Maria I. Zervou
- Athena Andreou
- Michail Matalliotakis
- Demetrios A. Spandidos
- George N. Goulielmos
- Elias E. Eliopoulos
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Affiliations: Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, 71003 Heraklion, Greece, Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, 11855 Athens, Greece, Laboratory of Clinical Virology, School of Medicine, University of Crete, 71003 Heraklion, Greece
Published online on: September 29, 2020 https://doi.org/10.3892/mmr.2020.11547
Pages: 4492-4498

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Abstract

Although genome‑wide association studies (GWAS) have identified hundreds of autoimmune disease‑associated loci, much of the genetics underlying these diseases remains unknown. In an attempt to identify potential causal variants, previous studies have determined that the rs35677470 missense variant of the Deoxyribonuclease I‑like 3 (DNASE1L3) gene was associated with the development of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and systemic sclerosis (SSc). DNase1L3 is a member of the human DNase I family, representing a nuclease that cleaves double‑stranded DNA during apoptosis and serving a role in the development of autoimmune diseases. The present study aimed to determine the role of the rs35677470 variant at the DNASE1L3 gene leading to the R206C mutation in SLE, RA and SSc. The underlying mechanism potentially affecting protein structure loss of function was also assessed. DNASE1L3 evolution was investigated to define conservation elements in the protein sequence. Additionally, 3D homology modeling and in silico mutagenesis was performed to localize the polymorphism under investigation. Evolutionary analysis revealed heavily conserved sequence elements among species, indicating structural/functional importance. In silico mutagenesis and 3D protein structural analysis also demonstrated the potentially varied impact of the DNASE1L3 (rs35677470) single nucleotide polymorphism (SNP), providing an explanation for its effect on the R206C variant. Structural analysis demonstrated that the rs35677470 SNP encodes a non‑conservative amino acid variation, R206C, which disrupted the conserved electrostatic network holding secondary protein structure elements in position. Specifically, the R206 to E170 interaction forming part of a salt bridge network stabilizing two α‑helices was interrupted, thereby affecting the molecular architecture. Previous studies on the effect of this SNP in Caucasian populations demonstrated lower DNAse1L3 activity levels, which is consistent with the current results. The present study comprehensively evaluated the shared autoimmune locus of DNASE1L3 (rs35677470), which produced an inactive form of DNaseIL3. Furthermore, structural analysis explained the potential role of the produced mutation by modifying the placement of structural elements and consequently introducing disorder in protein folding, affecting biological function.

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1	Goulielmos GN, Zervou MI, Myrthianou E, Burska A, Niewold TB and Ponchel F: Genetic data: The new challenge of personalized medicine, insights for rheumatoid arthritis patients. Gene. 583:90–101. 2016. View Article : Google Scholar : PubMed/NCBI
2	Ramos PS, Criswell LA, Moser KL, Comeau ME, Williams AH, Pajewski NM, Chung SA, Graham RR, Zidovetzki R, Kelly JA, et al: A comprehensive analysis of shared loci between systemic lupus erythematosus (SLE) and sixteen autoimmune diseases reveals limited genetic overlap. PLoS Genet. 7:e10024062011. View Article : Google Scholar : PubMed/NCBI
3	Martín JE, Bossini-Castillo L and Martín J: Unraveling the genetic component of systemic sclerosis. Hum Genet. 131:1023–1037. 2012. View Article : Google Scholar : PubMed/NCBI
4	International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN), ; Harley JB, Alarcón-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Moser KL, Tsao BP, Vyse TJ, Langefeld CD, et al: Genomewide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet. 40:204–210. 2008. View Article : Google Scholar : PubMed/NCBI
5	Gateva V, Sandling JK, Hom G, Taylor KE, Chung SA, Sun X, Ortmann W, Kosoy R, Ferreira RC, Nordmark G, et al: A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genet. 41:1228–1233. 2009. View Article : Google Scholar : PubMed/NCBI
6	Westra HJ, Martínez-Bonet M, Onengut-Gumuscu S, Lee A, Luo Y, Teslovich N, Worthington J, Martin J, Huizinga T, Klareskog L, et al: Fine-mapping and functional studies highlight potential causal variants for rheumatoid arthritis and type 1 diabetes. Nat Genet. 50:1366–1374. 2018. View Article : Google Scholar : PubMed/NCBI
7	Zochling J, Newell F, Charlesworth JC, Leo P, Stankovich J, Cortes A, Zhou Y, Stevens W, Sahhar J, Roddy J, et al: An ImmunoChip-based interrogation of scleroderma susceptibility variants identifies a novel association at DNASE1L3. Arthritis Res Ther. 16:4382014. View Article : Google Scholar : PubMed/NCBI
8	Sisirak VB, Sally B, D'Agati V, Martinez-Ortiz W, Özçakar ZB, David J, Rashidfarrokhi A, Yeste A, Panea C, Chida AS, et al: Digestion of chromatin in apoptotic cell microparticles prevents autoimmunity. Cell. 166:88–101. 2016. View Article : Google Scholar : PubMed/NCBI
9	Rodriguez AM, Rodin D, Nomura H, Morton CC, Weremowicz S and Schneider MC: Identification, localization, and expression of two novel human genes similar to deoxyribonuclease I. Genomics. 42:507–513. 1997. View Article : Google Scholar : PubMed/NCBI
10	Zeng Z, Parmelee D, Hyaw H, Coleman TA, Su K, Zhang J, Gentz R, Ruben S, Rosen C and Li Y: Cloning and characterization of a novel human DNase. Biochem Biophys Res Commun. 23:499–504. 1997. View Article : Google Scholar
11	Chen WJ, Lee IS, Chen CY and Liao TH: Biological functions of the disulfides in bovine pancreatic deoxyribonuclease. Protein Sci. 13:875–883. 2004. View Article : Google Scholar : PubMed/NCBI
12	Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, Liang MH, Kremers HM, Mayes MD, Merkel PA, et al: Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 58:15–25. 2008. View Article : Google Scholar : PubMed/NCBI
13	Firestein GS: Evolving concepts of rheumatoid arthritis. Nature. 423:356–361. 2003. View Article : Google Scholar : PubMed/NCBI
14	McAllister KM, Eyre S and Orozco G: Genetics of rheumatoid arthritis: GWAS and beyond. Open Access Rheumatology Res Rev. 3:31–46. 2013.
15	Gabrielli A, Avvedimento EV and Krieg T: Scleroderma. N Engl J Med. 360:1989–2003. 2009. View Article : Google Scholar : PubMed/NCBI
16	Barnes J and Mayes MD: Epidemiology of systemic sclerosis: Incidence, prevalence, survival, risk factors, malignancy, and environmental triggers. Curr Opin Rheumatol. 24:165–170. 2012. View Article : Google Scholar : PubMed/NCBI
17	Chizzolini C: T cells, B cells, and polarized immune response in the pathogenesisof fibrosis and systemic sclerosis. Curr Opin Rheumatol. 20:707–712. 2008. View Article : Google Scholar : PubMed/NCBI
18	Wallace B, Vummidi D and Khanna D: Management of connective tissue diseases associated interstitial lung disease: A review of the published literature. Curr Opin Rheumatol. 28:236–245. 2016. View Article : Google Scholar : PubMed/NCBI
19	Liu Z and Davidson A: Taming lupus-a new understanding of pathogenesis is leading to clinical advances. Nat Med. 18:871–882. 2012. View Article : Google Scholar : PubMed/NCBI
20	UniProt Consortium: UniProt: A worldwide hub of protein knowledge. Nucleic Acids Res. 47:D506–D515. 2019. View Article : Google Scholar : PubMed/NCBI
21	Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN and Bourne PE: The protein data bank. Nucleic Acids Res. 28:235–242. 2000. View Article : Google Scholar : PubMed/NCBI
22	Altschul SF, Madden TL, Schäffer AA, Zhang J, Zhang Z, Miller W and Lipman DJ: Gapped BLAST and PSI-BLAST: A new generation of protein database search programs. Nucleic Acids Res. 25:3389–3402. 1997. View Article : Google Scholar : PubMed/NCBI
23	Notredame C, Higgins DG and Heringa J: A novel method for fast and accurate multiple sequence alignment. Mol Biol. 302:205–217. 2000. View Article : Google Scholar
24	Robert X and Gouet P: Deciphering key features in protein structures with the new ENDscript server. Nucleic Acids Res. 42((Web Server Issue)): W320–W324. 2014. View Article : Google Scholar : PubMed/NCBI
25	Gouet P, Robert X and Courcelle E: ESPript/ENDscript: Extracting and rendering sequence and 3D information from atomic structures of proteins. Nucleic Acids Res. 31:3320–3323. 2003. View Article : Google Scholar : PubMed/NCBI
26	Felsenstein J: Confidence limits on phylogenies: An approach using the bootstrap. Evolution. 39:783–791. 1985. View Article : Google Scholar : PubMed/NCBI
27	Kumar S, Stecher G and Tamur K: MEGA7: Molecular evolutionary genetics analysis version 7.0 for bigger datasets. Mol Biol Evol. 33:870–1874. 2016. View Article : Google Scholar : PubMed/NCBI
28	Felsenstein J: Evolutionary trees from DNA sequences: A maximum likelihood approach. J Mol Evol. 17:368–376. 1981. View Article : Google Scholar : PubMed/NCBI
29	Saitou N and Nei M: The neighbor-joining method: A new method for reconstructing phylogenetic trees. Mol Biol Evol. 4:406–425. 1987.PubMed/NCBI
30	Gascuel O: BIONJ: An improved version of the NJ algorithm based on a simple model of sequence data. Mol Biol Evol. 14:685–695. 1997. View Article : Google Scholar : PubMed/NCBI
31	Tamura K, Nei M and Kumar S: Prospects for inferring very large phylogenies by using the neighbor-joining method. Proc Natl Acad Sci USA. 101:11030–11035. 2004. View Article : Google Scholar : PubMed/NCBI
32	Waterhouse A, Bertoni M, Bienert S, Studer G, Tauriello G, Gumienny R, Heer FT, de Beer TAP, Rempfer C, Bordoli L, et al: SWISS-MODEL: Homology modelling of protein structures and complexes. Nucleic Acids Res. 46:W296–W303. 2018. View Article : Google Scholar : PubMed/NCBI
33	Kabsch W, Mannherz HG, Suck D, Pai EF and Holmes KC: Atomic structure of the actin: DNase I complex. Nature. 347:37–44. 1990. View Article : Google Scholar : PubMed/NCBI
34	Parsiegla G, Noguere C, Santell L, Lazarus RA and Bourne Y: The structure of human DNase I bound to magnesium and phosphate ions points to a catalytic mechanism common to members of the DNase I-like superfamily. Biochemistry. 51:10250–10258. 2012. View Article : Google Scholar : PubMed/NCBI
35	Sasaki K, Sakabe K, Sakabe N, Kondo H and Shimomura M: Refined structure and solvent network of chicken gizzard G-actin DNase 1 complex at 1.8Å resolution. Acta Cryst. A49:C111–C112. 1993. View Article : Google Scholar
36	The PyMOL molecular graphics system, version 1.7.4. Schrödinger, LLC; simplehttp://www.pymol.org
37	Andreou A, Giastas P, Christoforides E and Eliopoulos EE: Structural and evolutionary insights within the polysaccharide deacetylase gene family of Bacillus anthracis and Bacillus cereus. Genes (Basel). 9:3862018. View Article : Google Scholar
38	Ueki M, Takeshita H, Fujihara J, Iida R, Yuasa I, Kato H, Panduro A, Nakajima T, Kominato Y and Yasuda T: Caucasian-specific allele in non-synonymous single nucleotide polymorphisms of the gene encoding deoxyribonuclease I-like 3, potentially relevant to autoimmunity, produces an inactive enzyme. Clin Chim Acta. 407:20–24. 2009. View Article : Google Scholar : PubMed/NCBI
39	Ueki M, Fujihara J, Takeshita H, Kimura-Kataoka K, Iida R, Yuasa I, Kato H and Yasuda T: Global genetic analysis of all single nucleotide polymorphisms in exons of the human deoxyribonuclease I-like 3 gene and their effect on its catalytic activity. Electrophoresis. 32:1465–1472. 2011. View Article : Google Scholar : PubMed/NCBI
40	López-Isac E, Acosta-Herrera M, Kerick M, Assassi S, Satpathy AT, Granja J, Mumbach MR, Beretta L, Simeón CP, Carreira P, et al: GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways. Nat Commun. 10:49552019. View Article : Google Scholar : PubMed/NCBI
41	Mayes MD, Bossini-Castillo L, Gorlova O, Martin JE, Zhou X, Chen WV, Assassi S, Ying J, Tan FK, Arnett FC, et al: Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis. Am J Hum Genet. 94:47–61. 2014. View Article : Google Scholar : PubMed/NCBI
42	Al-Mayouf SM, Sunker A, Abdwani R, Abrawi SA, Almurshedi F, Alhashmi N, Al Sonbul A, Sewairi W, Qari A, Abdallah E, et al: Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus. Nat Genet. 43:1186–1188. 2011. View Article : Google Scholar : PubMed/NCBI
43	Zhao Q, Yang C, Wang J, Li Y and Yang P: Serum level of DNase1l3 in patients with dermatomyositis/polymyositis, systemic lupus erythematosus and rheumatoid arthritis, and its association with disease activity. Clin Exp Med. 17:459–465. 2017. View Article : Google Scholar : PubMed/NCBI
44	Serpas L, Chan RWY, Jiang P, Ni M, Sun K, Rashidfarrokhi A, Soni C, Sisirak V, Lee WS, Cheng SH, et al: Dnase1l3 deletion causes aberrations in length and end-motif frequencies in plasma DNA. Proc Natl Acad Sci USA. 11:641–649. 2019. View Article : Google Scholar
45	Moser K, Kelly J, Lessard C and Harley JB: Recent insights into the genetic basis of systemic lupus erythematosus. Genes Immun. 10:373–379. 2009. View Article : Google Scholar : PubMed/NCBI
46	Goulielmos GN, Zervou MI, Vazgiourakis VM, Ghodke-Puranik Y, Garyfallos A and Niewold TB: The genetics and molecular pathogenesis of systemic lupus erythematosus (SLE) in populations of different ancestry. Gene. 668:59–72. 2018. View Article : Google Scholar : PubMed/NCBI
47	Niewold TB: Interferon alpha-induced lupus: Proof of principle. J Clin Rheumatol. 14:131–132. 2008. View Article : Google Scholar : PubMed/NCBI
48	Ko K, Koldobskaya Y, Rosenzweig E and Niewold TB: Activation of the interferon pathway is dependent upon autoantibodies in African-American SLE patients, but not in European-American SLE patients. Front Immunol. 4:3092013. View Article : Google Scholar : PubMed/NCBI
49	Rahman A and Isenberg DA: Systemic lupus erythematosus. N Engl J Med. 358:929–939. 2008. View Article : Google Scholar : PubMed/NCBI
50	Márquez A, Kerick M, Zhernakova A, Gutierrez-Achury J, Chen WM, Onengut-Gumuscu S, González-Álvaro I, Rodriguez- Rodriguez L, Rios-Fernández R, González-Gay MA, et al: Meta-analysis of Immunochip data of four autoimmune diseases reveals novel single-disease and cross-phenotype associations. Genome Med. 10:972018. View Article : Google Scholar : PubMed/NCBI