Impaired Deoxyribonuclease Activity in Monoglandular and Polyglandular Autoimmunity

Dittmar, Manuela; Poppe, Robert; Bischofs, Christian; Fredenhagen, G.; Kanitz, Michael; Kahaly, George J.

doi:10.1055/s-2007-967082

Cited by 12 publications

(9 citation statements)

References 17 publications

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“…These findings allow us to conclude that DNASE1 is able to tolerate the generation of non-synonymous SNPs, and furthermore that the amino acid substitutions resulting from the SNPs easily create alterations in the levels of enzyme activity in comparison with DNASE1L3. It has been reported that, in comparison with healthy subjects, levels of serum DNase I activity are reduced in patients with SLE [36][37][38][39]. Recently, Rekvig and colleagues have demonstrated that in lupus nephritis, which is the most serious complication of SLE, downregulation of renal DNase I results in reduced chromatin fragmentation and deposition of extracellular chromatin-IgG complexes in the glomerular basement membranes in subjects that produce IgG antibodies against chromatin [8,40].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of all non‐synonymous single nucleotide polymorphisms (SNPs) in the genes encoding human deoxyribonuclease I and I‐like 3 as a functional SNP potentially implicated in autoimmunity

et al. 2013

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The objectives of this study were to evaluate all the non-synonymous single nucleotide polymorphisms (SNPs) in the DNase I and DNase I-like 3 (1L3) genes potentially implicated in autoimmune diseases as a functional SNP in terms of alteration of the activity levels. We examined the genotype distributions of the 32 and 20 non-synonymous SNPs in DNASE1 and DNASE1L3, respectively, in three ethnic groups, and the effect of these SNPs on the DNase activities. Among a total of 44 and 25 SNPs including those characterized in our previous studies [Yasuda et al., Int J Biochem Cell Biol 42 (2010) 1216-1225; Ueki et al. Electrophoresis 32 (2012) 1465-1472], only four and one, respectively, exhibited genetic heterozygosity in one or all of the ethnic groups examined. On the basis of alterations in the activity levels resulting from the corresponding amino acid substitutions, 11 activity-abolishing and 11 activity-reducing SNPs in DNASE1 and two activity-abolishing and five activity-reducing SNPs in DNASE1L3 were confirmed as a functional SNP. Phylogenetic analysis showed that all of the amino acid residues in activity-abolishing SNPs were completely or well conserved in animal DNase I and 1L3 proteins. Although almost all non-synonymous SNPs in both genes that affected the catalytic activity showed extremely low genetic heterogeneity, it seems plausible that a minor allele of 13 activity-abolishing SNPs producing a loss-of-function variant in both the DNase genes would be a direct genetic risk factor for autoimmune diseases. These findings may have clinical implications in relation to the prevalence of autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

Evaluation of all non‐synonymous single nucleotide polymorphisms (SNPs) in the genes encoding human deoxyribonuclease I and I‐like 3 as a functional SNP potentially implicated in autoimmunity

et al. 2013

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“…It catalyzes DNA hydrolysis by cleaving double-stranded DNA. The activity of this enzyme was lowered in patients with PAS compared to healthy subjects (21,22). Such a deficiency in DNase 1 may result in reduced or delayed removal of DNA from nuclear antigens and, thereby, may promote disease susceptibility to autoimmune disorders.…”

Section: Innate Immunity and The Enzyme Deoxyribonucleasementioning

confidence: 94%

“…Decreased serum DNase activity with elevated levels of circulating DNA and resulting activation of the TLR9 immunostimulating pathway can also trigger organ-specific autoimmune disease. Most of the natural insulin Abs are polyreactive and bind in addition to insulin one or more antigens including thyroglobulin (Tg), IgG and DNA (21). Complexes containing DNA between polyreactive natural Abs, i.e.…”

Section: Innate Immunity and The Enzyme Deoxyribonucleasementioning

confidence: 99%

Polyglandular autoimmune syndromes

Kahaly

2009

European Journal of Endocrinology

206

106

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The polyglandular autoimmune syndromes (PAS) comprise a wide spectrum of autoimmune disorders and are divided into a very rare juvenile (PAS type I) and a relatively common adult type with (PAS II) or without adrenal failure (PAS III). First clinical manifestation of PAS I usually occurs in childhood, whereas PAS II mostly occurs during the third and fourth decades. PAS I is caused by mutations in the autoimmune regulatory (AIRE) gene on chromosome 21 and is inherited in an autosomal recessive manner. Mutations in the AIRE gene result in defect proteins which cause autoimmune destruction of target organs by disturbing the immunological tolerance of the patients. Genetic testing may identify patients with PAS I, but not those with PAS II/III. For PAS II/III, susceptibility genes are known which increase the risk for developing autoimmune disorders, but must not be causative. These are certain HLA genes, the cytotoxic T lymphocyte antigen gene, and the protein tyrosine phosphatase nonreceptor type 22 gene on chromosomes 6, 2 and 1 respectively. Actual diagnosis of PAS involves serological measurement of organ-specific autoantibodies and subsequent functional testing. Management of patients with PAS including their family relatives is best performed in centres with special expertise in autoimmune endocrine disorders.

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“…Blood samples were drawn in the morning and serum samples were immediately frozen at À20 C. Serum DNase activity was determined with a standardized, validated, and reproducible enzyme-linked-immunosorbent assay, as described earlier [20]. In brief, DNase substrate was used as a solid phase and the serum DNase degraded the DNase substrate.…”

Section: Measurement Of Dnase Activitymentioning

confidence: 99%

“…Recently, we have shown impaired DNase activity in patients with endocrine autoimmunity [20]. But so far, no molecular studies were performed in the DNASE1 gene in these patients.…”

Section: Introductionmentioning

confidence: 99%

A novel mutation in the DNASE1 gene is related with protein instability and decreased enzyme activity in thyroid autoimmunity

Dittmar

Bischofs

Matheis

et al. 2009

Journal of Autoimmunity

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Impaired Deoxyribonuclease Activity in Monoglandular and Polyglandular Autoimmunity

Cited by 12 publications

References 17 publications

Evaluation of all non‐synonymous single nucleotide polymorphisms (SNPs) in the genes encoding human deoxyribonuclease I and I‐like 3 as a functional SNP potentially implicated in autoimmunity

Evaluation of all non‐synonymous single nucleotide polymorphisms (SNPs) in the genes encoding human deoxyribonuclease I and I‐like 3 as a functional SNP potentially implicated in autoimmunity

Polyglandular autoimmune syndromes

A novel mutation in the DNASE1 gene is related with protein instability and decreased enzyme activity in thyroid autoimmunity

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