A biochemical and genetic study on all non-synonymous single nucleotide polymorphisms of the gene encoding human deoxyribonuclease I potentially relevant to autoimmunity

Yasuda, Toshihiro; Ueki, Misuzu; Takeshita, Hitoshi; Fujihara, Junko; Kimura-Kataoka, Kaori; Iida, Reiko; Tsubota, Etsuko; Soejima, Mikiko; Koda, Yoshiro; Kato, Hideaki; Panduro, Arturo

doi:10.1016/j.biocel.2010.04.012

Cited by 25 publications

(75 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the present study, we have extensively continued our previous studies on the genetic and functional characterization of non-synonymous SNPs in DNASE1 and DNASE1L3 potentially relevant to autoimmune diseases [11,13,17,18]; thereby, all of the non-synonymous SNPs (44 in DNASE1 and 25 in DNASE1L3) registered in the database or reported, which probably give rise to an alteration in the levels of in vivo DNase activity through amino acid substitution, could be evaluated as a functional SNP [27] ( Tables 1 and 2). To our knowledge, this study is the first to have comprehensively demonstrated the genetic distribution of all the non-synonymous SNPs in both the DNase genes, and also the effect of each SNP on the enzyme activity.…”

Section: Discussionmentioning

confidence: 81%

“…Development of a simple genotyping procedure for each SNP in DNASE1 and DNASE1L3 using a PCR-RFLP method A simple and novel genotyping procedure was developed using PCR restriction fragment length polymorphism (RFLP) for all of the 32 and 20 SNPs in DNASE1 and DNASE1L3, respectively; those for another 12 and 5 SNPs, respectively, had been developed previously [11,13,17,18]. As the substitution sites corresponding to the 19 and 11 SNPs in DNASE1 and DNASE1L3, respectively, neither suppressed nor created any known restriction enzyme recognition sites, we employed a mismatched PCR amplification method [19] for genotyping; incorporation of a deliberate mismatch close to the 3′-terminus of a PCR primer allows the creation of a recognition site for each enzyme.…”

Section: Resultsmentioning

confidence: 99%

“…n.d., the activity derived from the corresponding amino acid substituted construct could not be detected under our assay conditions. Taken from our previous study [11]. b Taken from our previous study [45].…”

Section: Discussionmentioning

confidence: 99%

“…In this context, triggered by nuclear antigens, the clearance of cell debris resulting from cell death through apoptosis and/or necrosis might be primarily involved in the prevention of autoimmune conditions such as systemic lupus erythematosus (SLE); DNase I has been especially highlighted for its possible involvement in the pathogenesis of autoimmune diseases [6][7][8]. Yasutomo et al [9] and Dittmar et al [10] have identified novel nonsense (p.Lys5Ter) and missense (p.Val111Met) mutations that abolished and reduced DNase I activity, respectively, in patients with autoimmune diseases [11]. Recently, in an SLE patient, Al-Mayouf et al [12] found a null mutation resulting from a homozygous 1-bp deletion (c.643delT; p.Trp215GlyfsX2) and also identified homozygosity for a missense mutation (p.Arg206Cys), the latter producing a loss-of-function variant of DNase 1L3 [13].…”

Section: Introductionmentioning

confidence: 99%

“…We have been focusing on non-synonymous SNPs that are likely to serve as a functional SNP, and in fact have previously performed genetic and expression analysis of 12 and 5 such SNPs in DNASE1 and DNASE1L3, respectively [11,13,17,18]. Since then, 32 and 20 non-synonymous SNPs in DNASE1 and DNASE1L3, respectively, which could potentially affect the activity, have been registered in the database.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Self Cite

View full text Add to dashboard Cite

show abstract

Global analysis of single nucleotide polymorphisms in the exons of human deoxyribonuclease I‐like 1 and 2 genes

et al. 2010

Self Cite

View full text Add to dashboard Cite

Several SNPs in the deoxyribonuclease I-like 1 (DNase 1L1) and DNase 1L2 were investigated. In the present study, the genotype distributions of three synonymous SNPs (V59V, rs1050095; P67P, rs1130929; A277A, rs17849495) in the DNase 1L1 gene and four non-synonymous SNPs, V122I (rs34952165), Q170H (rs6643670), and D227A (rs5987256) in the DNase 1L1 gene, as well as D197A (rs62621282) in the DNase 1L2 gene were investigated in 13 populations. In all the populations, no variation was found in four SNPs (V59V, Q170H, D227A, and A277A) in DNASE1L1 or in D197A in DNASE1L2. As for V122I, only the German population showed a low degree of polymorphism. The SNP V122I in DNASE1L1 was monoallelic for the G-allele in all of the Asian and African populations examined, with no polymorphism being evident. Since the A-allele in SNP V122I was distributed in only the Caucasian populations, not in the other ethnic groups, it was confirmed that the A-allele in SNP V122I was Caucasian-specific. On the other hand, only P67P in DNASE1L1 was polymorphic among three synonymous SNPs. The effect of nucleotide substitution corresponding to polymorphic SNP P67P on DNase 1L1 activity was examined: the corresponding nucleotide substitution in polymorphic SNP P67P has little effect on the DNase activity.

show abstract

Global genetic analysis of all single nucleotide polymorphisms in exons of the human deoxyribonuclease I‐like 3 gene and their effect on its catalytic activity

et al. 2011

Self Cite

View full text Add to dashboard Cite

Deoxyribonucleases (DNases) have been suggested to be implicated in the pathophysiology of autoimmune diseases. In the DNASE1L3 gene encoding human DNase I-like 3 (DNase 1L3), a member of the DNase I family, only two non-synonymous (R178 H and R206C) single nucleotide polymorphisms (SNPs) have been examined [Ueki et al., Clin. Chim. Acta 2009, 407, 20-24]. Three other non-synonymous (G82R, K96N, and I243M) and four synonymous (S17S, T84T, R92R, and A181A) SNPs, in addition to R206C and R178H, have been identified in DNASE1L3. We investigated the distribution of all these SNPs in exons of the gene in eight Asian, three African, and three Caucasian populations worldwide using newly devised genotyping methods. SNP T84T showed polymorphism in all the populations, and R92R was polymorphic in the three African and three Caucasian populations; R206C was distributed only in Caucasian populations. In contrast, no minor allele was found in five SNPs (S17S, G82R, K96N, A181A, and I243M) in DNASE1L3. Generally, the DNase 1L3 gene shows relatively low genetic diversity with regard to exonic SNPs. When the effect of amino acid/nucleotide substitutions resulting from the SNPs on DNase 1L3 activity was examined, none of the synonymous SNPs had any effect on the DNase 1L3 activity, whereas among non-synonymous SNPs, SNP G82R diminished the activity of the enzyme, being similar to R206C. These findings permit us to assume that, although only R206 exhibits polymorphisms in a Caucasian-specific manner, at least SNPs G82R and R206C in DNASE1L3 might be potential risk factors for autoimmune disease.

show abstract

A biochemical and genetic study on all non-synonymous single nucleotide polymorphisms of the gene encoding human deoxyribonuclease I potentially relevant to autoimmunity

Cited by 25 publications

References 38 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

Global analysis of single nucleotide polymorphisms in the exons of human deoxyribonuclease I‐like 1 and 2 genes

Global genetic analysis of all single nucleotide polymorphisms in exons of the human deoxyribonuclease I‐like 3 gene and their effect on its catalytic activity

Contact Info

Product

Resources

About