Alternative titles; symbols
HGNC Approved Gene Symbol: DNASE1
Cytogenetic location: 16p13.3 Genomic coordinates (GRCh38): 16:3,611,760-3,665,461 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.3 | {Systemic lupus erythematosus, susceptibility to} | 152700 | Autosomal dominant | 3 |
Deoxyribonuclease I (DNase I; EC 3.1.21.1), the first-discovered DNase, is an endonuclease that produces 5-prime phosphoryl dinucleotides and 5-prime phosphoryl oligonucleotides and occurs in different tissues and body fluids (summary by Kishi et al., 1990).
Kishi et al. (1989) isolated a DNase I from human urine and found heritable isozyme forms after analysis by polyacrylamide gel electrophoresis-isoelectric focusing (IEF-PAGE), followed by immunoblotting with anti-DNase antibody. The enzyme is a sialylated glycoprotein with a molecular mass of about 38,000.
Yasuda et al. (1995) determined that the DNASE1 gene is approximately 3.2 kb long with 9 exons separated by 8 introns. The first exon contains only the nontranslated sequences of mRNA. In addition to several putative regulatory elements, they observed TATA-like and CAAT-like sequences in the putative promoter region upstream of the translation initiation codon.
To localize the DNL1 gene, Yasuda et al. (1995) performed PCR using DNA extracted from a panel of cloned human/rodent hybrid cell lines carrying different human chromosomes. They could assign the DNL1 gene to human chromosome 16. Furthermore, regional localization to 16p13.3 was performed by PCR analysis of a high-resolution mouse/human somatic cell hybrid panel that contained defined portions of human chromosome 16.
Polymorphism
Family studies by Kishi et al. (1989) showed 3 common phenotypes and 4 rare phenotypes representing homozygosity or heterozygosity for 4 autosomal codominant alleles of DNase I. Data on the frequency of these alleles in a Japanese population were given.
Kishi et al. (1990) devised a zymogram method with high sensitivity and resolution for investigation of molecular heterogeneity and genetic polymorphism of DNase I. By this method they demonstrated 3 common phenotypes and 5 relatively rare phenotypes of serum DNase I and found by family studies that the inheritance was consistent with the segregation of 4 codominant alleles at a single locus. In addition to urine and serum, extracts of kidney, liver, and pancreas can be used for DNase I phenotyping.
Yasuda et al. (1990) demonstrated that the DNase I purified from a single individual consisted of multiple forms with different pI values. The findings were considered compatible with the existence of genetic polymorphism as reported by Kishi et al. (1989). The multiplicity of the urine enzyme might be due to variations in the primary structure and/or differences in the content of sialic acid.
Yasuda et al. (1995) demonstrated that the isoelectric focusing polymorphism of deoxyribonuclease I results from an 2317A-G transition in exon VIII. Wildtype DNASE1 was designated phenotype 1; the A-to-G change from wildtype gives rise to a gln222-to-arg substitution, designated phenotype 2. Yasuda et al. (1995) found that the predicted charge change attributable to this amino acid substitution is consistent with the isoelectric focusing profiles of these 2 isozymes.
Systemic Lupus Erythematosus
Yasutomo et al. (2001) described 2 patients with a heterozygous nonsense mutation in exon 2 of DNASE1, decreased DNASE1 activity and an extremely high immunoglobulin G titer against nucleosomal antigens. Yasutomo et al. (2001) concluded that their data were consistent with the hypothesis that a direct connection exists between low activity of DNASE1 and progression of human systemic lupus erythematosus (SLE; 152700).
Deoxyribonuclease I, in the form of a bovine pancreatic enzyme preparation, occupies an important place in the history of protein chemistry and enzymology: it was the first enzyme to be recognized as specific for DNA; it was the first DNase to be crystallized; and it was the first DNase for which a specific protein inhibitor was characterized (VAM).
Systemic lupus erythematosus (SLE; 152700) is a multifactorial autoimmune disease that is said to affect more than 1 million people in the United States. SLE is characterized by the presence of antinuclear antibodies (ANA) directed against naked DNA and entire nucleosomes. It was thought that the resulting immune complexes accumulate in vessel walls, glomeruli, and joints and cause a hypersensitivity reaction type III that manifests as glomerulonephritis, arthritis, and generalized vasculitis. Several studies had suggested that increased liberation or disturbed clearance of nuclear DNA-protein complexes after cell death may initiate and propagate the disease. Consequently, DNASE1, which is a major nuclease present in serum, urine, and secreta, may be responsible for the removal of DNA from nuclear antigens at sites of high cell turnover and thus prevent SLE. To test this hypothesis, Napirei et al. (2000) generated Dnase1-deficient mice by gene targeting. They found that these animals show the classic symptoms of SLE, namely the presence of ANA, the deposition of immune complexes in glomeruli, and full-blown glomerulonephritis in a Dnase1 dose-dependent manner. Moreover, in agreement with earlier reports, they found Dnase1 activities in serum to be lower in SLE patients than in normal subjects. The findings suggested that lack or reduction of Dnase1 is a critical factor in the initiation of human SLE.
In 2 females with systemic lupus erythematosus (SLE; 152700), Yasutomo et al. (2001) identified an A-to-G transition in exon 2 at position 172 of the DNASE1 coding sequence, which resulted in a lys-to-ter substitution at codon 5. These female patients, who were 13 and 17 years of age, respectively, were diagnosed as having SLE based on clinical features, high serum titers of antibodies against double-stranded DNA, and Sjogren syndrome. The 2 patients were unrelated and the family members did not have any signs or symptoms of SLE. The patients had substantially lower levels of DNASE1 activity in the sera than in other SLE patients without a DNASE1 mutation. However, the DNASE1 activity of SLE patients without DNASE1 mutations is lower than that of healthy controls. The patient's B cells had 30 to 50% of the DNASE1 activity of cells from controls, showing that heterozygous mutation of DNASE1 reduces the total activity of this enzyme.
In 350 Korean patients with SLE (152700) and 330 Korean controls, Shin et al. (2004) identified a nonsynonymous SNP in exon 8 of the DNASE1 gene, 2373A-G (Q244R), that was significantly associated with an increased risk of the production of anti-RNP and anti-dsDNA antibodies among SLE patients. The frequency of the arg/arg minor allele was much higher in patients who had the anti-RNP antibody (31%) than in patients who did not have this antibody (14%) (P = 0.0006).
Kishi, K., Yasuda, T., Awazu, S., Mizuta, K. Genetic polymorphism of human urine deoxyribonuclease I. Hum. Genet. 81: 295-297, 1989. [PubMed: 2921043] [Full Text: https://doi.org/10.1007/BF00279009]
Kishi, K., Yasuda, T., Ikehara, Y., Sawazaki, K., Sato, W., Iida, R. Human serum deoxyribonuclease I (DNase I) polymorphism: pattern similarities among isozymes from serum, urine, kidney, liver, and pancreas. Am. J. Hum. Genet. 47: 121-126, 1990. [PubMed: 2349940]
Napirei, M., Karsunky, H., Zevnik, B., Stephan, H., Mannherz, H. G., Moroy, T. Features of systemic lupus erythematosus in Dnase1-deficient mice. Nature Genet. 25: 177-181, 2000. [PubMed: 10835632] [Full Text: https://doi.org/10.1038/76032]
Shin, H. D., Park, B. L., Kim, L. H., Lee, H.-S., Kim, T.-Y., Bae, S.-C. Common DNase I polymorphism associated with autoantibody production among systemic lupus erythematosus patients. Hum. Molec. Genet. 13: 2343-2350, 2004. [PubMed: 15333586] [Full Text: https://doi.org/10.1093/hmg/ddh275]
Yasuda, T., Awazu, S., Sato, W., Iida, R., Tanaka, Y., Kishi, K. Human genetically polymorphic deoxyribonuclease: purification, characterization, and multiplicity of urine deoxyribonuclease I. J. Biochem. 108: 393-398, 1990. [PubMed: 2277032] [Full Text: https://doi.org/10.1093/oxfordjournals.jbchem.a123212]
Yasuda, T., Kishi, K., Yanagawa, Y., Yoshida, A. Structure of the human deoxyribonuclease I (DNase I) gene: identification of the nucleotide substitution that generates its classical genetic polymorphism. Ann. Hum. Genet. 59: 1-15, 1995. [PubMed: 7762978] [Full Text: https://doi.org/10.1111/j.1469-1809.1995.tb01601.x]
Yasuda, T., Nadano, D., Iida, R., Takeshita, H., Lane, S. A., Callen, D. F., Kishi, K. Chromosomal assignment of the human deoxyribonuclease I gene, DNASE1 (DNL1), to band 16p13.3 using the polymerase chain reaction. Cytogenet. Cell Genet. 70: 221-223, 1995. [PubMed: 7789176] [Full Text: https://doi.org/10.1159/000134038]
Yasutomo, K., Horiuchi, T., Kagami, S., Tsukamoto, H., Hashimura, C., Urushihara, M., Kuroda, Y. Mutation of DNASE1 in people with systemic lupus erythematosus. Nature Genet. 28: 313-314, 2001. [PubMed: 11479590] [Full Text: https://doi.org/10.1038/91070]