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DNASE1 mutation in SLE
Arthritis Research & Therapyvolume 3, Article number: 70800 (2001)
The gene encoding DNASE1 is about 3.2 Kb with nine exons and eight introns. It is localized to chromosome 16p13.3. Systemic lupus erythematosus (SLE) is a multifactorial disease characterized by the presence of antinuclear antibodies (ANAs) directed against naked DNA and entire nucleosomes. Mice deficient in DNASE1 (knockout) were found to present with SLE-like symptoms, ANA-positive, deposition of immunocomplexes in the glomeruli and glomerulonephritis.
Sequencing DNASE1 of 20 Japanese SLE patients revealed two with an A ? G transversion at position +172 (exon 2), creating a premature stop codon at residue 5. The two patients were female and aged 13 years old and 17 years old with high anti-DNA and Sjorgen syndrome-A (SS-A) antibody titers. Both were heterezygous for the mutation and had substantially lower levels of DNASE1 activity than other SLE patients without the mutation and healthy controls. In addition, SLE patients without the DNASE1 mutation had lower enzyme activity than the healthy controls. The two patients with the DNASE1 mutation exhibited levels of nucleosomal antibodies seven to eight times higher than other SLE patients and 70-80 times greater than the healthy controls.
These results suggest that lower levels of DNASE1 contribute to the SLE pathophysiology. The mutation was uncommon in SLE patients. It was interesting that other family members, who shared the mutation, did not exhibit symptoms or signs of SLE. Reduced DNASE1 activity affects the rate of removal of chromatin and chromatin-protein complexes, which may influence the expansion of lymphocytes responsive to nuclear antigens. SLE patients who lack the described mutation appear to have lower levels of DNASE1 activity, suggesting that other polymorphisms may exist in the DNASE1 regulating elements. The gene DNASE1 does not map to an area known to be in linkage with SLE. This suggests that DNASE1 is a disease-modifying gene or a severity marker.
Napirei M, Karsunky H, Zevnik B, Stephan H, Mannherz HG, Moroy T: Features of systemic lupus erythematosus in Dnase1-deficient mice. Nat Genet 2000, 25:177-181 (PubMed abstract).
Yasutomo K, Horiuchi T, Kagami S, Tsukamoto H, Hashimura C, Urushihara M, Kuroda Y: Mutation of DNASE1in people with systemic lupus erythematosus. Nat Genet. 2001, 28: 313-314.