APCDD1

Summary

APCDD1 (APC down-regulated 1, HGNC:15718) is a protein-coding gene on chromosome 18p11.22, encoding Protein APCDD1 (Q8J025). Negative regulator of the Wnt signaling pathway.

This locus encodes an inhibitor of the Wnt signaling pathway. Mutations at this locus have been associated with hereditary hypotrichosis simplex. Increased expression of this gene may also be associated with colorectal carcinogenesis.

Source: NCBI Gene 147495 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypotrichosis 1 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 183 total — 2 pathogenic
• Phenotypes (HPO): 13
• MANE Select transcript: NM_153000

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15718
Approved symbol	APCDD1
Name	APC down-regulated 1
Location	18p11.22
Locus type	gene with protein product
Status	Approved
Aliases	B7323
Ensembl gene	ENSG00000154856
Ensembl biotype	protein_coding
OMIM	607479
Entrez	147495

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 3 nonsense_mediated_decay

ENST00000355285, ENST00000423585, ENST00000578882, ENST00000579685, ENST00000582723, ENST00000584596

RefSeq mRNA: 1 — MANE Select: NM_153000 NM_153000

CCDS: CCDS11849

Canonical transcript exons

ENST00000355285 — 5 exons

Exon	Start	End
ENSE00001018142	10468469	10468652
ENSE00001428843	10454635	10455039
ENSE00001832122	10487590	10489949
ENSE00003520431	10485462	10485783
ENSE00003619676	10471530	10472061

Expression profiles

Bgee: expression breadth ubiquitous, 249 present calls, max score 99.80.

FANTOM5 (CAGE): breadth broad, TPM avg 20.3028 / max 1816.8901, expressed in 911 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
169407	12.1307	849
169408	7.3207	679
169409	0.2358	114
169406	0.2123	124
169411	0.1615	85
169413	0.1537	75
169412	0.0881	33

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper arm skin	UBERON:0004263	99.80	gold quality
nipple	UBERON:0002030	99.13	gold quality
decidua	UBERON:0002450	99.13	gold quality
mammalian vulva	UBERON:0000997	99.07	gold quality
upper leg skin	UBERON:0004262	98.91	gold quality
penis	UBERON:0000989	98.58	gold quality
skin of hip	UBERON:0001554	98.09	gold quality
urethra	UBERON:0000057	97.90	gold quality
cardiac muscle of right atrium	UBERON:0003379	97.47	gold quality
endometrium	UBERON:0001295	96.92	gold quality
skin of abdomen	UBERON:0001416	96.90	gold quality
zone of skin	UBERON:0000014	96.86	gold quality
skin of leg	UBERON:0001511	96.33	gold quality
lateral globus pallidus	UBERON:0002476	95.15	gold quality
cardia of stomach	UBERON:0001162	94.97	gold quality
medial globus pallidus	UBERON:0002477	94.74	gold quality
left uterine tube	UBERON:0001303	94.64	gold quality
globus pallidus	UBERON:0001875	94.55	gold quality
bronchial epithelial cell	CL:0002328	94.46	gold quality
bronchus	UBERON:0002185	94.30	gold quality
pylorus	UBERON:0001166	94.18	gold quality
vena cava	UBERON:0004087	94.00	gold quality
uterus	UBERON:0000995	93.73	gold quality
trachea	UBERON:0003126	93.68	gold quality
gall bladder	UBERON:0002110	93.59	gold quality
mucosa of stomach	UBERON:0001199	93.46	gold quality
pharyngeal mucosa	UBERON:0000355	93.43	gold quality
urinary bladder	UBERON:0001255	93.43	gold quality
fallopian tube	UBERON:0003889	93.22	gold quality
mammary duct	UBERON:0001765	93.14	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-23	yes	644.82
E-MTAB-10287	yes	617.31
E-MTAB-7407	yes	587.54
E-ANND-3	yes	16.48
E-MTAB-10290	no	582.04

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1, TCF7L2

miRNA regulators (miRDB)

78 targeting APCDD1, 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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4728-5P	99.85	69.39	4718

Literature-anchored findings (GeneRIF, showing 9)

• APCDD1 is a novel inhibitor of the Wnt signalling pathway with an essential role in human hair growth (PMID:20393562)
• Data show that the methylated VAPA-APCDD1 DNA in maternal plasma is predominantly derived from the fetus, and this novel fetal epigenetic marker in maternal plasma is useful for the noninvasive detection of fetal trisomy 18. (PMID:21152411)
• mutation in the APCDD1 gene is responsible for hereditary hypotrichosis simplex in a large Chinese family. (PMID:22512811)
• Unusual role of APCDD1 in dental follicle cells during osteogenic differentiation. APCDD1 sustains the expression and activation of beta-catenin. (PMID:25592970)
• This study demonstrated a critical role for Apcdd1 in OL differentiation after white matter injury that points to a potential therapeutic approach for inhibiting Wnt signaling in these disorders. (PMID:25946682)
• these novel findings suggest that APCDD1 positively regulates adipogenic differentiation and that its down-regulation by miR-130 during diet-induced obesity may contribute to impaired adipogenic differentiation and obesity-related metabolic disease. (PMID:28242765)
• Thus, we have provided the first evidence that APCDD1 expression is epigenetically silenced in OS, which may facilitate invasion and metastasis of OS cells. (PMID:28698141)
• Through integrative analysis, we identify MEIS1 as a super-enhancer-driven oncogene, which co-operates with EWS-FLI1 in transcriptional regulation, and plays a key pro-survival role in Ewing sarcoma. Moreover, APCDD1, another super-enhancer-associated gene, acting as a downstream target of both MEIS1 and EWS-FLI1, is also characterized as a novel tumor-promoting factor in this malignancy (PMID:30496486)
• Whole Exome Sequencing Identifies APCDD1 and HDAC5 Genes as Potentially Cancer Predisposing in Familial Colorectal Cancer. (PMID:33673279)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	APCDD1	ENSDARG00000098203
mus_musculus	Apcdd1	ENSMUSG00000071847
rattus_norvegicus	Apcdd1	ENSRNOG00000043304

Paralogs (1): APCDD1L (ENSG00000198768)

Protein

Protein identifiers

Protein APCDD1 — Q8J025 (reviewed: Q8J025)

Alternative names: Adenomatosis polyposis coli down-regulated 1 protein

All UniProt accessions (6): Q8J025, J3KTQ6, J3KTR1, J3QSE3, V9GY82, X6RH63

UniProt curated annotations — full annotation on UniProt →

Function. Negative regulator of the Wnt signaling pathway. Inhibits Wnt signaling in a cell-autonomous manner and functions upstream of beta-catenin. May act via its interaction with Wnt and LRP proteins. May play a role in colorectal tumorigenesis.

Subunit / interactions. Homodimer. Interacts with LRP5 and WNT3A.

Subcellular location. Cell membrane.

Tissue specificity. Abundantly expressed in heart, pancreas, prostate and ovary. Moderately expressed in lung, liver, kidney, spleen, thymus, colon and peripheral lymphocytes. Abundantly expressed in both the epidermal and dermal compartments of the hair follicle. Present in scalp skin Highly expressed in the hair follicle dermal papilla, the matrix, and the hair shaft (at protein level).

Post-translational modifications. N-Glycosylated.

Disease relevance. Hypotrichosis 1 (HYPT1) [MIM:605389] A rare form of non-syndromic hereditary hypotrichosis without characteristic hair shaft anomalies. Affected individuals typically show normal hair at birth, but hair loss and thinning of the hair shaft start during early childhood and progress with age. HYPT1 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Induction. Target gene of the Wnt/Beta-catenin pathway, transcriptionally regulated by the CTNNB1/TF7L2 complex.

Similarity. Belongs to the APCDD1 family.

RefSeq proteins (1): NP_694545* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029405	APCDD1_dom	Domain
IPR042425	APCDD1	Family

Pfam: PF14921

UniProt features (11 total): glycosylation site 3, sequence variant 2, topological domain 2, signal peptide 1, chain 1, transmembrane region 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8J025-F1	82.10	0.64

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 (3): 100, 168, 319

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 171 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, GOBP_EPITHELIUM_DEVELOPMENT, TSENG_IRS1_TARGETS_UP, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, CHANDRAN_METASTASIS_DN, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, ODONNELL_TARGETS_OF_MYC_AND_TFRC_UP, GOBP_REGULATION_OF_ODONTOGENESIS, GOBP_MOLTING_CYCLE, GOBP_EPIDERMIS_DEVELOPMENT, GOBP_GLIAL_CELL_MIGRATION, NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_DN, AFFAR_YY1_TARGETS_DN

GO Biological Process (5): hair follicle development (GO:0001942), Wnt signaling pathway (GO:0016055), negative regulation of Wnt signaling pathway (GO:0030178), regulation of odontogenesis of dentin-containing tooth (GO:0042487), astrocyte cell migration (GO:0043615)

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

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	2
hair cycle process	1
anatomical structure development	1
skin epidermis development	1
cell surface receptor signaling pathway	1
negative regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
odontogenesis of dentin-containing tooth	1
regulation of odontogenesis	1
glial cell migration	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

864 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APCDD1	LRP5	O75197	988
APCDD1	WNT3A	P56704	949
APCDD1	CD7	P09564	825
APCDD1	CDSN	Q15517	640
APCDD1	CTNNB1	P35222	612
APCDD1	AXIN2	Q9Y2T1	589
APCDD1	TRABD2A	Q86V40	571
APCDD1	NKD1	Q969G9	569
APCDD1	NOTUM	Q6P988	548
APCDD1	WNT3	P56703	537
APCDD1	ZNRF3	Q9ULT6	522
APCDD1	WIF1	Q9Y5W5	500
APCDD1	LPAR6	P43657	482
APCDD1	FZD6	O60353	476
APCDD1	LEF1	Q9UJU2	467

IntAct

12 interactions, top by confidence:

A	B	Type	Score
APCDD1	JCHAIN	psi-mi:“MI:0914”(association)	0.530
APCDD1	LRP5	psi-mi:“MI:0915”(physical association)	0.520
APCDD1	WNT3A	psi-mi:“MI:0915”(physical association)	0.520
APCDD1	APCDD1	psi-mi:“MI:0915”(physical association)	0.400
APCDD1	RXRB	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (8): MPO (Affinity Capture-MS), IGHA2 (Affinity Capture-MS), IGJ (Affinity Capture-MS), LTF (Affinity Capture-MS), HBB (Affinity Capture-MS), IGHA2 (Affinity Capture-MS), IGJ (Affinity Capture-MS), MPO (Affinity Capture-MS)

ESM2 similar proteins: A1L134, A4D1U4, A6NFY4, A7MB75, D3Z291, F1NNL1, O43292, O95870, P51571, P70295, Q0PGW2, Q0VF94, Q17RQ9, Q1JPD2, Q28DH9, Q2HJ63, Q2TBX5, Q3U128, Q3U284, Q3UHG7, Q3UX43, Q4R8P0, Q5FVM1, Q5HYA8, Q5NDE9, Q5NDF0, Q5NDF2, Q5R6S0, Q5RBT8, Q5REH6, Q5RJQ8, Q6DDX8, Q6MG55, Q8BJQ9, Q8BXQ2, Q8C1F4, Q8IU99, Q8J025, Q8TDX6, Q8VEC4

Diamond homologs: Q3U128, Q5R2I8, Q5R2J4, Q66KI8, Q6DF34, Q8J025, Q8NCL9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	113
Likely benign	24
Benign	34

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1701345	GRCh37/hg19 18p11.32-11.21(chr18:47390-14854037)x3	Pathogenic
3161	NM_153000.5(APCDD1):c.26T>G (p.Leu9Arg)	Pathogenic

SpliceAI

740 predictions. Top by Δscore:

Variant	Effect	Δscore
18:10472057:CCAAG:C	donor_loss	1.0000
18:10472062:G:C	donor_loss	1.0000
18:10472063:T:G	donor_loss	1.0000
18:10485780:AAAG:A	donor_loss	1.0000
18:10485781:AAGG:A	donor_loss	1.0000
18:10485782:AGG:A	donor_loss	1.0000
18:10485783:GGT:G	donor_loss	1.0000
18:10485785:T:G	donor_loss	1.0000
18:10487585:T:TA	acceptor_gain	1.0000
18:10487585:TGCA:T	acceptor_loss	1.0000
18:10487588:A:AG	acceptor_gain	1.0000
18:10487588:A:T	acceptor_loss	1.0000
18:10487588:AGT:A	acceptor_gain	1.0000
18:10487589:G:GT	acceptor_gain	1.0000
18:10487589:GT:G	acceptor_gain	1.0000
18:10487589:GTG:G	acceptor_gain	1.0000
18:10487589:GTGA:G	acceptor_gain	1.0000
18:10487589:GTGAA:G	acceptor_gain	1.0000
18:10455038:CGGTG:C	donor_loss	0.9900
18:10455039:GGT:G	donor_loss	0.9900
18:10455040:G:GA	donor_loss	0.9900
18:10455041:T:G	donor_loss	0.9900
18:10471523:T:A	acceptor_gain	0.9900
18:10472013:G:GT	donor_gain	0.9900
18:10485453:T:TA	acceptor_gain	0.9900
18:10485456:CTTCA:C	acceptor_loss	0.9900
18:10485457:TTCAG:T	acceptor_loss	0.9900
18:10485458:TCAG:T	acceptor_loss	0.9900
18:10485460:A:AG	acceptor_gain	0.9900
18:10485460:AGA:A	acceptor_loss	0.9900

AlphaMissense

3389 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:10485570:T:A	W295R	1.000
18:10485570:T:C	W295R	1.000
18:10485572:G:C	W295C	1.000
18:10485572:G:T	W295C	1.000
18:10485576:A:C	S297R	1.000
18:10485578:C:A	S297R	1.000
18:10485578:C:G	S297R	1.000
18:10485586:G:A	C300Y	1.000
18:10485651:T:A	W322R	1.000
18:10485651:T:C	W322R	1.000
18:10485653:G:C	W322C	1.000
18:10485653:G:T	W322C	1.000
18:10485687:T:A	C334S	1.000
18:10485687:T:C	C334R	1.000
18:10485688:G:A	C334Y	1.000
18:10485688:G:C	C334S	1.000
18:10487679:T:A	W396R	1.000
18:10487679:T:C	W396R	1.000
18:10487681:G:C	W396C	1.000
18:10487681:G:T	W396C	1.000
18:10487721:T:A	C410S	1.000
18:10487721:T:C	C410R	1.000
18:10487722:G:A	C410Y	1.000
18:10487722:G:C	C410S	1.000
18:10487723:C:G	C410W	1.000
18:10471565:G:T	R93M	0.999
18:10471688:C:T	S134F	0.999
18:10471690:T:A	W135R	0.999
18:10471690:T:C	W135R	0.999
18:10471692:G:C	W135C	0.999

dbSNP variants (sampled 300 via entrez): RS1000064024 (18:10466975 G>A,C), RS1000119478 (18:10460880 A>G), RS1000137318 (18:10476469 G>A), RS1000167598 (18:10473238 T>C), RS1000366760 (18:10484776 A>G), RS1000369564 (18:10463436 ACAAACACAGGAGCTC>A), RS1000405422 (18:10467427 G>T), RS1000415391 (18:10466628 G>A), RS1000418969 (18:10485266 G>C), RS1000483762 (18:10487474 T>C), RS1000555032 (18:10472296 C>T), RS1000670615 (18:10454925 T>C), RS1000697867 (18:10483650 G>A,C), RS1000742306 (18:10477842 G>T), RS1000751899 (18:10483827 G>A)

Disease associations

OMIM: gene MIM:607479 | disease phenotypes: MIM:605389

GenCC curated gene-disease

Disease	Classification	Inheritance
hypotrichosis 1	Strong	Autosomal dominant
hypotrichosis simplex	Supportive	Autosomal dominant

Mondo (2): hypotrichosis 1 (MONDO:0011549), hypotrichosis simplex (MONDO:0018914)

Orphanet (1): Hypotrichosis simplex (Orphanet:55654)

HPO phenotypes

13 total (13 of 13 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000164	Abnormality of the dentition
HP:0000653	Sparse eyelashes
HP:0000951	Abnormality of the skin
HP:0001596	Alopecia
HP:0001597	Abnormal nail morphology
HP:0002209	Sparse scalp hair
HP:0002215	Sparse axillary hair
HP:0002225	Sparse pubic hair
HP:0002231	Sparse body hair
HP:0008070	Sparse hair
HP:0011463	Childhood onset
HP:0045075	Sparse eyebrow

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001210_1	Non-small cell lung cancer	1.000000e-06
GCST002118_13	Metabolite levels (Pyroglutamine)	2.000000e-06
GCST002166_13	Serum protein levels (sST2)	9.000000e-07
GCST011939_31	Takayasu arteritis	5.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005408	pyroglutamine measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537160	Hypotrichosis simplex (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs564991	APCDD1		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression, decreases methylation	6
bisphenol A	decreases expression, decreases methylation, affects cotreatment, increases expression	3
Dexamethasone	increases expression, affects cotreatment	3
methylmercuric chloride	decreases expression, increases expression	2
sodium arsenite	decreases expression, increases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
bisphenol S	increases expression, affects cotreatment	2
Tetrachlorodibenzodioxin	affects expression, increases expression	2
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
sodium arsenate	decreases expression, increases abundance	1
trichostatin A	increases expression	1
beta-lapachone	decreases expression	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
ferrous chloride	decreases expression	1
aflatoxin B2	decreases methylation	1
1-nitropyrene	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
Sunitinib	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Calcitriol	decreases expression	1
Carbamazepine	affects expression	1
Doxorubicin	affects expression	1
Indomethacin	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03492866	PHASE2	UNKNOWN	Efficacy of Topical Gentamycin for Hereditary Hypotrichosis Simplex Caused by Nonsense Mutations in CDSN