Identification of functional SNPs potentially served as a genetic risk factor for the pathogenesis of parakeratosis in the gene encoding human deoxyribonuclease I-like 2 (DNase 1L2) implicated in terminal differentiation of keratinocytes

•DNase 1L2 implicated in DNA degradation in terminal differentiation of keratinocytes•Genetic and catalytic characterization on all the non-synonymous SNPs in DNASE1L2•Identification of 9 functional SNPs in DNASE1L2 producing a loss-of-function•Extremely low genetic distribution of all the non-synonymous SNPs in the gene•Functional SNPs as a possible genetic factor for the pathogenesis of parakeratosis

In the present study, we evaluated all of the 35 non-synonymous SNPs in the gene encoding DNase I-like 2 (DNase 1L2), implicated in terminal differentiation of keratinocytes, to seek a functional SNP that would potentially affect the levels of in vivo DNase 1L2 activity. Based on a compiled expression analysis of the amino acid-substituted DNase 1L2 corresponding to each of the 35 non-synonymous SNPs in the gene, these 35 SNPs were grouped into 4 classes according to the alteration of catalytic activity caused by the corresponding amino acid substitution in the DNase 1L2 protein; we were able to identify 12 non-synonymous SNPs as functional SNPs abolishing or substantially reducing the activity. Almost all of the amino acid residues corresponding to the SNPs abolishing the activity were completely or highly conserved in not only the DNase I family, but also animal DNase 1L2. Each of the minor alleles of these functional SNPs producing a loss-of-function or low activity-harboring variant was absent in 14 different populations derived from 3 ethnic groups, allowing us to assume that DNASE1L2 is generally well conserved with regard to these non-synonymous SNPs, thereby avoiding any marked reduction of the enzyme activity in human populations. However, it seems likely that each of the minor alleles for these SNPs may serve as a genetic risk factor for multiple skin diseases such as psoriasis, in which there is an aberrant retention of nuclear chromatin in cornified keratinocytes through incomplete DNA degradation.