ADAMTS15

Summary

ADAMTS15 (ADAM metallopeptidase with thrombospondin type 1 motif 15, HGNC:16305) is a protein-coding gene on chromosome 11q24.3, encoding A disintegrin and metalloproteinase with thrombospondin motifs 15 (Q8TE58). Metalloprotease which has proteolytic activity against the proteoglycan VCAN, cleaving it at the ‘Glu-1428-|-1429-Ala’ site.

This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. ADAMTS family members share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The encoded preproprotein is proteolytically processed to generate the mature enzyme, which may play a role in versican processing during skeletal muscle development. This gene may function as a tumor suppressor in colorectal and breast cancers.

Source: NCBI Gene 170689 — RefSeq curated summary.

At a glance

• Gene–disease (curated): arthrogryposis, distal, type 12 (Strong, GenCC)
• GWAS associations: 5
• Clinical variants (ClinVar): 186 total — 4 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 29
• MANE Select transcript: NM_139055

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16305
Approved symbol	ADAMTS15
Name	ADAM metallopeptidase with thrombospondin type 1 motif 15
Location	11q24.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000166106
Ensembl biotype	protein_coding
OMIM	607509
Entrez	170689

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000299164, ENST00000948453

RefSeq mRNA: 1 — MANE Select: NM_139055 NM_139055

CCDS: CCDS8488

Canonical transcript exons

ENST00000299164 — 8 exons

Exon	Start	End
ENSE00001099844	130461489	130461621
ENSE00001099887	130462497	130462780
ENSE00001099937	130471208	130471383
ENSE00001099986	130469262	130469439
ENSE00001100031	130470920	130471101
ENSE00001100104	130462087	130462254
ENSE00001126484	130448645	130449930
ENSE00001130225	130473047	130476645

Expression profiles

Bgee: expression breadth ubiquitous, 182 present calls, max score 90.02.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
decidua	UBERON:0002450	90.02	gold quality
left ventricle myocardium	UBERON:0006566	90.02	gold quality
kidney epithelium	UBERON:0004819	88.07	silver quality
cardiac muscle of right atrium	UBERON:0003379	87.61	silver quality
parietal pleura	UBERON:0002400	87.24	gold quality
heart right ventricle	UBERON:0002080	84.49	gold quality
apex of heart	UBERON:0002098	84.13	gold quality
myocardium	UBERON:0002349	83.81	silver quality
mammary duct	UBERON:0001765	83.66	gold quality
cardiac atrium	UBERON:0002081	83.58	gold quality
epithelium of mammary gland	UBERON:0003244	83.58	gold quality
peritoneum	UBERON:0002358	83.56	gold quality
omental fat pad	UBERON:0010414	83.56	gold quality
right atrium auricular region	UBERON:0006631	83.55	gold quality
adipose tissue of abdominal region	UBERON:0007808	83.26	gold quality
heart left ventricle	UBERON:0002084	82.86	gold quality
cardiac ventricle	UBERON:0002082	82.79	gold quality
left uterine tube	UBERON:0001303	82.54	gold quality
heart	UBERON:0000948	82.04	gold quality
placenta	UBERON:0001987	81.96	gold quality
mammary gland	UBERON:0001911	81.86	gold quality
tibial artery	UBERON:0007610	81.80	gold quality
adipose tissue	UBERON:0001013	81.79	gold quality
popliteal artery	UBERON:0002250	81.79	gold quality
thoracic mammary gland	UBERON:0005200	81.69	gold quality
subcutaneous adipose tissue	UBERON:0002190	80.92	gold quality
left coronary artery	UBERON:0001626	80.35	gold quality
coronary artery	UBERON:0001621	80.19	gold quality
lower lobe of lung	UBERON:0008949	80.17	gold quality
right coronary artery	UBERON:0001625	78.22	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.29

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

163 targeting ADAMTS15, 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-6748-5P	100.00	65.81	1057
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-548AW	99.99	72.57	3559
HSA-LET-7I-5P	99.98	72.37	1788
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-6793-5P	99.97	65.95	758
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-345-3P	99.89	70.23	1421

Literature-anchored findings (GeneRIF, showing 11)

• negative effect of TGFbeta1 on ADAMTS-1, -5, -9, and -15 coupled with increases in their inhibitor, TIMP-3 may aid the accumulation of versican in the stromal compartment of the prostate in BPH and prostate cancer (PMID:15599946)
• ADAMTS8 and ADAMTS15 have emerged as novel predictors of survival in patients with breast carcinoma (PMID:16152618)
• ADAMTS15 may be target of inactivating mutations in human cancer. (PMID:19458070)
• ADAMTS-15 but not ADAMTS-1 expression was downregulated by androgen in LNCaP prostate cancer cells, possibly through androgen response elements associated with the gene (PMID:20590445)
• Versican processing by ADAMTS5 and ADAMTS15 contribute to muscle fiber formation. (PMID:23233679)
• ADAMTS-15 has multiple actions on tumor pathophysiology including modulation of cell-extracellular matrix interactions, which likely involve syndecan-4. (PMID:25099234)
• ADAMTS15 is a candidate gene for intracranial aneurysms (PMID:25649796)
• ADAMTS15 expression is significantly upregulated in human masticatory mucosa during wound healing (PMID:28005267)
• ADAMTS4 and ADAMTS15 were upregulated in symptomatic uterine leiomyomas. (PMID:28323982)
• ADAMTS-15 Has a Tumor Suppressor Role in Prostate Cancer. (PMID:32354091)
• Biallelic variants in ADAMTS15 cause a novel form of distal arthrogryposis. (PMID:35962790)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	adamts15a	ENSDARG00000029124
danio_rerio	adamts15b	ENSDARG00000033544
mus_musculus	Adamts15	ENSMUSG00000033453
rattus_norvegicus	Adamts15	ENSRNOG00000009892

Paralogs (25): ADAMTS6 (ENSG00000049192), ADAMTS2 (ENSG00000087116), PAPLN (ENSG00000100767), ADAMTS8 (ENSG00000134917), ADAMTS7 (ENSG00000136378), ADAMTS14 (ENSG00000138316), ADAMTS17 (ENSG00000140470), ADAMTS18 (ENSG00000140873), ADAMTS10 (ENSG00000142303), ADAMTSL4 (ENSG00000143382), ADAMTS16 (ENSG00000145536), ADAMTS19 (ENSG00000145808), ADAMTS12 (ENSG00000151388), ADAMTS1 (ENSG00000154734), ADAMTS5 (ENSG00000154736), ADAMTS3 (ENSG00000156140), ADAMTSL3 (ENSG00000156218), ADAMTS4 (ENSG00000158859), ADAMTS13 (ENSG00000160323), ADAMTS9 (ENSG00000163638), ADAMTS20 (ENSG00000173157), ADAMTSL1 (ENSG00000178031), ADAMTSL5 (ENSG00000185761), THSD4 (ENSG00000187720), ADAMTSL2 (ENSG00000197859)

Protein

Protein identifiers

A disintegrin and metalloproteinase with thrombospondin motifs 15 — Q8TE58 (reviewed: Q8TE58)

All UniProt accessions (1): Q8TE58

UniProt curated annotations — full annotation on UniProt →

Function. Metalloprotease which has proteolytic activity against the proteoglycan VCAN, cleaving it at the ‘Glu-1428-|-1429-Ala’ site. Cleaves VCAN in the pericellular matrix surrounding myoblasts, facilitating myoblast contact and fusion which is required for skeletal muscle development and regeneration.

Subcellular location. Secreted. Extracellular space. Extracellular matrix. Cell surface.

Tissue specificity. Expressed in fetal liver and kidney, but not in any of the adult tissues examined.

Post-translational modifications. The precursor is cleaved by a furin endopeptidase. Glycosylated. Can be O-fucosylated by POFUT2 on a serine or a threonine residue found within the consensus sequence C1-X(2)-(S/T)-C2-G of the TSP type-1 repeat domains where C1 and C2 are the first and second cysteine residue of the repeat, respectively. Fucosylated repeats can then be further glycosylated by the addition of a beta-1,3-glucose residue by the glucosyltransferase, B3GALTL. Fucosylation mediates the efficient secretion of ADAMTS family members. Can be C-glycosylated with one or two mannose molecules on tryptophan residues within the consensus sequence W-X-X-W of the TPRs. Also N-glycosylated. These other glycosylations can also facilitate secretion.

Disease relevance. Arthrogryposis, distal, 12 (DA12) [MIM:620545] A form of distal arthrogryposis, a disease characterized by congenital joint contractures that mainly involve two or more distal parts of the limbs, in the absence of a primary neurological or muscle disease. DA12 is an autosomal recessive form characterized by congenital contractures, primarily affecting the small joints of the fingers and toes. Additional features include knee, Achilles tendon, and toe contractures, spinal stiffness, scoliosis, and orthodontic abnormalities. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 zinc ion per subunit.

Domain organisation. The spacer domain and the TSP type-1 domains are important for a tight interaction with the extracellular matrix. The conserved cysteine present in the cysteine-switch motif binds the catalytic zinc ion, thus inhibiting the enzyme. The dissociation of the cysteine from the zinc ion upon the activation-peptide release activates the enzyme.

RefSeq proteins (1): NP_620686* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000884	TSP1_rpt	Repeat
IPR001590	Peptidase_M12B	Domain
IPR002870	Peptidase_M12B_N	Domain
IPR006586	ADAM_Cys-rich	Domain
IPR010294	ADAMTS_spacer1	Domain
IPR013273	ADAMTS/ADAMTS-like	Family
IPR013277	Pept_M12B_ADAM-TS8	Family
IPR024079	MetalloPept_cat_dom_sf	Homologous_superfamily
IPR036383	TSP1_rpt_sf	Homologous_superfamily
IPR041645	ADAMTS_CR_2	Domain
IPR045371	ADAMTS_CR_3	Domain
IPR050439	ADAMTS_ADAMTS-like	Family

Pfam: PF00090, PF01421, PF01562, PF05986, PF17771, PF19030, PF19236

Enzyme classification (BRENDA):

• EC 3.4.24.B12 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

UniProt features (39 total): disulfide bond 11, sequence variant 6, domain 5, binding site 4, glycosylation site 4, region of interest 3, signal peptide 1, propeptide 1, short sequence motif 1, compositionally biased region 1, active site 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TE58-F1	77.87	0.31

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 (1): 362

Ligand- & substrate-binding residues (4): 174 (in inhibited form); 361; 365; 371

Disulfide bonds (11): 293–345, 322–327, 339–422, 377–406, 448–470, 459–480, 465–499, 493–504, 528–565, 532–570, 543–555

Glycosylation sites (4): 141, 591, 623, 679

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-5083635	Defective B3GALTL causes PpS
R-HSA-5173214	O-glycosylation of TSR domain-containing proteins
R-HSA-1643685	Disease
R-HSA-3781865	Diseases of glycosylation
R-HSA-3906995	Diseases associated with O-glycosylation of proteins
R-HSA-392499	Metabolism of proteins
R-HSA-5173105	O-linked glycosylation
R-HSA-5668914	Diseases of metabolism
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 230 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, RNGTGGGC_UNKNOWN, BENPORATH_ES_WITH_H3K27ME3, GOMF_METALLOPEPTIDASE_ACTIVITY, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOCC_CELL_SURFACE, BILD_HRAS_ONCOGENIC_SIGNATURE, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, GOMF_GLYCOSAMINOGLYCAN_BINDING, GOBP_MYOTUBE_DIFFERENTIATION, GOBP_EXTRACELLULAR_MATRIX_DISASSEMBLY, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS

GO Biological Process (4): proteolysis (GO:0006508), myoblast fusion (GO:0007520), extracellular matrix disassembly (GO:0022617), extracellular matrix organization (GO:0030198)

GO Molecular Function (9): endopeptidase activity (GO:0004175), metalloendopeptidase activity (GO:0004222), heparin binding (GO:0008201), zinc ion binding (GO:0008270), extracellular matrix binding (GO:0050840), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (5): obsolete extracellular space (GO:0005615), cell surface (GO:0009986), extracellular matrix (GO:0031012), extracellular region (GO:0005576), obsolete collagen-containing extracellular matrix (GO:0062023)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Diseases associated with O-glycosylation of proteins	1
O-linked glycosylation	1
Diseases of metabolism	1
Diseases of glycosylation	1
Post-translational protein modification	1
Disease	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
peptidase activity	2
cellular anatomical structure	2
protein metabolic process	1
syncytium formation by cell-cell fusion	1
myotube differentiation	1
cellular component disassembly	1
extracellular matrix organization	1
extracellular structure organization	1
external encapsulating structure organization	1
endopeptidase activity	1
metallopeptidase activity	1
glycosaminoglycan binding	1
sulfur compound binding	1
transition metal ion binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
cation binding	1
external encapsulating structure	1

Protein interactions and networks

STRING

734 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADAMTS15	ACAN	P16112	671
ADAMTS15	FURIN	P09958	536
ADAMTS15	CD36	P16671	467
ADAMTS15	BCAN	Q96GW7	467
ADAMTS15	SCARB2	Q14108	441
ADAMTS15	THSD1	Q9NS62	431
ADAMTS15	SCARB1	Q8WTV0	430
ADAMTS15	SERPINE3	A8MV23	429
ADAMTS15	RNF213	Q63HN8	385
ADAMTS15	ZNF222	Q9UK12	377
ADAMTS15	HAPLN4	Q86UW8	376
ADAMTS15	MMP16	P51512	370
ADAMTS15	TIMP3	P35625	364
ADAMTS15	MMP24	Q9Y5R2	358
ADAMTS15	SHISAL2A	Q6UWV7	354

IntAct

5 interactions, top by confidence:

A	B	Type	Score
PDGFRA	GXYLT2	psi-mi:“MI:0914”(association)	0.350
NOTCH2	ZNF320	psi-mi:“MI:0914”(association)	0.350
CCL3	KRBA1	psi-mi:“MI:0914”(association)	0.350
ST14	LIPT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (10): ADAMTS15 (Affinity Capture-MS), ADAMTS15 (Affinity Capture-RNA), ADAMTS15 (Protein-RNA), ADAMTS15 (Affinity Capture-RNA), ADAMTS15 (Affinity Capture-MS), ADAMTS15 (Affinity Capture-MS), ADAMTS15 (Affinity Capture-MS), ADAMTS15 (Affinity Capture-MS), ADAMTS4 (Negative Genetic), DDX39B (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A8M9PFP2, A2A863, A2VE29, A6X935, O02668, P01029, P01030, P08649, P0C0L4, P0C0L5, P16144, P19069, P19823, P19827, P56652, P58459, P59384, P79263, P97278, P97279, P97280, P97857, Q06033, Q06274, Q0VCM5, Q14624, Q1EHB3, Q29052, Q3T052, Q5RB37, Q5RER0, Q60750, Q61702, Q61703, Q61704, Q63416, Q64632, Q68SA9, Q86UX2, Q8BG22

Diamond homologs: A2VEC9, A6QNY1, B3EWZ3, B3EWZ8, C0HL12, C5IAW9, D3YXG0, D3ZTD8, F1LW30, O08721, O08722, O08747, O14514, O15072, O55225, O60241, O60242, O75173, O88783, O95185, O95450, P04275, P07358, P07996, P27918, P35441, P35442, P35448, P55314, P57110, P58397, P58459, P59384, P79331, P80012, P97857, P98088, P98092, P98160, P98164

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	3
Uncertain significance	157
Likely benign	9
Benign	4

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
2584761	NM_139055.4(ADAMTS15):c.123C>G (p.Tyr41Ter)	Pathogenic
2584762	NM_139055.4(ADAMTS15):c.1903-2A>G	Pathogenic
2584763	NM_139055.4(ADAMTS15):c.2281G>A (p.Gly761Ser)	Pathogenic
563878	GRCh37/hg19 11q24.2-25(chr11:127690585-132404117)x1	Pathogenic
150923	GRCh38/hg38 11q24.3-25(chr11:128867946-133086998)x1	Likely pathogenic
2584764	NM_139055.4(ADAMTS15):c.2715C>G (p.Cys905Trp)	Likely pathogenic
4277881	NM_139055.4(ADAMTS15):c.1903-2A>C	Likely pathogenic

SpliceAI

1453 predictions. Top by Δscore:

Variant	Effect	Δscore
11:130461480:ACCC:A	acceptor_gain	1.0000
11:130461617:GCTGG:G	donor_gain	1.0000
11:130461618:C:G	donor_gain	1.0000
11:130461618:CTGGG:C	donor_loss	1.0000
11:130461619:TGGG:T	donor_loss	1.0000
11:130461620:GG:G	donor_gain	1.0000
11:130461621:GG:G	donor_gain	1.0000
11:130461621:GGTAA:G	donor_loss	1.0000
11:130461622:G:GG	donor_gain	1.0000
11:130461622:GTAA:G	donor_loss	1.0000
11:130461623:T:G	donor_loss	1.0000
11:130462085:A:AG	acceptor_gain	1.0000
11:130462085:A:AT	acceptor_loss	1.0000
11:130462086:G:GA	acceptor_gain	1.0000
11:130462086:GGC:G	acceptor_gain	1.0000
11:130462086:GGCC:G	acceptor_gain	1.0000
11:130462086:GGCCA:G	acceptor_gain	1.0000
11:130462250:GCACG:G	donor_gain	1.0000
11:130462254:GGT:G	donor_loss	1.0000
11:130462255:G:GC	donor_loss	1.0000
11:130462255:G:GG	donor_gain	1.0000
11:130462256:T:G	donor_loss	1.0000
11:130462493:GCA:G	acceptor_loss	1.0000
11:130462494:CAG:C	acceptor_loss	1.0000
11:130462495:A:AG	acceptor_gain	1.0000
11:130462495:A:C	acceptor_loss	1.0000
11:130462496:G:GG	acceptor_gain	1.0000
11:130462496:G:T	acceptor_loss	1.0000
11:130462496:GGT:G	acceptor_gain	1.0000
11:130462779:GG:G	donor_gain	1.0000

AlphaMissense

6145 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:130449851:G:A	C293Y	1.000
11:130449852:T:G	C293W	1.000
11:130461495:T:A	C322S	1.000
11:130461496:G:A	C322Y	1.000
11:130461496:G:C	C322S	1.000
11:130461511:G:A	C327Y	1.000
11:130461546:T:A	C339S	1.000
11:130461547:G:A	C339Y	1.000
11:130461547:G:C	C339S	1.000
11:130461564:T:C	C345R	1.000
11:130461565:G:A	C345Y	1.000
11:130461566:C:G	C345W	1.000
11:130461571:T:A	V347D	1.000
11:130461612:C:G	H361D	1.000
11:130461616:A:T	E362V	1.000
11:130462203:T:A	W403R	1.000
11:130462203:T:C	W403R	1.000
11:130462205:G:C	W403C	1.000
11:130462205:G:T	W403C	1.000
11:130462580:T:A	C448S	1.000
11:130462581:G:C	C448S	1.000
11:130462645:G:C	W469C	1.000
11:130462645:G:T	W469C	1.000
11:130469276:G:C	W519C	1.000
11:130469276:G:T	W519C	1.000
11:130469285:G:C	W522C	1.000
11:130469285:G:T	W522C	1.000
11:130471008:G:C	W603C	1.000
11:130471008:G:T	W603C	1.000
11:130471045:T:A	C616S	1.000

dbSNP variants (sampled 300 via entrez): RS1000062615 (11:130453049 A>G), RS1000153626 (11:130461916 A>C,G), RS1000201193 (11:130464123 G>A,T), RS1000203797 (11:130451295 A>G), RS1000303514 (11:130470442 C>T), RS1000348955 (11:130464694 C>G), RS1000405202 (11:130458388 C>A,T), RS1000406952 (11:130446774 A>C), RS1000501705 (11:130469148 T>C), RS1000524855 (11:130466623 T>C), RS1000986952 (11:130473959 G>A), RS1001043151 (11:130468541 G>A), RS1001168286 (11:130475795 T>C), RS1001437686 (11:130465772 C>T), RS1001573570 (11:130463302 C>T)

Disease associations

OMIM: gene MIM:607509 | disease phenotypes: MIM:620545

GenCC curated gene-disease

Disease	Classification	Inheritance
arthrogryposis, distal, type 12	Strong	Autosomal recessive

Mondo (2): arthrogryposis, distal, type 12 (MONDO:0957819), neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000034	Hydrocele testis
HP:0000218	High palate
HP:0000316	Hypertelorism
HP:0000369	Low-set ears
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000678	Dental crowding
HP:0001032	Absent distal interphalangeal creases
HP:0001249	Intellectual disability
HP:0001634	Mitral valve prolapse
HP:0001762	Talipes equinovarus
HP:0001771	Achilles tendon contracture
HP:0002650	Scoliosis
HP:0002942	Thoracic kyphosis
HP:0003306	Spinal rigidity
HP:0003577	Congenital onset
HP:0004209	Clinodactyly of the 5th finger
HP:0005879	Congenital finger flexion contractures
HP:0006089	Palmar hyperhidrosis
HP:0006380	Knee flexion contracture
HP:0006466	Ankle flexion contracture
HP:0009130	Hand muscle atrophy
HP:0009884	Tapered distal phalanges of finger
HP:0031006	Acroparesthesia
HP:0033748	Hypoesthesia
HP:0200160	Agenesis of maxillary incisor

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002127_22	Periodontitis (Mean PAL)	4.000000e-06
GCST002127_9	Periodontitis (Mean PAL)	3.000000e-06
GCST002830_11	Urate levels in lean individuals	4.000000e-06
GCST002830_19	Urate levels in lean individuals	2.000000e-06
GCST009391_1448	Metabolite levels	7.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0010409	triacylglycerol 50:2 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — M12: Astacin/Adamalysin

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	4
sodium arsenite	decreases expression, increases expression	3
Particulate Matter	affects expression, increases abundance, decreases expression	3
trichostatin A	affects cotreatment, increases expression	2
mono-(2-ethylhexyl)phthalate	increases expression, decreases expression	2
S-(1,2-dichlorovinyl)cysteine	decreases expression, affects response to substance, increases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
bisphenol A	increases expression	1
sulforaphane	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	increases expression, affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1
belinostat	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	decreases expression	1
Air Pollutants	affects expression, increases abundance, decreases expression	1
Allergens	decreases expression	1
Arsenic	affects methylation	1
Vehicle Emissions	decreases methylation	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	decreases expression	1
Estradiol	increases expression	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment, decreases expression	1
Oxygen	increases expression	1
Phenylmercuric Acetate	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice