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language
eng
Author
Fujihara , Junko Department of Legal Medicine, Shimane University School of Medicine
Ueki, Misuzu Division of Medical Genetics and Biochemistry, University of Fukui
Kimura-Kataoka, Kaori Department of Legal Medicine, Shimane University School of Medicine
Iida, Reiko Division of Life Sciences, Faculty of Medical Sciences, University of Fukui
Takeshita, Haruo Department of Legal Medicine, Shimane University School of Medicine
Yasuda, Toshihiro Division of Medical Genetics and Biochemistry, University of Fukui
Description
OBJECTIVE: To continue our previous investigations, we have extensively investigated the function of the 61, 41, and 35 non-synonymous single nucleotide polymorphisms (SNPs) in the human genes encoding DNASE1, DNASE1L3, and DNASE2, respectively, potentially relevant to autoimmune diseases.
METHODS: The site-directed mutagenesis was employed to amino acid-substituted constructs corresponding to each SNP. The COS-7 cells were transfected with each vector and DNase activity was assayed by the single radial enzyme diffusion method. By using PolyPhen-2, changes in the DNase function of each non-synonymous SNP were predicted. Genotyping of all the non-synonymous SNPs was performed in 14 different populations including 3 ethnic groups using the polymerase chain reaction followed by the restriction fragment length polymorphism method.
RESULTS: Expression analysis demonstrated these SNPs to be classified into four categories with regard to the effect on DNase activity: SNPs not affecting the activity level, ones reducing it, ones abolishing it, and ones elevating it. In particular, 9, 5, and 4 SNPs producing a loss-of-function variant of the enzymes in DNASE1, DNASE1L3, and DNASE2, respectively, were confirmed. SNPs producing DNase loss of function can be estimated by PolyPhen-2 to be "probably damaging" with a high accuracy of prediction. Almost all of these functional SNPs producing a loss of function or substantially low activity-harboring forms exhibited a mono-allelic distribution in all of the populations.
CONCLUSION: A minor allele of functional SNPs, despite the remarkably low genetic heterogeneity of the SNPs, might be a genetic risk factor for autoimmune diseases.
Subject
Autoimmunity
deoxyribonuclease (DNase) family
functional SNPs
genetic distribution
genotype
loss-of-function
Journal Title
Immunological investigations
Volume
45
Issue
5
Start Page
406
End Page
419
ISSN
08820139
Published Date
2016-07
DOI
DOI Date
2017-09-06
PubMed ID
NCID
AA10519794
Publisher
Taylor & Francis
NII Type
Journal Article
Format
PDF
Rights
This is an Accepted Manuscript of an article published by Taylor & Francis in Immunological investigations on 2016, available online: http://www.tandfonline.com/10.3109/08820139.2016.1157813.
Text Version
著者版
Gyoseki ID
e32475
e31895
e31830
OAI-PMH Set
Faculty of Medicine
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