DKKL1

Summary

DKKL1 (dickkopf like acrosomal protein 1, HGNC:16528) is a protein-coding gene on chromosome 19q13.33, encoding Dickkopf-like protein 1 (Q9UK85). Involved in fertilization by facilitating sperm penetration of the zona pellucida.

The dickkopf protein family interacts with the Wnt signaling pathway and its members are characterized by two conserved cysteine-rich domains. This gene encodes a secreted protein that has low sequence similarity to the dickkopf-3 protein. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.

Source: NCBI Gene 27120 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 50 total
• MANE Select transcript: NM_014419

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16528
Approved symbol	DKKL1
Name	dickkopf like acrosomal protein 1
Location	19q13.33
Locus type	gene with protein product
Status	Approved
Aliases	SGY-1, CT34
Ensembl gene	ENSG00000104901
Ensembl biotype	protein_coding
OMIM	605418
Entrez	27120

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000221498, ENST00000594268, ENST00000596402, ENST00000597546, ENST00000597873, ENST00000598682

RefSeq mRNA: 3 — MANE Select: NM_014419 NM_001197301, NM_001197302, NM_014419

CCDS: CCDS12762

Canonical transcript exons

ENST00000221498 — 5 exons

Exon	Start	End
ENSE00000720034	49365793	49365885
ENSE00001116436	49363877	49364008
ENSE00003495273	49374717	49375116
ENSE00003503977	49365509	49365649
ENSE00003504430	49364582	49364754

Expression profiles

Bgee: expression breadth ubiquitous, 152 present calls, max score 98.86.

FANTOM5 (CAGE): breadth broad, TPM avg 1.0182 / max 335.1561, expressed in 317 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
176970	0.3909	183
176971	0.1563	23
176966	0.1522	80
176965	0.1202	74
176972	0.1155	5
176969	0.0219	5
176968	0.0209	6
176973	0.0156	3
176967	0.0155	3
176974	0.0092	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	98.86	gold quality
right testis	UBERON:0004534	98.67	gold quality
testis	UBERON:0000473	95.89	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.51	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.13	gold quality
adult organism	UBERON:0007023	85.78	gold quality
heart right ventricle	UBERON:0002080	81.45	gold quality
parotid gland	UBERON:0001831	80.62	gold quality
type B pancreatic cell	CL:0000169	76.15	gold quality
olfactory bulb	UBERON:0002264	75.98	gold quality
cerebellar vermis	UBERON:0004720	73.82	gold quality
biceps brachii	UBERON:0001507	72.97	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	72.91	gold quality
tongue squamous epithelium	UBERON:0006919	71.70	gold quality
vastus lateralis	UBERON:0001379	71.13	gold quality
nasal cavity epithelium	UBERON:0005384	70.80	gold quality
secondary oocyte	CL:0000655	70.55	gold quality
quadriceps femoris	UBERON:0001377	70.53	gold quality
ventricular zone	UBERON:0003053	69.79	gold quality
gluteal muscle	UBERON:0002000	69.69	gold quality
triceps brachii	UBERON:0001509	69.26	gold quality
male germ cell	CL:0000015	68.07	silver quality
Brodmann (1909) area 46	UBERON:0006483	67.81	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	67.57	gold quality
ganglionic eminence	UBERON:0004023	67.27	gold quality
diaphragm	UBERON:0001103	66.75	gold quality
sperm	CL:0000019	65.88	silver quality
middle temporal gyrus	UBERON:0002771	65.30	gold quality
lateral nuclear group of thalamus	UBERON:0002736	65.28	gold quality
gingiva	UBERON:0001828	65.24	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	29.18
E-ANND-3	no	2.04

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 6)

• DKKL1/Dkkl1 may play an important role in testicular development and spermatogenesis and may be an important factor in male infertility. (PMID:22817830)
• Unliganded VDR upregulates the expression of hairless, the gene product of which acts as a downstream comodulator to feedback-repress DKKL1 and SOSTDC1. (PMID:24190897)
• Findings suggest that Dkk-3 plays a role in the regulation of cell interactions during retinoic acid-induced neuronal differentiation; effect on apoptosis was also observed upon expression of the related protein Dkkl-1 (PMID:24909558)
• DKKL was overexpressed in colorectal cancer tissue compared with healthy colon. DKKL expression positively correlated with colorectal cancer progression. (PMID:27635108)
• previously unreported alternative splicing patterns in the genes ZNF419 and DKKL1 (PMID:27826023)
• The Clinical Significance of Dickkopf Wnt Signaling Pathway Inhibitor Gene Family in Head and Neck Squamous Cell Carcinoma. (PMID:33281184)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Dkkl1	ENSMUSG00000030792
rattus_norvegicus	Dkkl1	ENSRNOG00000020686

Protein

Protein identifiers

Dickkopf-like protein 1 — Q9UK85 (reviewed: Q9UK85)

Alternative names: Cancer/testis antigen 34, Protein soggy-1

All UniProt accessions (7): Q9UK85, A0A140VK15, M0QYJ2, M0QZP1, M0R1E5, M0R1Q7, M0R2X7

UniProt curated annotations — full annotation on UniProt →

Function. Involved in fertilization by facilitating sperm penetration of the zona pellucida. May promote spermatocyte apoptosis, thereby limiting sperm production. In adults, may reduce testosterone synthesis in Leydig cells. Is not essential either for development or fertility.

Subunit / interactions. Interacts with SLXL1; Co-localize in seminiferous tubules. Interacts with SLY.

Subcellular location. Secreted. Cytoplasmic vesicle. Secretory vesicle. Acrosome.

Tissue specificity. More highly expressed in adult testis than in fetal testis. Exclusively expressed in the testis (at protein level). Intense expression in stages II, III and IV of spermatogenesis, whereas expression is lower in stage I.

Post-translational modifications. N-glycosylated during spermatogenesis. Not N-glycosylated in mature sperm.

Domain organisation. Contains a N-terminal domain similar to that of the N-terminal section of DKK3.

Induction. Abnormal expression in testes of patients with male infertility.

RefSeq proteins (3): NP_001184230, NP_001184231, NP_055234* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR039863	DKK1-4	Family
IPR049632	DKKL1	Family

UniProt features (10 total): sequence variant 6, glycosylation site 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UK85-F1	55.19	0.00

Functional residue map

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

Glycosylation sites (2): 97, 112

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 145 (showing top): GOBP_SINGLE_FERTILIZATION, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOCC_SECRETORY_GRANULE, GOBP_POSITIVE_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_STEROID_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_KETONE_METABOLIC_PROCESS, GOBP_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOBP_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_KETONE_METABOLIC_PROCESS

GO Biological Process (7): penetration of zona pellucida (GO:0007341), anatomical structure morphogenesis (GO:0009653), positive regulation of apoptotic process (GO:0043065), positive regulation of fat cell differentiation (GO:0045600), canonical Wnt signaling pathway (GO:0060070), negative regulation of canonical Wnt signaling pathway (GO:0090090), negative regulation of testosterone biosynthetic process (GO:2000225)

GO Molecular Function (2): co-receptor binding (GO:0039706), receptor antagonist activity (GO:0048019)

GO Cellular Component (4): acrosomal vesicle (GO:0001669), obsolete extracellular space (GO:0005615), extracellular region (GO:0005576), cytoplasmic vesicle (GO:0031410)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
single fertilization	1
multi-multicellular organism process	1
multicellular organismal reproductive process	1
developmental process	1
anatomical structure development	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
fat cell differentiation	1
positive regulation of cell differentiation	1
regulation of fat cell differentiation	1
Wnt signaling pathway	1
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
negative regulation of steroid biosynthetic process	1
testosterone biosynthetic process	1
negative regulation of small molecule metabolic process	1
regulation of testosterone biosynthetic process	1
protein binding	1
signaling receptor binding	1
signaling receptor inhibitor activity	1
secretory granule	1
cellular anatomical structure	1
cytoplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

862 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DKKL1	KASH5	Q8N6L0	915
DKKL1	WNT2B	Q93097	762
DKKL1	DKK1	O94907	761
DKKL1	CAGE1	Q8TC20	761
DKKL1	LRP5	O75197	745
DKKL1	RAB11B	Q15907	722
DKKL1	DKK4	Q9UBT3	643
DKKL1	DKK2	Q9UBU2	594
DKKL1	CNDP2	Q96KP4	583
DKKL1	CTNNB1	P35222	561
DKKL1	WNT3A	P56704	528
DKKL1	WNT1	P04628	473
DKKL1	WNT6	Q9Y6F9	465
DKKL1	SAMSN1	Q9NSI8	461
DKKL1	SPATA19	Q7Z5L4	451

IntAct

11 interactions, top by confidence:

A	B	Type	Score
DKKL1	DENND11	psi-mi:“MI:0914”(association)	0.640
DKKL1	ABL1	psi-mi:“MI:0915”(physical association)	0.400
CRK	DKKL1	psi-mi:“MI:0915”(physical association)	0.400
FYN	DKKL1	psi-mi:“MI:0915”(physical association)	0.400
DKKL1	FJX1	psi-mi:“MI:0915”(physical association)	0.370
C11orf71	DKKL1	psi-mi:“MI:0915”(physical association)	0.370
DKKL1	Hoxa1	psi-mi:“MI:0915”(physical association)	0.370
DKKL1	VWA8	psi-mi:“MI:0914”(association)	0.350

BioGRID (170): PCDHGA11 (Affinity Capture-MS), PEX6 (Affinity Capture-MS), NUCB1 (Affinity Capture-MS), PCSK1N (Affinity Capture-MS), ITIH2 (Affinity Capture-MS), MGAT4B (Affinity Capture-MS), FAT4 (Affinity Capture-MS), RAD51B (Affinity Capture-MS), XRCC2 (Affinity Capture-MS), CELSR2 (Affinity Capture-MS), KIAA1147 (Affinity Capture-MS), CANT1 (Affinity Capture-MS), ADAMTS2 (Affinity Capture-MS), ITGA8 (Affinity Capture-MS), RAD51D (Affinity Capture-MS)

ESM2 similar proteins: A0A096P2H6, A0A0D9S1R4, A0A1B0GTZ2, A4UZ23, A5A777, A6NFE2, B3IXK1, B8VIX3, D3ZNV2, E2RE76, O46617, O70514, O76061, O88452, O97561, P05371, P0DKU6, P0DKW1, P0DKW3, P0DKY3, P10909, P11682, P14018, P15522, P17697, P25473, P55056, P57679, Q06890, Q15846, Q29482, Q29549, Q3ZRW6, Q3ZRW7, Q3ZRW9, Q5CCK0, Q5E9H1, Q5RAT2, Q5U2T4, Q5ZK77

Diamond homologs: P0CJ13, Q90839, Q9QUN9, Q9QZL9, Q9UBP4, Q9UK85

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	37
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1119 predictions. Top by Δscore:

Variant	Effect	Δscore
19:49364751:GAAA:G	donor_gain	1.0000
19:49364752:A:T	donor_gain	1.0000
19:49364752:AAA:A	donor_gain	1.0000
19:49364752:AAAGT:A	donor_loss	1.0000
19:49364754:AGTAA:A	donor_loss	1.0000
19:49364755:G:GG	donor_gain	1.0000
19:49365552:T:TA	acceptor_gain	1.0000
19:49365663:G:GT	donor_gain	1.0000
19:49365663:G:T	donor_gain	1.0000
19:49374714:CAGGT:C	acceptor_loss	1.0000
19:49374715:A:AG	acceptor_gain	1.0000
19:49374715:AG:A	acceptor_gain	1.0000
19:49374716:G:GA	acceptor_gain	1.0000
19:49374716:GG:G	acceptor_gain	1.0000
19:49374716:GGT:G	acceptor_gain	1.0000
19:49374716:GGTA:G	acceptor_gain	1.0000
19:49362374:T:TA	donor_gain	0.9900
19:49362375:C:A	donor_gain	0.9900
19:49363644:GAC:G	donor_gain	0.9900
19:49364580:A:AG	acceptor_gain	0.9900
19:49364581:G:GG	acceptor_gain	0.9900
19:49364601:AAGGC:A	acceptor_gain	0.9900
19:49364750:TGAAA:T	donor_gain	0.9900
19:49364751:GAAAG:G	donor_gain	0.9900
19:49364753:AA:A	donor_gain	0.9900
19:49364756:T:A	donor_loss	0.9900
19:49365506:CAG:C	acceptor_loss	0.9900
19:49365507:A:AG	acceptor_gain	0.9900
19:49365507:AG:A	acceptor_gain	0.9900
19:49365508:G:GG	acceptor_gain	0.9900

AlphaMissense

1570 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:49365649:G:C	K108N	0.952
19:49365649:G:T	K108N	0.952
19:49374811:T:C	I171T	0.922
19:49374804:T:C	F169L	0.912
19:49374806:C:A	F169L	0.912
19:49374806:C:G	F169L	0.912
19:49374898:T:C	I200T	0.911
19:49365826:T:C	S120P	0.909
19:49374894:G:C	A199P	0.900
19:49365812:G:T	G115V	0.890
19:49374898:T:A	I200N	0.889
19:49374901:G:C	R201P	0.888
19:49375003:T:C	I235T	0.877
19:49374898:T:G	I200S	0.874
19:49364734:T:C	F55L	0.872
19:49364736:C:A	F55L	0.872
19:49364736:C:G	F55L	0.872
19:49374811:T:G	I171S	0.870
19:49374999:T:G	Y234D	0.860
19:49365824:T:C	I119T	0.857
19:49374805:T:C	F169S	0.852
19:49365844:T:C	S126P	0.850
19:49374910:T:C	L204P	0.850
19:49365809:C:T	T114I	0.849
19:49374885:C:A	R196S	0.847
19:49365821:T:C	L118P	0.843
19:49365636:T:C	L104P	0.840
19:49374886:G:C	R196P	0.837
19:49365824:T:G	I119S	0.832
19:49365824:T:A	I119N	0.803

dbSNP variants (sampled 300 via entrez): RS1000005557 (19:49371375 T>G), RS1000176810 (19:49371707 T>A), RS1000268053 (19:49365334 G>A,C), RS1000498711 (19:49359692 G>A,T), RS1000551422 (19:49375355 T>A,C), RS1000674175 (19:49365747 A>G), RS1000873209 (19:49363857 C>A,T), RS1000934523 (19:49370035 A>G,T), RS1001003756 (19:49365919 C>A,T), RS1001879988 (19:49368794 T>C), RS1001880043 (19:49371639 T>C), RS1001909100 (19:49363079 T>C), RS1001992850 (19:49368554 C>A), RS1002858314 (19:49361607 C>T), RS1002886344 (19:49367567 T>C)

Disease associations

OMIM: gene MIM:605418 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001198_17	Multiple sclerosis	5.000000e-09
GCST005531_68	Multiple sclerosis	6.000000e-15

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
ethyl-p-hydroxybenzoate	decreases expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Arsenic	affects expression	1
Benzo(a)pyrene	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Clorgyline	increases expression	1
Fenfluramine	increases expression	1
Silicon Dioxide	decreases expression	1
Valproic Acid	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E0VJ	Ubigene Huh-7 DKKL1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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