Key result
The DNASE1L3 rs35677470 polymorphism (R206C) disrupts a conserved electrostatic salt bridge network, destabilizing the protein's secondary structure and potentially impairing its biological function.
Why the study?
The rs35677470 variant of DNASE1L3 is associated with SLE, RA, and SSc, but the role of this variant and the structural mechanism affecting protein loss of function remained to be determined.
Structural analysis reveals that the rs35677470 polymorphism in DNASE1L3 disrupts a critical salt bridge network, leading to an inactive enzyme form associated with autoimmune diseases like SLE, RA, and SSc.
Provides structural rationale for DNase1L3 deficiency in autoimmunity; leaves open clinical utility of variant screening or targeted therapies.
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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Zervou et al. (2020) studied Systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis. DNASE1L3 rs35677470 polymorphism (R206C mutation) vs. Wild-type DNASE1L3 was evaluated on Protein structural stability and salt bridge network disruption. The DNASE1L3 rs35677470 polymorphism (R206C) disrupts a conserved electrostatic salt bridge network, destabilizing the protein's secondary structure and potentially impairing its biological function.
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