WLS

Summary

WLS (Wnt ligand secretion mediator, HGNC:30238) is a protein-coding gene on chromosome 1p31.3, encoding Protein wntless homolog (Q5T9L3). Regulates Wnt proteins sorting and secretion in a feedback regulatory mechanism.

Enables Wnt-protein binding activity and identical protein binding activity. Involved in Wnt protein secretion; intracellular protein transport; and positive regulation of cell communication. Located in several cellular components, including Golgi apparatus; early endosome; and endoplasmic reticulum membrane. Implicated in Zaki syndrome.

Source: NCBI Gene 79971 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• Gene–disease (curated): Zaki syndrome (Strong, GenCC)
• GWAS associations: 28 (top 5% of genes corpus-wide)
• Clinical variants (ClinVar): 6 total
• GTEx eGene: eQTL in 24 tissues, sQTL in 29 (q < 0.05)
• Phenotypes (HPO): 52
• Constraint (gnomAD): pLI 0.99 (loss-of-function intolerant), LOEUF 0.47 (moderately constrained)
• MANE Select transcript: NM_024911

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30238
Approved symbol	WLS
Name	Wnt ligand secretion mediator
Location	1p31.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ23091, MRP, EVI, mig-14
Ensembl gene	ENSG00000116729
Ensembl biotype	protein_coding
OMIM	611514
Entrez	79971

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 16 protein_coding, 5 nonsense_mediated_decay, 4 protein_coding_CDS_not_defined

MANE Select: ENST00000262348

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 4, TSL 2: 1, TSL 3: 2, TSL 4: 4, TSL 5: 3

ENST00000262348, ENST00000354777, ENST00000370971, ENST00000370973, ENST00000370976, ENST00000471243, ENST00000491076, ENST00000491811, ENST00000497187, ENST00000498615, ENST00000527864, ENST00000530486, ENST00000533537, ENST00000534713, ENST00000911092, ENST00000911093, ENST00000963588, ENST00001008226, ENST00001008227, ENST00001057306, ENST00001057308, ENST00001057310, ENST00001057311, ENST00001110854, ENST00001145506

RefSeq mRNA: 3 — MANE Select: NM_024911 NM_001002292, NM_001193334, NM_024911

CCDS: CCDS30750, CCDS53331, CCDS642

Canonical transcript exons

ENST00000262348 — 12 exons

Exon	Start	End
ENSE00001007048	68137780	68137933
ENSE00001066661	68125360	68126335
ENSE00001454029	68232194	68232523
ENSE00003491318	68155099	68155260
ENSE00003507366	68150188	68150356
ENSE00003539589	68193955	68194227
ENSE00003593243	68145869	68146012
ENSE00003599222	68148136	68148199
ENSE00003611288	68144569	68144652
ENSE00003611996	68159123	68159247
ENSE00003684625	68148563	68148660
ENSE00003786865	68153517	68153653

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 98.79.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 62.0527 / max 1912.9067, expressed in 1636 samples.

Highest expression (Bgee): stromal cell of endometrium, choroid plexus epithelium, pigmented layer of retina, corpus epididymis, lower esophagus muscularis layer.

Genetic regulation across tissues (GTEx eQTL / sQTL)

WLS is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 24 tissues and its splicing (sQTL) in 29 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 53 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	sqtl	2.0e-43	-0.85	1:68125722:G:A
Skin Not Sun Exposed Suprapubic	sqtl	3.1e-38	-0.74	1:68125490:A:G
Lung	sqtl	4.0e-35	-0.75	1:68125490:A:G
Skin Sun Exposed Lower leg	sqtl	9.8e-34	-0.66	1:68125722:G:A
Testis	eqtl	2.8e-30	+0.55	1:68193074:A:G
Pancreas	sqtl	2.0e-26	+0.88	1:68131438:G:A
Cells Cultured fibroblasts	eqtl	2.3e-26	-0.33	1:68386511:A:G
Colon Sigmoid	sqtl	7.4e-25	-0.77	1:68125722:G:A
Esophagus Gastroesophageal Junction	sqtl	1.3e-22	-0.77	1:68125169:A:G
Whole Blood	eqtl	1.7e-20	+0.34	1:68271700:C:A
Testis	sqtl	1.2e-17	+0.82	1:68131438:G:A
Esophagus Muscularis	eqtl	3.0e-16	-0.39	1:68255075:G:A
Colon Sigmoid	eqtl	4.0e-14	-0.38	1:68255075:G:A
Esophagus Gastroesophageal Junction	eqtl	5.0e-14	-0.37	1:68255075:G:A
Nerve Tibial	sqtl	6.3e-14	+0.45	1:68124252:T:G
Prostate	sqtl	2.6e-12	-0.78	1:68125169:A:G
Adipose Subcutaneous	sqtl	1.0e-11	+0.45	1:68125490:A:G
Esophagus Mucosa	sqtl	3.8e-11	+0.50	1:68142763:A:G
Stomach	sqtl	2.3e-10	-0.66	1:68125169:A:G
Esophagus Muscularis	sqtl	3.6e-09	+0.38	1:68123989:C:CT

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
12782	50.2976	1614
12783	11.7552	1537

Top tissues by expression

showing 100 of 287 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	98.79	gold quality
choroid plexus epithelium	UBERON:0003911	98.41	gold quality
pigmented layer of retina	UBERON:0001782	98.32	gold quality
corpus epididymis	UBERON:0004359	97.85	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.83	gold quality
lower esophagus	UBERON:0013473	97.80	gold quality
mucosa of stomach	UBERON:0001199	97.79	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.72	gold quality
islet of Langerhans	UBERON:0000006	97.66	gold quality
gall bladder	UBERON:0002110	97.37	gold quality
cranial nerve II	UBERON:0000941	97.26	gold quality
endothelial cell	CL:0000115	97.25	gold quality
bronchial epithelial cell	CL:0002328	97.18	gold quality
caput epididymis	UBERON:0004358	97.05	gold quality
seminal vesicle	UBERON:0000998	96.92	gold quality
secondary oocyte	CL:0000655	96.90	gold quality
germinal epithelium of ovary	UBERON:0001304	96.82	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.79	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	96.76	gold quality
rectum	UBERON:0001052	96.29	gold quality
smooth muscle tissue	UBERON:0001135	96.18	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.09	gold quality
urinary bladder	UBERON:0001255	96.07	gold quality
renal medulla	UBERON:0000362	95.95	gold quality
cauda epididymis	UBERON:0004360	95.92	gold quality
pancreas	UBERON:0001264	95.91	gold quality
esophagus squamous epithelium	UBERON:0006920	95.82	gold quality
left ovary	UBERON:0002119	95.79	gold quality
epithelium of bronchus	UBERON:0002031	95.75	gold quality
bronchus	UBERON:0002185	95.64	gold quality
stomach	UBERON:0000945	95.60	gold quality
esophagus	UBERON:0001043	95.60	gold quality
body of stomach	UBERON:0001161	95.57	gold quality
body of pancreas	UBERON:0001150	95.56	gold quality
olfactory bulb	UBERON:0002264	95.40	gold quality
urethra	UBERON:0000057	95.35	gold quality
right ovary	UBERON:0002118	95.26	gold quality
caudate nucleus	UBERON:0001873	95.24	gold quality
fundus of stomach	UBERON:0001160	95.18	gold quality
lateral globus pallidus	UBERON:0002476	95.15	gold quality
endometrium	UBERON:0001295	95.01	gold quality
epithelium of esophagus	UBERON:0001976	94.99	gold quality
palpebral conjunctiva	UBERON:0001812	94.97	gold quality
visceral pleura	UBERON:0002401	94.94	gold quality
putamen	UBERON:0001874	94.90	gold quality
skin of abdomen	UBERON:0001416	94.74	gold quality
colon	UBERON:0001155	94.71	gold quality
nipple	UBERON:0002030	94.71	gold quality
ovary	UBERON:0000992	94.69	gold quality
transverse colon	UBERON:0001157	94.66	gold quality
large intestine	UBERON:0000059	94.62	gold quality
decidua	UBERON:0002450	94.59	gold quality
amygdala	UBERON:0001876	94.52	gold quality
lateral nuclear group of thalamus	UBERON:0002736	94.49	gold quality
nucleus accumbens	UBERON:0001882	94.30	gold quality
endocervix	UBERON:0000458	94.24	gold quality
adrenal tissue	UBERON:0018303	94.15	gold quality
corpus callosum	UBERON:0002336	94.08	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.08	gold quality
colonic epithelium	UBERON:0000397	94.06	gold quality
parietal pleura	UBERON:0002400	93.94	gold quality
prostate gland	UBERON:0002367	93.72	gold quality
adult mammalian kidney	UBERON:0000082	93.71	gold quality
cingulate cortex	UBERON:0003027	93.70	gold quality
anterior cingulate cortex	UBERON:0009835	93.70	gold quality
hypothalamus	UBERON:0001898	93.68	gold quality
esophagus mucosa	UBERON:0002469	93.59	gold quality
intestine	UBERON:0000160	93.56	gold quality
right lung	UBERON:0002167	93.50	gold quality
vagina	UBERON:0000996	93.49	gold quality
descending thoracic aorta	UBERON:0002345	93.47	gold quality
squamous epithelium	UBERON:0006914	93.46	gold quality
ectocervix	UBERON:0012249	93.35	gold quality
pleura	UBERON:0000977	93.30	gold quality
dorsal plus ventral thalamus	UBERON:0001897	93.28	gold quality
zone of skin	UBERON:0000014	93.27	gold quality
metanephros cortex	UBERON:0010533	93.20	gold quality
right coronary artery	UBERON:0001625	93.15	gold quality
female reproductive system	UBERON:0000474	93.14	gold quality
placenta	UBERON:0001987	93.13	gold quality
right adrenal gland cortex	UBERON:0035827	93.11	gold quality
right uterine tube	UBERON:0001302	92.92	gold quality
kidney	UBERON:0002113	92.91	gold quality
left uterine tube	UBERON:0001303	92.90	gold quality
penis	UBERON:0000989	92.85	gold quality
skin of leg	UBERON:0001511	92.85	gold quality
trachea	UBERON:0003126	92.85	gold quality
upper lobe of left lung	UBERON:0008952	92.84	gold quality
substantia nigra	UBERON:0002038	92.79	gold quality
gingival epithelium	UBERON:0001949	92.78	gold quality
thoracic aorta	UBERON:0001515	92.76	gold quality
upper lobe of lung	UBERON:0008948	92.72	gold quality
ascending aorta	UBERON:0001496	92.67	gold quality
adrenal gland	UBERON:0002369	92.66	gold quality
right adrenal gland	UBERON:0001233	92.62	gold quality
adult organism	UBERON:0007023	92.62	gold quality
temporal lobe	UBERON:0001871	92.61	gold quality
gingiva	UBERON:0001828	92.57	gold quality
midbrain	UBERON:0001891	92.57	gold quality
heart left ventricle	UBERON:0002084	92.56	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-MTAB-7008	yes	996.69
E-MTAB-9154	yes	705.99
E-HCAD-56	yes	562.72
E-MTAB-10485	yes	430.17
E-HCAD-5	yes	396.12
E-GEOD-75140	yes	370.22
E-MTAB-6108	yes	349.34
E-MTAB-10018	yes	250.07
E-GEOD-84465	yes	11.29
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Choroid plexus	tissue	221.2
Thalamus	tissue	138.6
Epididymis	tissue	128.3	medium
Retina	tissue	127.1
Superior colliculi	tissue	125.3
Midbrain	tissue	105.6
Seminal vesicle	tissue	96.1	medium
Spinal cord	tissue	94.1
Periaqueductal gray	tissue	88.4
Hippocampus	tissue	87.5	not detected
Kidney	tissue	86.4	high
Pons	tissue	84.4
Nucleus accumbens	tissue	79.2
Pancreas	tissue	78.8	medium
Postcentral gyrus	tissue	77.8
Ovary	tissue	76.6	medium
Locus coeruleus	tissue	76.3
Placenta	tissue	72.6	high
Prostate	tissue	67.2	low
Gallbladder	tissue	64.0	low
Substantia nigra	tissue	63.8
Medulla oblongata	tissue	60.8
Urinary bladder	tissue	60.1	medium
Heart muscle	tissue	59.7	not detected
Esophagus	tissue	58.5	low
Smooth muscle	tissue	57.8	medium
Colon	tissue	57.4	medium
Rectum	tissue	53.8	medium
Lung	tissue	49.9	medium
Endometrium 1	tissue	45.9	medium
Fallopian tube	tissue	45.8	medium
Stomach 1	tissue	45.7	not detected
Hippocampal formation	tissue	44.2
Cervix	tissue	44.0	low
Skin 1	tissue	43.4	medium
Putamen	tissue	42.3
Basal ganglia	tissue	40.5	not detected
Corpus callosum	tissue	40.4
Adrenal gland	tissue	40.4	high
Septum	tissue	39.0
Hypothalamus	tissue	38.4
Prefrontal cortex	tissue	37.5
Cerebral cortex	tissue	37.5	low
Motor cortex	tissue	36.4
Parathyroid gland	tissue	36.2	medium
Vagina	tissue	36.0	low
Entorhinal cortex	tissue	34.7
Amygdala	tissue	34.6
Adipose tissue	tissue	34.5	medium
Retrosplenial cortex	tissue	34.5
Breast	tissue	34.0	high
Olfactory bulb	tissue	32.2
Retrosplenial and cingulate cortex	tissue	32.0
Frontal cortex	tissue	30.9
Temporal cortex	tissue	30.7
Insular cortex	tissue	30.6
Ventral forebrain	tissue	30.2
Somatosensory cortex	tissue	29.2
Spleen	tissue	28.0	low
Occipital cortex	tissue	26.7

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Habenula (237.2), Periaquaductal grey, lateral (230.5), Pretectal area (203.5), Area postrema (190.7), Medial dorsal thalamic nucleus (179.2).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting WLS by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 49 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-200A-5P	99.76	69.10	949
HSA-MIR-200B-5P	99.76	69.05	948
HSA-MIR-29B-2-5P	99.67	68.98	1726
HSA-MIR-4470	99.66	69.35	1767
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-3975	99.62	65.97	697
HSA-MIR-451B	99.55	68.28	1380
HSA-MIR-549A-3P	99.54	68.17	825
HSA-MIR-888-3P	99.53	69.77	1057
HSA-MIR-154-3P	99.50	70.05	831
HSA-MIR-487A-3P	99.50	69.95	840
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-548V	99.29	69.47	1157
HSA-MIR-548AS-3P	99.12	69.12	2294

Functional genomics

gnomAD constraint: pLI 0.995, LOEUF 0.475, missense Z 1.73 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000262348 — one region, missense o/e 0.88.

Literature-anchored findings (GeneRIF, showing 34)

• These findings suggest a previously unrecognized role for GPR177 in regulating cellular response to opioid agonist drugs, and could create new avenues of investigation regarding the pharmacotherapy of drug dependence. (PMID:20214800)
• The relatively ubiquitous expression of GPR177 suggests that this protein may serve to regulate Wnt secretion in a variety of embryonic and adult tissue types. (PMID:20652957)
• Findings demonstrate that endocytosis motifs can occur in the intracellular loops of multipass membrane proteins and, moreover, provide direct evidence that the trafficking of Wls is required for efficient secretion of Wnt signaling proteins. (PMID:22027831)
• The Evi/Wls overexpression is sufficient to promote downstream Wnt signalling. (PMID:22147553)
• WLS functions as a negative regulator of melanoma proliferation and spontaneous metastasis by activating WNT/beta-catenin signalling. (PMID:23129487)
• findings lead to a proposed mechanism by which Gpr177 controls skeletal development through modulation of autocrine and paracrine Wnt signals in a lineage-specific fashion (PMID:23188710)
• The data suggest that the common variants of WLS analyzed in this study are not associated with opioid or cocaine addiction. (PMID:23566366)
• Evi expression in psoriatic skin biopsies is down-regulated, suggesting that Evi-deficient mice developed skin lesions that resemble human psoriasis. (PMID:23918954)
• Colorectal tumors express elevated levels of Wnt3 and GPR177. (PMID:24162018)
• endogenous WLS binds Wnts in the endoplasmic reticulum, cycles to the plasma membrane, and then returns to the endoplasmic reticulum through the Golgi. (PMID:24768165)
• GPR177 played an essential role in disease relapse and poor survival in patients with B-cell precursor acute lymphoblastic leukemia. (PMID:25115440)
• This study has revealed a strong association between the expression of WLS and HER2 that has important biological and clinical implications. (PMID:25258105)
• This study identified CMTM8 as a new candidate tumor suppressor gene and GPR177 as a new candidate oncogene in osteosarcoma. (PMID:25551557)
• Dysfunction of Wntless triggers the retrograde Golgi-to-ER transport of Wingless and induces ER stress. (PMID:26887613)
• Genetic variation at the WLS and CCDC170/ESR1 loci were found to be significantly associated with bone mineral density (PMID:26911590)
• These results indicate that WLS may play a role in invasion and metastasis of colorectal carcinoma. (PMID:27102079)
• we identified novel associations in WLS , ARHGAP1 , and 5’ of MEF2C ( P- values < 8x10 - 5 ; false discovery rate (FDR) q-values < 0.01) that were much more strongly associated with BMD compared to the GWAS SNPs. (PMID:27616567)
• Our data suggest that Wls protein is related to tumor metastasis and advanced TNM stage, and may be used as a new marker for prognosis of gastric carcinoma. (PMID:28110490)
• Wls-SEC12 binding is stable, with the interacting interface biochemically mapped to cytosolic segments of individual proteins. Mutant Wls that fails to communicate with the COPII machinery cannot effectively support Wnt secretion. These data suggest that formation of early Wnt secretory vesicles is carefully regulated to ensure proper export of functional ligands (PMID:28515233)
• WLS is an important locus for osteoporosis and its related quantitative phenotypes in a large sample derived from the Chinese Han population. In addition to the significant single SNPs that we identified, a possible regulatory role for the 20 kb genomic region around the most significant SNP, rs2566752, was defined by combining our results with ENCODE histone mark data. (PMID:29057911)
• These data showed that Wls was differentially expressed in HCC. Statistical analysis results suggest that Wls expression might increase as HCC progresses. (PMID:29127606)
• Wls is differentially expressed in Intrahepatic Cholangiocarcinoma tissues and positively related to tumor stage and lymphatic invasion. (PMID:29526886)
• GPR177 as a novel candidate for prognostic marker as well as a promising target for treatment of gastric cancer patients. (PMID:29555015)
• This study provides a brand new evidence that GOLPH3 promotes glioma cell proliferation by facilitating Wls recycling and Wnt/beta-catenin signaling. (PMID:29990993)
• MicroRNA-31 Regulates Expression of Wntless in Both Drosophila melanogaster and Human Oral Cancer Cells. (PMID:33007980)
• SNHG17 upregulates WLS expression to accelerate lung adenocarcinoma progression by sponging miR-485-5p. (PMID:33109341)
• Structural Basis of WLS/Evi-Mediated Wnt Transport and Secretion. (PMID:33357447)
• Responses of Porcupine and Wntless proteins to oxidative, hypoxic and endoplasmic reticulum stresses. (PMID:34015469)
• Cryo-EM structure of human Wntless in complex with Wnt3a. (PMID:34315898)
• GPR177 in A-fiber sensory neurons drives diabetic neuropathic pain via WNT-mediated TRPV1 activation. (PMID:35385340)
• Mutations in the WLS are associated with dental anomalies, torus palatinus, and torus mandibularis. (PMID:36374649)
• The role of Evi/Wntless in exporting Wnt proteins. (PMID:36763105)
• Compound heterozygous variants in WLS gene causes Zaki syndrome. (PMID:37005218)
• Expanding the phenotypic spectrum and clinical severity associated with WLS gene. (PMID:37106064)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	wls	ENSDARG00000009534
mus_musculus	Wls	ENSMUSG00000028173
rattus_norvegicus	Wls	ENSRNOG00000036816
drosophila_melanogaster	wls	FBGN0036141
caenorhabditis_elegans		WBGENE00003246

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1915401) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 117 distinct phenotype terms.

Mouse phenotype (MP)	Records
failure of primitive streak formation	3
absent cerebellum	2
absent mesoderm	2
embryonic growth arrest	2
absent choroid plexus	2
embryonic lethality during organogenesis, complete penetrance	2
cutaneous mastocytosis	2
delayed bone ossification	1
abnormal neurocranium morphology	1
cleft palate	1
increased neutrophil cell number	1
decreased neutrophil cell number	1
decreased cell proliferation	1
abnormal hair follicle morphology	1
decreased hair follicle number	1
sparse hair	1
abnormal craniofacial morphology	1
hydronephrosis	1
short limbs	1
abnormal forelimb morphology	1
abnormal hindlimb morphology	1
adactyly	1
oligodactyly	1
abnormal salivary gland morphology	1
abnormal muscle development	1

+92 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Drosophila persimilis	B4GZN1	99.8%	Diamond
Drosophila pseudoobscura pseudoobscura	Q2LZ37	99.8%	Diamond
Pongo abelii	Q5R9R3	99.8%	Diamond
Drosophila sechellia	B4HEB1	99.6%	Diamond
Drosophila simulans	B4QPR1	99.6%	Diamond
Drosophila yakuba	B4PF15	99.1%	Diamond
Drosophila erecta	B3NGS7	97.5%	Diamond
Xenopus laevis	Q5FWK6	95.9%	Diamond
Drosophila ananassae	B3M3X7	95.7%	Diamond
Drosophila grimshawi	B4J2W3	95.4%	Diamond
Drosophila virilis	B4LC58	95.4%	Diamond
Drosophila mojavensis	B4L184	93.6%	Diamond
Drosophila willistoni	B4N5D3	89.0%	Diamond
Gallus gallus	Q5ZLR1	87.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
GNG12-AS1	ncRNA	100289178
GNG12	protein-coding	55970
DIRAS3	protein-coding	9077
MIR1262	ncRNA	100302279
GADD45A	protein-coding	1647

Protein

Protein identifiers

Protein wntless homolog — Q5T9L3 (reviewed: Q5T9L3)

Alternative names: Integral membrane protein GPR177, Protein evenness interrupted homolog, Putative NF-kappa-B-activating protein 373

All UniProt accessions (8): E9PJW4, E9PKJ0, E9PM23, E9PM62, E9PQK1, Q5T9L3, H0YCG9, Q7Z430

UniProt curated annotations — full annotation on UniProt →

Function. Regulates Wnt proteins sorting and secretion in a feedback regulatory mechanism. This reciprocal interaction plays a key role in the regulation of expression, subcellular location, binding and organelle-specific association of Wnt proteins. Plays also an important role in establishment of the anterior-posterior body axis formation during development.

Subunit / interactions. Interacts with WNT3A. Interacts with WNT1, WNT3 and WNT5A.

Subcellular location. Golgi apparatus membrane. Cytoplasmic vesicle membrane. Cell membrane. Endoplasmic reticulum membrane. Early endosome membrane.

Post-translational modifications. N-glycosylated.

Disease relevance. Zaki syndrome (ZKS) [MIM:619648] An autosomal recessive disorder characterized by developmental delay, progressive microcephaly, and short stature, as well as dysmorphic features including sparse scalp hair, cupped ears, wide nose and mouth, short philtrum, and high-arched palate. Other variable features have been observed, including ocular, skeletal, cardiac, and renal anomalies. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the wntless family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q5T9L3-1	1	yes
Q5T9L3-2	2
Q5T9L3-3	3

RefSeq proteins (3): NP_001002292, NP_001180263, NP_079187* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009551	Wntless	Family
IPR047843	WLS-like_TM	Domain
IPR053936	WLS_GOLD	Domain

Pfam: PF06664, PF21883

UniProt features (67 total): helix 21, strand 16, topological domain 9, transmembrane region 8, sequence variant 5, splice variant 3, turn 2, chain 1, region of interest 1, sequence conflict 1

Structure

Experimental structures (PDB)

9 structures by resolution:

PDB	Title	Method	Resolution (Å)
7DRT	Human Wntless in complex with Wnt3a	ELECTRON MICROSCOPY	2.2
9Z4O	Cryo-EM structure of human Wntless in its apo state	ELECTRON MICROSCOPY	2.63
9Z4H	Cryo-EM structure of human Wntless in complex with Wnt5a at 1:1 stoichiometry	ELECTRON MICROSCOPY	2.64
8TZO	Structure of human Wnt7a bound to WLS and CALR	ELECTRON MICROSCOPY	3.1
7KC4	Human WLS in complex with WNT8A	ELECTRON MICROSCOPY	3.19
8TZP	Structure of human Wnt7a bound to WLS and RECK	ELECTRON MICROSCOPY	3.23
9Z67	Cryo-EM structure of human Wntless-Wnt5a 2:2 complex - Composite map	ELECTRON MICROSCOPY	3.32
8TZR	Structure of human Wnt3a bound to WLS and CALR	ELECTRON MICROSCOPY	3.5
8TZS	Structure of human WLS	ELECTRON MICROSCOPY	3.84

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5T9L3-F1	82.84	0.48

Human Protein Atlas

Protein class: Transporters, Accessory Factors Involved in Transport, Predicted membrane proteins, GPCRHMM predicted membrane proteins, Predicted intracellular proteins, Disease related genes, Potential drug targets

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; endoplasmic reticulum

Antibody reliability (HPA): IH approved · IF approved

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

ID	Pathway	Evidence
R-HSA-3238698	WNT ligand biogenesis and trafficking	curated
R-HSA-162582	Signal Transduction	—
R-HSA-195721	Signaling by WNT	—

MSigDB gene sets: 432 (showing top): GOBP_HINDBRAIN_DEVELOPMENT, GOBP_AXIS_SPECIFICATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, PAL_PRMT5_TARGETS_UP, GOZGIT_ESR1_TARGETS_DN, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_TOOTH_MINERALIZATION, GOBP_CELL_CELL_SIGNALING, GOBP_PANCREAS_DEVELOPMENT, GOBP_DIGESTIVE_SYSTEM_DEVELOPMENT, PICCALUGA_ANGIOIMMUNOBLASTIC_LYMPHOMA_UP

GO Biological Process (13): mesoderm formation (GO:0001707), intracellular protein transport (GO:0006886), anterior/posterior axis specification (GO:0009948), Wnt signaling pathway (GO:0016055), positive regulation of Wnt signaling pathway (GO:0030177), midbrain development (GO:0030901), hindbrain development (GO:0030902), exocrine pancreas development (GO:0031017), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), Wnt protein secretion (GO:0061355), positive regulation of Wnt protein secretion (GO:0061357), cementum mineralization (GO:0071529), positive regulation of canonical Wnt signaling pathway (GO:0090263)

GO Molecular Function (3): Wnt-protein binding (GO:0017147), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (14): Golgi membrane (GO:0000139), early endosome (GO:0005769), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), trans-Golgi network (GO:0005802), plasma membrane (GO:0005886), endomembrane system (GO:0012505), endocytic vesicle membrane (GO:0030666), organelle membrane (GO:0031090), cytoplasmic vesicle (GO:0031410), early endosome membrane (GO:0031901), extracellular exosome (GO:0070062), cytoplasmic vesicle membrane (GO:0030659)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Signaling by WNT	1
Signal Transduction	1

GO top-level categories

57 GO namespaces:

Category	Terms
cytoplasm	3
brain development	2
animal gross anatomical part developmental process	2
protein binding	2
bounding membrane of organelle	2
endomembrane system	2
intracellular membrane-bounded organelle	2
membrane	2
formation of primary germ layer	1
mesoderm morphogenesis	1
intracellular protein localization	1
protein transport	1
intracellular transport	1
axis specification	1
anterior/posterior pattern specification	1
cell surface receptor signaling pathway	1
positive regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
pancreas development	1
exocrine system development	1
gland development	1
digestive system development	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
protein secretion	1
signal release	1
positive regulation of cell communication	1
positive regulation of signaling	1
positive regulation of protein secretion	1
Wnt protein secretion	1
regulation of Wnt protein secretion	1
tooth mineralization	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
binding	1
Golgi apparatus	1
endosome	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
Golgi apparatus subcompartment	1
cell periphery	1
vacuole	1
plasma membrane	1
cellular anatomical structure	1
endocytic vesicle	1
cytoplasmic vesicle membrane	1
membrane-bounded organelle	1
intracellular vesicle	1
early endosome	1
endosome membrane	1
extracellular vesicle	1
vesicle membrane	1
cytoplasmic vesicle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 15 of 30 annotations. The rest are phylogenetic / computational / electronic (IEA).

15 experimentally-supported GO terms:

GO term	NS	Evidence
Wnt protein secretion	BP	mutant phenotype
intracellular protein transport	BP	mutant phenotype
positive regulation of Wnt protein secretion	BP	mutant phenotype
positive regulation of Wnt signaling pathway	BP	mutant phenotype
positive regulation of canonical Wnt signaling pathway	BP	mutant phenotype
Golgi apparatus	CC	direct assay
Golgi membrane	CC	direct assay
cytoplasmic vesicle	CC	direct assay
early endosome	CC	direct assay
endoplasmic reticulum	CC	direct assay
endoplasmic reticulum membrane	CC	direct assay
plasma membrane	CC	direct assay
trans-Golgi network	CC	direct assay
Wnt-protein binding	MF	physical interaction
identical protein binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 804 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WLS	TGFBR3	Q03167	776
WLS	WNT1	P04628	768
WLS	PORCN	Q9H237	741
WLS	AXIN2	Q9Y2T1	696
WLS	WNT3A	P56704	685
WLS	LRP5	O75197	677
WLS	WNT4	P56705	632
WLS	WNT5A	P41221	615
WLS	SNX3	O60493	577
WLS	CTNNB1	P35222	571
WLS	VPS35	Q96QK1	559
WLS	WNT2B	Q93097	554
WLS	WNT7B	P56706	541
WLS	WNT3	P56703	529
WLS	NOTUM	Q6P988	513

IntAct

Human interaction partners of WLS in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

22 partners by confidence:

Partner	Interaction type	MIscore	Records
OPRM1	physical association	0.820	11
WNT3A	physical association	0.780	4
WNT5A	physical association	0.560	1
WNT7A	physical association	0.560	1
CHRNB1	association	0.530	1
SLC6A3	physical association	0.520	2
ADORA2A	physical association	0.400	1
EBP	physical association	0.400	1
FAM241B	physical association	0.400	1
OPRK1	physical association	0.400	1
WNT1	physical association	0.400	1
WNT5B	physical association	0.400	1
WNT7B	physical association	0.400	1
WNT8A	physical association	0.400	1
WNT8B	physical association	0.400	1
WNT9A	physical association	0.400	1
WNT9B	physical association	0.400	1
CCR2	physical association	0.370	1
DRD2	physical association	0.370	1
GPR37	physical association	0.370	1
HRH1	physical association	0.370	1
SMO	physical association	0.370	1

BioGRID (162 interactions; top human partners by supporting records): OPRM1 (Two-hybrid; 4 records), CLEC4E (Affinity Capture-MS; 3 records), HTR3C (Affinity Capture-MS; 3 records), WNT4 (Affinity Capture-MS; 3 records), CHRND (Affinity Capture-MS; 2 records), GOLPH3 (Affinity Capture-Western; 2 records), HTR3A (Affinity Capture-MS; 2 records), KRAS (Proximity Label-MS; 2 records), RHOB (Proximity Label-MS; 2 records), SLC22A9 (Affinity Capture-MS; 2 records), TMPRSS4 (Affinity Capture-MS; 2 records), WNT5A (Affinity Capture-MS; 2 records), WNT7A (Affinity Capture-MS; 2 records), ARF6 (Proximity Label-MS), ATP2A1 (Proximity Label-MS)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
WLS	“up-regulates activity”	WNT3A	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 22 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
WNT ligand biogenesis and trafficking	10	211.5×	2e-20
Class B/2 (Secretin family receptors)	10	95.2×	7e-17
TCF dependent signaling in response to WNT	6	35.3×	4e-07

GO biological processes:

GO term	Partners	Fold	FDR
cell fate commitment	10	140.8×	2e-17
cellular response to retinoic acid	8	89.2×	2e-12
canonical Wnt signaling pathway	10	73.0×	9e-15
neuron differentiation	10	47.8×	5e-13
phospholipase C-activating G protein-coupled receptor signaling pathway	6	37.6×	7e-07

Disease & clinical

Genetic variants

Variant evidence for WLS: 6 ClinVar records (0 pathogenic / likely pathogenic); 28 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	4
Likely benign	1
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 36 predictions of 1,705):

Position(s)	Effect	Δscore	Sites
1:68137778–68137779	donor_loss	1.0000	5
1:68155097–68155098	donor_loss	1.0000	5
1:68159121–68159122	donor_loss	1.0000	5
1:68159248–68159249	acceptor_loss	1.0000	6
1:68193953	donor_gain	1.0000
1:68194084	donor_gain	1.0000
1:68134137	donor_gain	0.9900
1:68137934–68137935	acceptor_loss	0.9900	6
1:68144567–68144568	donor_loss	0.9900	5
1:68146025	acceptor_gain	0.9900

AlphaMissense

1,848 missense substitutions predicted likely pathogenic (of 3,641 scored), across 415 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M103	9	0.878	0.983
M480	9	0.874	0.992
M296	9	0.867	0.980
D301	8	0.994	0.998
F318	8	0.990	0.999
H322	8	0.988	0.998
N482	8	0.988	0.999
F432	8	0.987	0.999
F230	8	0.984	1.000
F314	8	0.984	0.999
D353	8	0.981	0.996
F352	8	0.979	0.998
F365	8	0.973	0.995
F307	8	0.953	0.989
F450	8	0.944	0.996
N210	8	0.943	0.998
F92	8	0.941	0.995
F107	8	0.937	0.997
F235	8	0.928	0.995
N227	8	0.925	0.996

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	3.21e-11

Disease associations

OMIM: gene MIM:611514 | disease phenotypes:

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
Zaki syndrome	Strong	Autosomal recessive	3

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (3 panels, 3 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

3 panels:

Panel	Rating
Fetal anomalies	green
Severe microcephaly	green
Structural eye disease	green

Mondo (1): Zaki syndrome (MONDO:0859209)

HPO phenotypes

52 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000104	Renal agenesis
HP:0000126	Hydronephrosis
HP:0000154	Wide mouth
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000322	Short philtrum
HP:0000340	Sloping forehead
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000378	Cupped ear
HP:0000384	Preauricular skin tag
HP:0000431	Wide nasal bridge
HP:0000445	Wide nose
HP:0000463	Anteverted nares
HP:0000750	Delayed speech and language development
HP:0000776	Congenital diaphragmatic hernia
HP:0000960	Sacral dimple
HP:0000974	Hyperextensible skin
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001276	Hypertonia
HP:0001320	Cerebellar vermis hypoplasia
HP:0001347	Hyperreflexia
HP:0001643	Patent ductus arteriosus
HP:0001655	Patent foramen ovale
HP:0001770	Toe syndactyly
HP:0001800	Hypoplastic toenails
HP:0002064	Spastic gait
HP:0002079	Hypoplasia of the corpus callosum
HP:0002194	Delayed gross motor development
HP:0002198	Dilated fourth ventricle
HP:0002209	Sparse scalp hair
HP:0002317	Unsteady gait
HP:0002376	Developmental regression
HP:0002650	Scoliosis
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0004322	Short stature
HP:0004396	Poor appetite
HP:0005338	Sparse lateral eyebrow
HP:0006610	Wide intermamillary distance
HP:0009836	Broad distal phalanx of finger
HP:0010746	Hypoplasia of the phalanges of the toes
HP:0010862	Delayed fine motor development
HP:0012434	Delayed early-childhood social milestone development
HP:0012488	Intraventricular arachnoid cyst
HP:0034185	Median pseudocleft lip
HP:0045075	Sparse eyebrow
HP:0100257	Ectrodactyly
HP:0100807	Long fingers

GWAS associations

28 associations:

Study	Trait	p-value
GCST006979_761	Heel bone mineral density	2e-59
GCST001482_29	Lumbar spine bone mineral density	3e-45
GCST005796_2	Lumbar spine bone mineral density	4e-23
GCST006288_129	Heel bone mineral density	5e-21
GCST009724_9	Vertical cup-disc ratio (multi-trait analysis)	4e-20
GCST005795_13	Femoral neck bone mineral density	5e-20
GCST000494_6	Bone mineral density (spine)	3e-13
GCST010699_69	Brain morphology (min-P)	3e-13
GCST000495_13	Bone mineral density (hip)	2e-12
GCST002276_14	Bone mineral density	1e-11
GCST006288_659	Heel bone mineral density	6e-11
GCST010698_75	Subcortical volume (min-P)	7e-11
GCST009724_8	Vertical cup-disc ratio (multi-trait analysis)	1e-10
GCST010703_45	Brain morphology (MOSTest)	2e-10
GCST009723_13	Vertical cup-disc ratio (adjusted for vertical disc diameter)	5e-10
GCST006288_471	Heel bone mineral density	6e-10
GCST010700_63	Cortical thickness (MOSTest)	2e-9
GCST003380_1	Bone mineral density (spine)	3e-9
GCST010701_113	Cortical surface area (MOSTest)	6e-9
GCST010696_16	Cortical thickness (min-P)	7e-9
GCST010697_29	Cortical surface area (min-P)	9e-9
GCST010702_41	Subcortical volume (MOSTest)	4e-8
GCST010268_2	Femoral neck bone mineral density	5e-8
GCST010266_3	Femoral neck bone mineral density and trunk fat mass adjusted by trunk lean mass	3e-7
GCST001621_15	Airflow obstruction	3e-6
GCST007981_3	Postoperative complication after cardiac surgery	6e-6
GCST011743_26	HDL cholesterol levels in HIV infection	6e-6
GCST008767_1	Perceived intensity of sucrose	9e-6

EFO canonical traits (from GWAS)

10 canonical traits:

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0007701	spine bone mineral density
EFO:0007785	femoral neck bone mineral density
EFO:0009270	heel bone mineral density
EFO:0005323	post-operative sign or symptom
EFO:0009951	response to surgery
EFO:0006939	cup-to-disc ratio measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0004612	high density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

55 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases methylation	5
sodium arsenite	affects methylation, decreases expression, affects cotreatment, increases abundance	3
methylmercuric chloride	decreases expression, increases expression	2
bisphenol A	decreases expression, increases methylation	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
Tretinoin	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
propionaldehyde	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
decabromobiphenyl ether	decreases expression	1
cobaltous chloride	decreases expression	1
tetrabromobisphenol A	decreases expression	1
manganese chloride	increases abundance, affects cotreatment, decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
tetrachlorodian	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
ICG 001	decreases expression	1
dorsomorphin	increases expression, affects cotreatment	1
Decitabine	affects expression	1
Zoledronic Acid	decreases expression	1
Panobinostat	affects cotreatment, increases expression	1
Acrolein	increases abundance, affects cotreatment, increases oxidation	1
Atrazine	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E2P8	HAP1 WLS (-) 1	Cancer cell line	Male
CVCL_E2P9	HAP1 WLS (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.