title: Survey of single-nucleotide polymorphisms in the gene encoding human deoxyribonuclease I-like 2 producing loss of function potentially implicated in the pathogenesis of parakeratosis.
abstract: Dysfunction of DNase I-like 2 (DNase 1L2) has been assumed to play a role in the etiology of parakeratosis through incomplete degradation of DNA in the epidermis. However, the pathogenetic background factor for such pathophysiologic conditions remains unknown. In this context, non-synonymous single-nucleotide polymorphisms (SNPs) in DNASE1L2 that would potentially result in loss of in vivo DNase 1L2 activity might serve as a genetic risk factor for such pathophysiologic conditions. Our aim was to effectively survey the non-synonymous SNPs of DNASE1L2 that would produce a loss-of-function variant of the enzyme together with a genetic distribution in the various populations. Here, the effects of all of the SNPs predicted by PolyPhen-2 analysis to be "probably damaging" (score = 1.000), and derived from frameshift/nonsense mutations, on the activity of DNase 1L2 were examined using the corresponding DNase 1L2 variants expressed in COS-7 cells. Genotyping of these SNPs was also performed in three ethnic groups including 14 different populations. Among the 28 SNPs examined, the minor allele of 23 SNPs was defined as a loss-of-function variant resulting in loss of DNase 1L2 function, indicating that Polyphen-2 analysis could be effective for surveys of at least non-synonymous SNPs resulting in loss of function. On the other hand, these minor alleles were not distributed worldwide, thereby avoiding any marked reduction of the enzyme activity in human populations. Furthermore, all of the 19 SNPs originating from frameshift/ nonsense mutations found in DNASE1L2 resulted in loss of function of the enzyme. Thus, the present findings suggest that each of the minor alleles for these SNPs may serve as one of genetic risk factors for parakeratotic skin diseases such as psoriasis, even though they lack a worldwide genetic distribution.
authors.affiliation: Department of Medical Genetics and Biochemistry, Faculty of Medical Sciences, University of Fukui, Eiheiji, Fukui, Japan.
authors.forename: Misuzu
authors.initials: M
authors.lastname: Ueki
authors.affiliation: Department of Legal Medicine, Shimane University School of Medicine, Enya, Izumo, Japan.
authors.forename: Haruo
authors.identifier: http://orcid.org/0000-0001-6291-4279
authors.initials: H
authors.lastname: Takeshita
authors.affiliation: Department of Dermatology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Fukui, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Utsunomiya
authors.affiliation: Department of Dermatology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Fukui, Japan.
authors.forename: Takanao
authors.initials: T
authors.lastname: Chino
authors.affiliation: Department of Dermatology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Fukui, Japan.
authors.forename: Noritaka
authors.initials: N
authors.lastname: Oyama
authors.affiliation: Department of Dermatology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Fukui, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Hasegawa
authors.affiliation: Department of Legal Medicine, Shimane University School of Medicine, Enya, Izumo, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Kimura-Kataoka
authors.affiliation: Department of Legal Medicine, Shimane University School of Medicine, Enya, Izumo, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Fujihara
authors.affiliation: Department of Life Sciences, Faculty of Medical Sciences, University of Fukui, Eiheiji, Fukui, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Iida
authors.affiliation: Department of Medical Genetics and Biochemistry, Faculty of Medical Sciences, University of Fukui, Eiheiji, Fukui, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Yasuda
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003850:Deoxyribonuclease I / Q000235:genetics* / Q000378:metabolism; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D010241:Parakeratosis / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012984:Software
chemical_list: C107519:DNASE1L2 protein, human; D003850:Deoxyribonuclease I