DNASE1L2

Summary

DNASE1L2 (deoxyribonuclease 1 like 2, HGNC:2958) is a protein-coding gene on chromosome 16p13.3, encoding Deoxyribonuclease-1-like 2 (Q92874). Divalent cation-dependent acid DNA endonuclease involved in the breakdown of the nucleus during corneocyte formation of epidermal keratinocytes.

Predicted to enable DNA binding activity and deoxyribonuclease I activity. Predicted to be involved in DNA catabolic process. Predicted to act upstream of or within corneocyte development and hair follicle development. Predicted to be located in cytoplasm and extracellular region. Predicted to be active in nucleus.

Source: NCBI Gene 1775 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 40 total
• MANE Select transcript: NM_001374

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2958
Approved symbol	DNASE1L2
Name	deoxyribonuclease 1 like 2
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	DNAS1L2
Ensembl gene	ENSG00000167968
Ensembl biotype	protein_coding
OMIM	602622
Entrez	1775

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000320700, ENST00000382437, ENST00000564065, ENST00000567494, ENST00000569184, ENST00000613572

RefSeq mRNA: 2 — MANE Select: NM_001374 NM_001301680, NM_001374

CCDS: CCDS42105

Canonical transcript exons

ENST00000320700 — 7 exons

Exon	Start	End
ENSE00001118803	2237218	2237301
ENSE00001118806	2237038	2237126
ENSE00001241641	2237767	2238018
ENSE00001241656	2237376	2237649
ENSE00001297609	2236778	2236960
ENSE00001302945	2238362	2238711
ENSE00003849815	2236444	2236560

Expression profiles

Bgee: expression breadth ubiquitous, 164 present calls, max score 89.44.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.6113 / max 33.9260, expressed in 126 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
152218	0.6113	126

Top tissues by expression

281 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
skin of abdomen	UBERON:0001416	89.44	gold quality
skin of leg	UBERON:0001511	89.41	gold quality
upper arm skin	UBERON:0004263	87.72	silver quality
zone of skin	UBERON:0000014	87.22	gold quality
right hemisphere of cerebellum	UBERON:0014890	84.02	gold quality
cerebellar hemisphere	UBERON:0002245	82.26	gold quality
cerebellar cortex	UBERON:0002129	82.02	gold quality
cerebellum	UBERON:0002037	80.29	gold quality
buccal mucosa cell	CL:0002336	78.24	silver quality
right lobe of thyroid gland	UBERON:0001119	77.72	gold quality
left lobe of thyroid gland	UBERON:0001120	77.32	gold quality
triceps brachii	UBERON:0001509	77.25	gold quality
gluteal muscle	UBERON:0002000	77.20	gold quality
right frontal lobe	UBERON:0002810	76.18	gold quality
upper leg skin	UBERON:0004262	75.88	gold quality
mammalian vulva	UBERON:0000997	75.35	gold quality
hair follicle	UBERON:0002073	75.17	gold quality
thyroid gland	UBERON:0002046	75.13	gold quality
Brodmann (1909) area 9	UBERON:0013540	72.21	gold quality
diaphragm	UBERON:0001103	72.16	gold quality
anterior cingulate cortex	UBERON:0009835	71.78	gold quality
cingulate cortex	UBERON:0003027	71.77	gold quality
lower esophagus mucosa	UBERON:0035834	71.76	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	71.13	gold quality
mucosa of transverse colon	UBERON:0004991	71.03	gold quality
nucleus accumbens	UBERON:0001882	70.97	gold quality
adenohypophysis	UBERON:0002196	70.88	gold quality
pituitary gland	UBERON:0000007	70.72	gold quality
cortical plate	UBERON:0005343	70.20	gold quality
putamen	UBERON:0001874	70.12	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.91

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

7 targeting DNASE1L2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-4660	97.79	67.44	1328
HSA-MIR-6762-5P	96.55	64.62	972
HSA-MIR-6845-5P	96.55	64.65	969

Literature-anchored findings (GeneRIF, showing 9)

• DNAS1L2 is activated via the NF-kappaB pathway, and an NF-kappaB binding site located within the 5’ flanking region is identified as the cis-responsive element (PMID:15203207)
• DNase1L2 plays an essential role in DNA degradation during terminal differentiation of epidermal KC. (PMID:16902420)
• Terminal differentiation of nail matrix keratinocytes involves up-regulation of DNas1L2 but is independent of caspase 14. (PMID:17490414)
• Genotyping of all the non-synonymous SNPs of was performed in three ethnic groups including six different populations using the PCR-RFLP method newly developed. (PMID:20503202)
• Several SNPs in the deoxyribonuclease I-like 1 (DNase 1L1) and DNase 1L2 were investigated. (PMID:20967767)
• Genotyping of 17 SNPs in the human deoxyribonuclease I-like 2 gene was performed using the PCR-RFLP method in three ethnic groups including 14 different populations. (PMID:23161465)
• DNASE1L2 is generally well conserved with regard to the non-synonymous single nucleotide polymorphisms, thereby avoiding any marked reduction of the enzyme activity in human populations. (PMID:25576224)
• Study surveyed the non-synonymous SNPs of DNASE1L2: 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. (PMID:28394916)
• DNASE1L2, as a Carcinogenic Marker, Affects the Phenotype of Breast Cancer Cells Via Regulating Epithelial-Mesenchymal Transition Process. (PMID:32343605)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	dnase1	ENSDARG00000012539
mus_musculus	Dnase1l2	ENSMUSG00000024136
rattus_norvegicus	Dnase1l2	ENSRNOG00000042352

Paralogs (3): DNASE1L1 (ENSG00000013563), DNASE1L3 (ENSG00000163687), DNASE1 (ENSG00000213918)

Protein

Protein identifiers

Deoxyribonuclease-1-like 2 — Q92874 (reviewed: Q92874)

Alternative names: DNase I homolog protein DHP1, Deoxyribonuclease I-like 2

All UniProt accessions (2): Q92874, H3BPU8

UniProt curated annotations — full annotation on UniProt →

Function. Divalent cation-dependent acid DNA endonuclease involved in the breakdown of the nucleus during corneocyte formation of epidermal keratinocytes. May play an immune role by eliminating harmful DNA released into the extracellular environment by damaged epidermal cells.

Subcellular location. Cytoplasm. Secreted.

Tissue specificity. Preferentially expressed in the skin and up-regulated during keratinocytes differentiation. Highly abundant (at protein level) in the stratum granulosum.

Induction. Up-regulated by inflammatory cytokines.

Miscellaneous. Specifically expressed in peripheral blood leukocytes.

Similarity. Belongs to the DNase I family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q92874-1	1, DNAS1L2-L	yes
Q92874-2	2, DNAS1L2-S

RefSeq proteins (2): NP_001288609, NP_001365* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005135	Endo/exonuclease/phosphatase	Domain
IPR016202	DNase_I	Family
IPR018057	Deoxyribonuclease-1_AS	Active_site
IPR033125	DNASE_I_2	Conserved_site
IPR036691	Endo/exonu/phosph_ase_sf	Homologous_superfamily

Pfam: PF03372

UniProt features (6 total): active site 2, signal peptide 1, chain 1, disulfide bond 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92874-F1	90.24	0.84

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 99; 170

Disulfide bonds (1): 209–245

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 84 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, GOMF_ENDONUCLEASE_ACTIVITY, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOMF_NUCLEASE_ACTIVITY, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_DNA_CATABOLIC_PROCESS, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, MODULE_99, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, GOBP_MOLTING_CYCLE, GOBP_EPIDERMIS_DEVELOPMENT, MORF_RAB3A, STONER_ESOPHAGEAL_CARCINOGENESIS_UP, SPIELMAN_LYMPHOBLAST_EUROPEAN_VS_ASIAN_UP, GOBP_SKIN_DEVELOPMENT

GO Biological Process (4): hair follicle development (GO:0001942), corneocyte development (GO:0003335), DNA metabolic process (GO:0006259), DNA catabolic process (GO:0006308)

GO Molecular Function (10): DNA binding (GO:0003677), deoxyribonuclease I activity (GO:0004530), DNA nuclease activity (GO:0004536), calcium ion binding (GO:0005509), catalytic activity (GO:0003824), nuclease activity (GO:0004518), endonuclease activity (GO:0004519), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (3): extracellular region (GO:0005576), nucleus (GO:0005634), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nuclease activity	2
cellular anatomical structure	2
hair cycle process	1
anatomical structure development	1
skin epidermis development	1
keratinocyte development	1
cell development	1
nucleic acid metabolic process	1
DNA nuclease activity	1
DNA metabolic process	1
nucleic acid catabolic process	1
nucleic acid binding	1
DNA endonuclease activity, producing 5’-phosphomonoesters	1
catalytic activity, acting on DNA	1
metal ion binding	1
molecular_function	1
catalytic activity, acting on a nucleic acid	1
binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

829 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DNASE1L2	XRN2	Q9H0D6	854
DNASE1L2	DXO	O77932	821
DNASE1L2	TJAP1	Q5JTD0	766
DNASE1L2	ERI2	A8K979	712
DNASE1L2	DNASE2	O00115	680
DNASE1L2	DNASE2B	Q8WZ79	484
DNASE1L2	KRTAP4-16	G5E9R7	448
DNASE1L2	DPEP1	P16444	447
DNASE1L2	CCDC15	Q0P6D6	436
DNASE1L2	A6NDT3	A6NDT3	432
DNASE1L2	DFFB	O76075	428
DNASE1L2	KRT27	Q7Z3Y8	423
DNASE1L2	TREX2	Q9BQ50	394
DNASE1L2	FOXN1	O15353	380
DNASE1L2	KRTAP21-1	Q3LI58	368

IntAct

27 interactions, top by confidence:

A	B	Type	Score
SLC19A2	ATP5F1B	psi-mi:“MI:0914”(association)	0.730
ANXA9	PPL	psi-mi:“MI:0914”(association)	0.660
DNASE1L2	HSPA5	psi-mi:“MI:0915”(physical association)	0.620
DNASE1L2	HSPA5	psi-mi:“MI:0914”(association)	0.620
BLVRA	DDHD2	psi-mi:“MI:0914”(association)	0.530
FBXL4	DUSP14	psi-mi:“MI:0914”(association)	0.530
PHF13	DNASE1L2	psi-mi:“MI:0914”(association)	0.530
SLC25A21	DNASE1L2	psi-mi:“MI:0914”(association)	0.530
ABL1	DNASE1L2	psi-mi:“MI:0915”(physical association)	0.400
FYN	DNASE1L2	psi-mi:“MI:0915”(physical association)	0.400
DNASE1L2	INSR	psi-mi:“MI:0914”(association)	0.350
TBX20	TLE3	psi-mi:“MI:0914”(association)	0.350
INKA2	CDC42BPA	psi-mi:“MI:0914”(association)	0.350
MYO1E	MYO1C	psi-mi:“MI:0914”(association)	0.350
ZNF154	A2ML1	psi-mi:“MI:0914”(association)	0.350
PTDSS1	IGLL5	psi-mi:“MI:0914”(association)	0.350
POLL	SULT1C2	psi-mi:“MI:0914”(association)	0.350
PPIE	PLRG1	psi-mi:“MI:0914”(association)	0.350
PHF13	BLVRA	psi-mi:“MI:0914”(association)	0.350
SLC25A21	BLVRA	psi-mi:“MI:0914”(association)	0.350
TBX20	TLE1	psi-mi:“MI:0914”(association)	0.350
PEMT	FABP7	psi-mi:“MI:0914”(association)	0.350

BioGRID (36): DNASE1L2 (Affinity Capture-MS), DNASE1L2 (Affinity Capture-MS), DNASE1L2 (Affinity Capture-MS), DNASE1L2 (Affinity Capture-MS), CCT6B (Affinity Capture-MS), RPL23 (Affinity Capture-MS), CSK (Affinity Capture-MS), DNASE1L2 (Affinity Capture-MS), DNASE1L2 (Affinity Capture-MS), DNASE1L2 (Affinity Capture-MS), DNASE1L2 (Affinity Capture-MS), DNASE1L2 (Affinity Capture-MS), DNASE1L2 (Affinity Capture-MS), DNASE1L2 (Affinity Capture-MS), INSR (Affinity Capture-MS)

ESM2 similar proteins: O18835, O18998, O42446, O55070, O77588, O77695, O89107, O97524, O97860, P00639, P04066, P08236, P11936, P11937, P12265, P13686, P21704, P22412, P24855, P49183, P49184, P70158, Q01459, Q01460, Q02809, Q13609, Q2QDE6, Q2QDE7, Q2QDE9, Q2QDF0, Q2QDF1, Q4AEE3, Q4FAT7, Q4FZV0, Q5R5N6, Q5R9N3, Q5RFI5, Q63321, Q641Z7, Q6AYS4

Diamond homologs: D3SGB1, Q2QDE7, Q2QDF0, Q92874, O18998, O42446, O55070, O89107, P00639, P11936, P11937, P21704, P24855, P49183, P49184, Q13609, Q2QDE6, Q2QDE9, Q2QDF1, Q4AEE3, Q767J3, Q9D1G0, Q9D7J6, Q9YGI5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

40 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	38
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1026 predictions. Top by Δscore:

Variant	Effect	Δscore
16:2237216:A:AG	acceptor_gain	1.0000
16:2237217:G:GG	acceptor_gain	1.0000
16:2237217:GC:G	acceptor_gain	1.0000
16:2237217:GCGT:G	acceptor_gain	1.0000
16:2237298:ACAGG:A	donor_loss	1.0000
16:2237300:AGG:A	donor_loss	1.0000
16:2237301:GGTGA:G	donor_loss	1.0000
16:2237371:CCTA:C	acceptor_loss	1.0000
16:2237372:CTA:C	acceptor_loss	1.0000
16:2237373:TA:T	acceptor_loss	1.0000
16:2237374:A:AG	acceptor_gain	1.0000
16:2237374:A:C	acceptor_loss	1.0000
16:2237374:AG:A	acceptor_gain	1.0000
16:2237375:G:GG	acceptor_gain	1.0000
16:2237375:G:GT	acceptor_loss	1.0000
16:2237375:GG:G	acceptor_gain	1.0000
16:2237375:GGAAA:G	acceptor_gain	1.0000
16:2237536:GCA:G	acceptor_gain	1.0000
16:2237647:GAC:G	donor_gain	1.0000
16:2237650:G:GG	donor_gain	1.0000
16:2237992:G:GT	donor_gain	1.0000
16:2237995:G:GT	donor_gain	1.0000
16:2236959:AGG:A	donor_loss	0.9900
16:2236960:GGT:G	donor_loss	0.9900
16:2236961:G:A	donor_loss	0.9900
16:2236962:T:A	donor_loss	0.9900
16:2237025:C:A	acceptor_gain	0.9900
16:2237033:CCCA:C	acceptor_loss	0.9900
16:2237034:CCAG:C	acceptor_loss	0.9900
16:2237036:A:AG	acceptor_gain	0.9900

AlphaMissense

1950 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:2237863:T:A	W230R	0.996
16:2237863:T:C	W230R	0.996
16:2237921:G:C	R249P	0.996
16:2238374:A:C	S286R	0.992
16:2238376:C:A	S286R	0.992
16:2238376:C:G	S286R	0.992
16:2237249:A:C	S89R	0.991
16:2237251:C:A	S89R	0.991
16:2237251:C:G	S89R	0.991
16:2237920:C:A	R249S	0.991
16:2236895:T:C	F27L	0.990
16:2236897:C:A	F27L	0.990
16:2236897:C:G	F27L	0.990
16:2237566:C:G	H170D	0.989
16:2237783:G:T	G203V	0.989
16:2237865:G:C	W230C	0.989
16:2237865:G:T	W230C	0.989
16:2236900:C:A	N28K	0.988
16:2236900:C:G	N28K	0.988
16:2237787:C:A	D204E	0.988
16:2237787:C:G	D204E	0.988
16:2238375:G:T	S286I	0.988
16:2238380:C:G	H288D	0.987
16:2238382:C:A	H288Q	0.987
16:2238382:C:G	H288Q	0.987
16:2237782:G:C	G203R	0.986
16:2237789:T:C	F205S	0.985
16:2237289:T:C	L102P	0.984
16:2237786:A:T	D204V	0.984
16:2237431:T:C	F125L	0.983

dbSNP variants (sampled 300 via entrez): RS1000359585 (16:2236089 T>A), RS1000753426 (16:2239156 C>T), RS1001019631 (16:2238316 G>T), RS1001281994 (16:2237708 G>T), RS1001637331 (16:2237112 G>A), RS1002232838 (16:2238530 G>A,C,T), RS1002690317 (16:2238696 C>T), RS1004794792 (16:2238587 C>T), RS1005497237 (16:2234773 G>A,T), RS1005619516 (16:2236506 G>A,C,T), RS1006904652 (16:2235192 T>C), RS1007707738 (16:2237331 CG>C), RS1007860244 (16:2235805 C>A,G,T), RS1007911094 (16:2236013 C>T), RS1008078690 (16:2235258 C>A,G,T)

Disease associations

OMIM: gene MIM:602622 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST012227_364	Hip circumference adjusted for BMI	6.000000e-13

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
sodium arsenate	decreases expression, increases abundance	1
arsenite	increases methylation	1
sodium arsenite	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
clothianidin	decreases expression	1
bisphenol S	decreases methylation	1
(+)-JQ1 compound	increases expression	1
MT19c compound	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Carmustine	decreases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Valproic Acid	increases methylation	1
Isotretinoin	decreases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.