DNASE1 – Systemic Lupus Erythematosus

Deoxyribonuclease I (DNASE1) encodes the principal extracellular endonuclease responsible for clearance of circulating DNA. Impaired DNase I activity is hypothesized to promote persistence of autoantigens, driving autoimmunity in systemic lupus erythematosus (MONDO:0007915). Monogenic forms of SLE have been linked to loss-of-function variants in nucleases, including DNASE1, suggesting a potential Mendelian contribution in subsets of patients.

Genetic evidence for DNASE1 in SLE remains sparse. Whole-genome sequencing of 71 Swedish SLE trios identified one ultra-rare heterozygous coding DNASE1 variant in a single proband, enriching rare variants in monogenic SLE genes (PMID:30707351). In contrast, targeted exon 2 screening in Tunisian SLE, rheumatoid arthritis and Sjögren syndrome cohorts failed to detect the previously reported K5X (c.??A>T) or 46_72del mutations in DNASE1 (PMID:19360410). Similarly, an early-onset SLE whole-exome study noted DNASE1 variants among other lupus-associated genes but without specific pathogenic allele assignment (PMID:35964089).

Functional assays provide moderate support for DNASE1’s role in autoimmunity. The DNASE1*6 allele (c.1826C>T (p.Arg185Cys)) yields an unstable isoenzyme with altered isoelectric focusing and decreased stability in COS-7 cells (PMID:10381379). High-throughput evaluation of missense and nonsense SNPs identified c.319A>G (p.Arg107Gly) as a loss-of-function variant abolishing nuclease activity (PMID:31541133). In Dnase1 knockout mice, selective loss of enzyme activity uncovered a novel anti-DNA clearance function, underscoring its relevance to autoantibody regulation (PMID:15015938).

Mechanistically, DNASE1 loss-of-function variants reduce extracellular chromatin degradation, leading to accumulation of immunogenic DNA and promoting type I interferon–mediated inflammation. Concordant in vitro instability assays and in vivo knockout models support a haploinsufficiency model whereby reduced enzyme activity predisposes to SLE.

No conflicting human genetic evidence has robustly refuted DNASE1 involvement; however, lack of recurrent pathogenic alleles and negative screens emphasize the need for larger cohorts. Functional data exceed the current genetic case count, suggesting additional rare variants remain to be discovered.

In summary, DNASE1 exhibits limited genetic evidence but moderate functional support for an autosomal recessive loss-of-function mechanism in SLE. While routine DNASE1 screening is not yet clinically actionable, functional assays highlight its potential as a biomarker and therapeutic target for precision management of SLE.

References

• Human genetics • 2019 • Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus. PMID:30707351
• Pediatric rheumatology online journal • 2022 • Characteristics and genetic analysis of patients suspected with early-onset systemic lupus erythematosus. PMID:35964089
• Rheumatology international • 2009 • DNase1 exon2 analysis in Tunisian patients with rheumatoid arthritis, systemic lupus erythematosus and Sjögren syndrome and healthy subjects. PMID:19360410
• Biochemical and biophysical research communications • 1999 • A new allele, DNASE1*6, of human deoxyribonuclease I polymorphism encodes an Arg to Cys substitution responsible for its instability. PMID:10381379
• Scientific reports • 2019 • 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. PMID:31541133
• The Biochemical journal • 2004 • Expression pattern of the deoxyribonuclease 1 gene: lessons from the Dnase1 knockout mouse. PMID:15015938

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