Deoxyribonuclease I gene polymorphism and susceptibility to systemic lupus erythematosus

Mohammadoo‐Khorasani, Milad; Musavi, Mahsa; Mousavi, Mahdieh; Moossavi, Maryam; Khoddamian, Maryam; Sandoughi, Mahnaz; Zakeri, Zahra

doi:10.1007/s10067-015-3111-y

Cited by 17 publications

(7 citation statements)

References 27 publications

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“…The presence of a 56-bp variable-number tandem repeat polymorphism (VNTR) with 6 types of different repeats in intron 4 of DNASE1 in linkage disequilibrium with SNP p.Gln244Arg was revealed 45 . Among these alleles, SLE patients showed a higher distribution of allele 5 than the controls 46,47 . The fact that allele 5, together with allele 4, in the VNTR is associated with the G allele in SNP p.Gln244Arg, producing a DNase I isoform with low activity, suggests that the VNTR in DNASE1 likely confers susceptibility to SLE.…”

Section: Discussionmentioning

confidence: 92%

Evaluation of the functional effects of genetic variants‒missense and nonsense SNPs, indels and copy number variations‒in the gene encoding human deoxyribonuclease I potentially implicated in autoimmunity

Ueki

Kimura-Kataoka

Fujihara

et al. 2019

Sci Rep

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Genetic variants, such as single nucleotide polymorphisms (SNPs), in the deoxyribonuclease I (DNase I) gene which remarkably reduce or abolish the activity are assumed to be substantially responsible for the genetic backgrounds determining susceptibility to autoimmune dysfunction. Here, we evaluated many genetic variants, including missense and nonsense SNPs, and indel (inframe) variants in the gene, potentially implicated in autoimmune diseases as functional variants resulting in altered activity levels. Eighteen missense and 7 nonsense SNPs, and 9 indel (inframe) variants were found to result in loss of function and disappearance of DNase I activity. Furthermore, considering the positions in the DNase I protein corresponding to the various nonsense SNPs, all of the other nonsense SNPs and frameshift variants registered in the Ensembl database (https://asia.ensembl.org) appear likely to exert a pathogenetic effect through loss of the activity. Accordingly, a total of 60 genetic variants in the DNase 1 gene (DNASE1) inducing abolishment or marked reduction of the DNase I activity could be identified as genetic risk factors for autoimmunity, irrespective of how sparsely they were distributed in the population. It was noteworthy that SNP p.Gln244Arg, reportedly associated with autoimmunity and reducing the activity to about half of that of the wild type, and SNP p.Arg107Gly, abolishing the activity completely, were distributed worldwide and in African populations at the polymorphic level, respectively. On the other hand, with regard to copy number variations in DNASE1 where loss of copy leads to a reduction of the in vivo enzyme activity, only 2 diploid copy numbers were distributed in Japanese and German populations, demonstrating no loss of copy. These exhaustive data for genetic variants in DNASE1 resulting in loss or marked reduction of the DNase I activity are highly informative when considering genetic predisposition leading to autoimmune dysfunction.

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Section: Discussionmentioning

confidence: 92%

Evaluation of the functional effects of genetic variants‒missense and nonsense SNPs, indels and copy number variations‒in the gene encoding human deoxyribonuclease I potentially implicated in autoimmunity

Ueki

Kimura-Kataoka

Fujihara

et al. 2019

Sci Rep

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“…Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by pathogenic autoantibody formation against the host's nuclear antigens, immune complex deposition, and end-organ damage 1 . The exact aetiology of this disease is unknown but genetic and environmental factors have important roles in SLE pathogenesis 2 . The prevalence of this disease in women is about 8-10 times more than men and in African Americans is about 3-4 times more than Caucasian Americans 3 .…”

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confidence: 99%

Interleukin-1β (IL-1β) & IL-4 gene polymorphisms in patients with systemic lupus erythematosus (SLE) & their association with susceptibility to SLE

et al. 2016

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Background & objectives:Interleukin-1 (IL-1) is one of the pro-inflammatory cytokines that plays a main role in the regulation of immune and inflammatory responses. Interleukin 4 (IL-4) as an anti-inflammatory cytokine regulates balance between Th1 and Th2 immune responses. This study was undertaken to investigate the IL-1β and IL-4 genes polymorphisms in patients with systemic lupus erythematosus (SLE) and also association between the polymorphisms and susceptibility to SLE.Methods:One hundred and sixty three SLE patients and 180 healthy controls were genotyped for the IL-4 VNTR (variable number tandem repeat), IL-1β C-511T and IL-1β T-31C polymorphisms by polymerase chain reaction (PCR) or PCR-RFLP (restriction fragment length polymorphism) method.Results:The frequencies of CC genotype and C allele of the IL-1β T-31C polymorphism were significantly (P<0.01) lower in SLE patients than controls. Moreover, the frequencies of RP1/RP2 genotype and RP2 allele of IL-4 VNTR polymorphism were significantly (P<0.05) higher in the SLE patients. No association was observed between IL-1β C-511T polymorphism and increased risk of SLE. We observed increased frequency of CT and TT genotypes of IL-1β C-511T polymorphism in SLE patients with malar rash compared to SLE patients without this manifestation.Interpretation & conclusions:The present findings suggest that IL-1β T-31C and IL-4 VNTR polymorphisms but not IL-1β C-511T polymorphism may contribute in SLE pathogenesis. In addition, CT and TT genotypes of IL-1β C-511T polymorphism were associated with SLE.

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“…Similarly, the involvement of DNASE1 in SLE pathogenesis in humans remains unclear. Genetic studies have identified a heterozygous non-sense mutation in DNASE1 of SLE patients (82) and single nucleotide polymorphisms (SNP) in DNASE1 that are associated with susceptibility to SLE (165,166). Nevertheless, follow up studies failed to shed light on mutations in DNASE1 in numerous cohorts of SLE patients (167-171).…”

Section: Extracellular Dnases: Key Regulators Of Cfdna-mediated Systementioning

confidence: 99%

The Role of Nucleases and Nucleic Acid Editing Enzymes in the Regulation of Self-Nucleic Acid Sensing

et al. 2021

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Detection of microbial nucleic acids by the innate immune system is mediated by numerous intracellular nucleic acids sensors. Upon the detection of nucleic acids these sensors induce the production of inflammatory cytokines, and thus play a crucial role in the activation of anti-microbial immunity. In addition to microbial genetic material, nucleic acid sensors can also recognize self-nucleic acids exposed extracellularly during turn-over of cells, inefficient efferocytosis, or intracellularly upon mislocalization. Safeguard mechanisms have evolved to dispose of such self-nucleic acids to impede the development of autoinflammatory and autoimmune responses. These safeguard mechanisms involve nucleases that are either specific to DNA (DNases) or RNA (RNases) as well as nucleic acid editing enzymes, whose biochemical properties, expression profiles, functions and mechanisms of action will be detailed in this review. Fully elucidating the role of these enzymes in degrading and/or processing of self-nucleic acids to thwart their immunostimulatory potential is of utmost importance to develop novel therapeutic strategies for patients affected by inflammatory and autoimmune diseases.

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Deoxyribonuclease I gene polymorphism and susceptibility to systemic lupus erythematosus

Cited by 17 publications

References 27 publications

Evaluation of the functional effects of genetic variants‒missense and nonsense SNPs, indels and copy number variations‒in the gene encoding human deoxyribonuclease I potentially implicated in autoimmunity

Evaluation of the functional effects of genetic variants‒missense and nonsense SNPs, indels and copy number variations‒in the gene encoding human deoxyribonuclease I potentially implicated in autoimmunity

Interleukin-1β (IL-1β) & IL-4 gene polymorphisms in patients with systemic lupus erythematosus (SLE) & their association with susceptibility to SLE

The Role of Nucleases and Nucleic Acid Editing Enzymes in the Regulation of Self-Nucleic Acid Sensing

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