MGP

Summary

MGP (matrix Gla protein, HGNC:7060) is a protein-coding gene on chromosome 12p12.3, encoding Matrix Gla protein (P08493). Associates with the organic matrix of bone and cartilage.

This gene encodes a member of the osteocalcin/matrix Gla family of proteins. The encoded vitamin K-dependent protein is secreted by chondrocytes and vascular smooth muscle cells, and functions as a physiological inhibitor of ectopic tissue calcification. Carboxylation status of the encoded protein is associated with calcification of the vasculature in human patients with cardiovascular disease and calcification of the synovial membranes in osteoarthritis patients. Mutations in this gene cause Keutel syndrome in human patients, which is characterized by abnormal cartilage calcification, peripheral pulmonary stenosis and facial hypoplasia.

Source: NCBI Gene 4256 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Keutel syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 126 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 52
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000900

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7060
Approved symbol	MGP
Name	matrix Gla protein
Location	12p12.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000111341
Ensembl biotype	protein_coding
OMIM	154870
Entrez	4256

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 retained_intron

ENST00000228938, ENST00000507170, ENST00000539261, ENST00000545199, ENST00000905127

RefSeq mRNA: 2 — MANE Select: NM_000900 NM_000900, NM_001190839

CCDS: CCDS53752, CCDS8669

Canonical transcript exons

ENST00000539261 — 4 exons

Exon	Start	End
ENSE00000723035	14882972	14883047
ENSE00000999864	14885731	14885854
ENSE00000999865	14884213	14884245
ENSE00002283356	14880864	14882280

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 99.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 270.3359 / max 51604.4776, expressed in 999 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
129867	270.3359	999

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ascending aorta	UBERON:0001496	99.99	gold quality
thoracic aorta	UBERON:0001515	99.99	gold quality
descending thoracic aorta	UBERON:0002345	99.99	gold quality
right coronary artery	UBERON:0001625	99.98	gold quality
aorta	UBERON:0000947	99.96	gold quality
coronary artery	UBERON:0001621	99.96	gold quality
left coronary artery	UBERON:0001626	99.96	gold quality
artery	UBERON:0001637	99.95	gold quality
popliteal artery	UBERON:0002250	99.95	gold quality
tibial artery	UBERON:0007610	99.95	gold quality
metanephros cortex	UBERON:0010533	99.95	gold quality
blood vessel layer	UBERON:0004797	99.94	gold quality
left uterine tube	UBERON:0001303	99.93	gold quality
mammary duct	UBERON:0001765	99.92	gold quality
pericardium	UBERON:0002407	99.91	gold quality
saphenous vein	UBERON:0007318	99.91	gold quality
calcaneal tendon	UBERON:0003701	99.90	gold quality
synovial joint	UBERON:0002217	99.88	gold quality
vena cava	UBERON:0004087	99.86	gold quality
left lobe of thyroid gland	UBERON:0001120	99.85	gold quality
cauda epididymis	UBERON:0004360	99.85	gold quality
right lobe of thyroid gland	UBERON:0001119	99.84	gold quality
gall bladder	UBERON:0002110	99.84	gold quality
right atrium auricular region	UBERON:0006631	99.84	gold quality
body of uterus	UBERON:0009853	99.84	gold quality
seminal vesicle	UBERON:0000998	99.83	gold quality
tendon of biceps brachii	UBERON:0008188	99.82	gold quality
mucosa of stomach	UBERON:0001199	99.81	gold quality
left adrenal gland	UBERON:0001234	99.81	gold quality
urethra	UBERON:0000057	99.80	gold quality

Single-cell (SCXA)

Detected in 50 experiment(s), a significant marker in 48.

Experiment	Marker?	Max mean expression
E-MTAB-10855	yes	63591.94
E-GEOD-135922	yes	34086.99
E-HCAD-36	yes	26608.84
E-MTAB-9841	yes	24730.53
E-MTAB-8410	yes	20496.07
E-HCAD-15	yes	18479.34
E-CURD-7	yes	14329.90
E-ENAD-21	yes	14095.76
E-MTAB-10885	yes	13002.42
E-CURD-126	yes	12170.06
E-HCAD-1	yes	11481.78
E-MTAB-6653	yes	9856.42
E-MTAB-8322	yes	9842.37
E-GEOD-134144	yes	9471.67
E-MTAB-6701	yes	7394.99

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, FOSL1, JUN, RUNX2, SP1, SP3, THRA

miRNA regulators (miRDB)

53 targeting MGP, 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-3064-3P	100.00	70.09	1254
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-5580-3P	99.70	69.41	2052
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-6832-5P	99.58	64.82	1132
HSA-MIR-141-5P	99.57	67.86	897
HSA-MIR-451B	99.55	68.28	1380
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-4770	99.49	69.09	1451

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• REVIEW: an important inhibitor of pathologic calcification, and deficiency contributes to pathogenesis of cardiovascular calcifications in dialysis patients. (PMID:12207096)
• Genetic variations at the MGP locus did not affect the rate of tooth loss in the elderly. However, the MGP locus may be associated with some determinants for tooth loss in elderly women. (PMID:12721790)
• the effect of MGP on calcification and osteogenic differentiation is determined by availability of BMP-2 (PMID:14587031)
• Serum MGP levels were lower in patients with coronary artery calcification (CAC) than in those without. As the severity of CAC increased, there was a decrease in serum MGP levels, suggesting a role for MGP in the development of vascular calcification. (PMID:15045141)
• matrix gamma-carboxyglutamic acid protein and bone morphogenetic protein-2 processing and transport in cultured human vascular smooth muscle cells is regulated by serum fetuin (PMID:15280384)
• MGP has a novel binding activity for vitronectin (PMID:15982861)
• Chronic kidney disease and hemodialysis patients have a different distribution of MGP gene polymorphism as compared to the normal population. (PMID:16210837)
• Finds increased frequencies of the MGP G-7A G allele and the G7-A GG genotype in Mexicans compared to Europeans. For the T-138C genotype, we found differences among the Mexicans. (PMID:16392639)
• Matrix Gla protein is associated with individual coronary heart disease CHD) risk factors and the Framingham CHD risk score in men and women free of clinically apparent CHD. (PMID:16973975)
• accelerated vascular calcification observed in CKD have recently become clearer, leading to the hypothesis that a lack of natural inhibitors of calcification like matrix Gla may trigger calcium deposition (PMID:17014561)
• MGP gene polymorphism is associated with kidney stones and influences genetic susceptibility to kidney stones. (PMID:17509359)
• High expression of MGP in varicose veins may contribute to venous wall remodeling by affecting proliferation and mineralization processes probably through impaired carboxylation of MGP. (PMID:17643059)
• Matrix GLA protein is an inhibitory morphogen in pulmonary vascular development (PMID:17670744)
• lower ratio of Gla-MGP over Glu-MGP in pathological fibroblasts compared to controls suggests these cells may play an important role in the ectopic calcification in pseudoxanthoma elasticum (PMID:17724449)
• gamma-glutamyl carboxylation and serine phosphorylation of MGP contribute to its function as a calcification inhibitor and that MGP may inhibit calcification via binding to vascular smooth cell-derived vesicles. (PMID:17848178)
• Undercarboxylated MGP levels were inversely associated with phosphate, positively associated with serum fetuin-A levels, and inversely associated with the aortic augmentation index (PMID:17890861)
• Results suggest a role for the local calcification inhibitor matrix Gla protein in pseudoxanthoma elasticum manifestation. (PMID:18222176)
• Circulating levels of MGP and fetuin-A could not be identified as independent predictors of vascular stiffness or other carotid artery parameters in pediatric renal transplant recipients. (PMID:18286307)
• Suggest that BMP-4 and calcium binding in MGP are independent but functionally intertwined processes and that the BMP binding is essential for prevention of vascular calcification. (PMID:18369157)
• Developed ELISA for measuring serum matrix Gla. Serum matrix Gla may be used as a biomarker to identify those at risk for developing vascular calcification. (PMID:18401181)
• MGP is a potent inhibitor of arterial calcification (PMID:18841280)
• the kidney is able to extract matrix Gla-protein from the plasma at a constant level of 12.8%, independent of renal function in hypertensive subjects (PMID:18971553)
• We have investigated the synthesis and localization of fetuin-A and MGP in bone of hemodialysis patients (PMID:19151998)
• Uncarboxylated matrix Gla protein (ucMGP) is associated with coronary artery calcification in haemodialysis patients. (PMID:19190822)
• Examine circulating Matrix Gla-Protein and anticoagulation status in patients with aortic valve calcification. (PMID:19350115)
• The results of this study suggest a role for MGP genetic variants in coronary atherosclerosis among men that is not reflected in serum MGP concentrations. (PMID:19352064)
• Heat shock protein 70 enhances vascular bone morphogenetic protein-4 signaling by binding matrix Gla protein. (PMID:19661459)
• Upregulation of MGP results in increased cell migration in glioblastoma. (PMID:19712474)
• possible role of SNPs in the promoter region of MGP gene with relation to lead toxicity was investigated for the first time in the Indian population (PMID:19730704)
• Plasma MGP increased progressively in a chronic kidney disease setting and was associated with the severity of aortic calcification. (PMID:20133489)
• matric gla protein is a potent inhibitor of calcification in vitro and may thus play a role in the regulation of peritoneal calcium homeostasis. (PMID:20368306)
• higher FGF23 and lower ucMGP levels are independently associated with mortality and cardiovascular disease events (PMID:20479029)
• Report increased matrix Gla protein levels in patients with type 2 diabetes and/or ischemic heart disease. (PMID:21143859)
• a dysregulated MGP system could be involved in left ventricular dysfunction in patients with chronic heart failure (PMID:21294711)
• There may be an association between hand osteoarthritis and genetic polymorphism at the matrix Gla protein (MGP) locus that is not reflected by total MGP serum concentrations. (PMID:21724703)
• Mgp gene deletion may have a role in arteriovenous malformations (PMID:21765215)
• MGP A/A variant of MGP promoter G-7–>A polymorphism is a risk factor of ACS in Ukrainian population. (PMID:21870514)
• The change in serum fetuin-A, matrix Gla protein (MGP), and osteopontin (OPN) levels after intracerebral hemorrhage (ICH) indicates that these parameters play a role in the pathophysiological processes leading to an ICH. (PMID:22115341)
• MGP level correlated negatively with proinflammatory cytokines & acute phase proteins in acute pancreatitis, & positively with lipase, fetuin A, & albumin, indicating a possible role in calcium & phosphate metabolism disturbances in AP. (PMID:22239033)
• Angiotensin II exacerbates vascular calcification through activation of transcription factors, and regulation of MGP and inflammatory cytokine expression in vascular smooth muscle cells. (PMID:22796540)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	mgp	ENSDARG00000086189
mus_musculus	Mgp	ENSMUSG00000030218
rattus_norvegicus	Mgp	ENSRNOG00000005695

Protein

Protein identifiers

Matrix Gla protein — P08493 (reviewed: P08493)

Alternative names: Cell growth-inhibiting gene 36 protein

All UniProt accessions (2): P08493, H0YGZ6

UniProt curated annotations — full annotation on UniProt →

Function. Associates with the organic matrix of bone and cartilage. Thought to act as an inhibitor of bone formation.

Subcellular location. Secreted.

Post-translational modifications. Requires vitamin K-dependent gamma-carboxylation for its function.

Disease relevance. Keutel syndrome (KTLS) [MIM:245150] An autosomal recessive disorder characterized by abnormal cartilage calcification, peripheral pulmonary stenosis neural hearing loss and midfacial hypoplasia. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the osteocalcin/matrix Gla protein family.

Isoforms (2)

UniProt ID	Names	Canonical?
P08493-1	1	yes
P08493-2	2

RefSeq proteins (2): NP_000891, NP_001177768 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000294	GLA_domain	Domain
IPR002384	Osteocalcin/MGP	Family
IPR027118	MGP	Family
IPR035972	GLA-like_dom_SF	Homologous_superfamily
IPR058704	BGLAP-like_C	Domain

Pfam: PF25890

UniProt features (18 total): modified residue 8, sequence variant 2, sequence conflict 2, signal peptide 1, chain 1, disulfide bond 1, splice variant 1, propeptide 1, domain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9L24	ELECTRON MICROSCOPY	3.1
9WFC	ELECTRON MICROSCOPY	3.33
9NUB	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08493-F1	82.56	0.35

Functional residue map

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

Post-translational modifications (8): 67, 71, 21, 22, 25, 28, 56, 60

Disulfide bonds (1): 73–79

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 398 (showing top): RNGTGGGC_UNKNOWN, HORIUCHI_WTAP_TARGETS_DN, TSENG_IRS1_TARGETS_UP, MCLACHLAN_DENTAL_CARIES_UP, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, HSIAO_HOUSEKEEPING_GENES, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, WOO_LIVER_CANCER_RECURRENCE_UP, DOANE_RESPONSE_TO_ANDROGEN_DN, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_CDC25_UP, GOBP_BONE_MINERALIZATION, GOMF_EXTRACELLULAR_MATRIX_STRUCTURAL_CONSTITUENT

GO Biological Process (6): cartilage condensation (GO:0001502), ossification (GO:0001503), cell differentiation (GO:0030154), regulation of bone mineralization (GO:0030500), system development (GO:0048731), cartilage development (GO:0051216)

GO Molecular Function (4): extracellular matrix structural constituent (GO:0005201), calcium ion binding (GO:0005509), structural constituent of bone (GO:0008147), protein binding (GO:0005515)

GO Cellular Component (4): extracellular matrix (GO:0031012), extracellular exosome (GO:0070062), extracellular region (GO:0005576), obsolete collagen-containing extracellular matrix (GO:0062023)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
structural molecule activity	2
skeletal system morphogenesis	1
cartilage development	1
cell aggregation	1
multicellular organismal process	1
cellular developmental process	1
regulation of ossification	1
bone mineralization	1
regulation of biomineral tissue development	1
multicellular organism development	1
anatomical structure development	1
skeletal system development	1
animal organ development	1
connective tissue development	1
extracellular matrix	1
metal ion binding	1
binding	1
external encapsulating structure	1
extracellular vesicle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1634 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MGP	AHSG	P02765	977
MGP	GGCX	P38435	952
MGP	BGLAP	P02818	933
MGP	SPP1	P10451	920
MGP	BMP2	P12643	918
MGP	ABCC6	P78420	896
MGP	PROS1	P07225	872
MGP	VKORC1	Q9BQB6	848
MGP	ELN	P15502	789
MGP	UCMA	Q8WVF2	762
MGP	F2	P00734	752
MGP	SPP2	Q13103	730
MGP	BMP4	P12644	720
MGP	VTN	P01141	689
MGP	RUNX2	Q13950	683

IntAct

6 interactions, top by confidence:

A	B	Type	Score
ERBB2	HAX1	psi-mi:“MI:0914”(association)	0.530
CFTR	MGP	psi-mi:“MI:0915”(physical association)	0.370
MGP		psi-mi:“MI:0915”(physical association)	0.370
ATG16L1		psi-mi:“MI:0914”(association)	0.350
TIMM10	IGLL5	psi-mi:“MI:0914”(association)	0.350

BioGRID (5): MGP (Affinity Capture-MS), MGP (Affinity Capture-Western), MGP (Affinity Capture-MS), MGP (Affinity Capture-MS), MGP (PCA)

ESM2 similar proteins: A0A125S9E6, A0A172M477, A0A3G3C7U9, A0A411D538, B3SVF0, B3SVF1, C6KGD8, D4HRK4, D5L5Q7, F8J4S0, G8YYA6, O18417, O42413, P02808, P07507, P08493, P08494, P0C640, P0CY73, P0DME4, P0DUS1, P14213, P14214, P15450, P19788, P24510, P36193, P47841, P58846, Q24395, Q32KM8, Q3YEG9, Q3YEH2, Q3YEH4, Q566V9, Q5RDP6, Q6XMH8, Q800Y2, Q8HY86, Q8MJ39

Diamond homologs: O42413, P07507, P08493, P08494, P19788, P47841, P56620, Q5RDP6, Q6QN06, Q800Y2, Q8MJ39, P83347

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	44
Likely benign	49
Benign	13

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
14341	NM_000900.5(MGP):c.43del (p.Ala14_Val15insTer)	Pathogenic
14342	NM_000900.5(MGP):c.62-2A>G	Pathogenic
14343	NM_000900.5(MGP):c.87T>A (p.Tyr29Ter)	Pathogenic
1987659	NM_000900.5(MGP):c.94+2T>C	Likely pathogenic

SpliceAI

361 predictions. Top by Δscore:

Variant	Effect	Δscore
12:14882279:TC:T	acceptor_gain	1.0000
12:14882280:CC:C	acceptor_gain	1.0000
12:14882281:C:CC	acceptor_gain	1.0000
12:14882288:G:C	acceptor_gain	1.0000
12:14882288:G:GC	acceptor_gain	1.0000
12:14883049:T:C	acceptor_gain	1.0000
12:14884211:A:AC	donor_gain	1.0000
12:14884212:C:CC	donor_gain	1.0000
12:14884212:CT:C	donor_gain	1.0000
12:14884212:CTA:C	donor_gain	1.0000
12:14884212:CTAA:C	donor_gain	1.0000
12:14884212:CTAAG:C	donor_gain	1.0000
12:14884244:TT:T	acceptor_gain	1.0000
12:14884244:TTC:T	acceptor_loss	1.0000
12:14884245:TC:T	acceptor_loss	1.0000
12:14884246:C:A	acceptor_loss	1.0000
12:14884246:C:CC	acceptor_gain	1.0000
12:14884247:T:A	acceptor_loss	1.0000
12:14884252:T:C	acceptor_gain	1.0000
12:14884252:T:TC	acceptor_gain	1.0000
12:14882277:GATC:G	acceptor_gain	0.9900
12:14882278:ATC:A	acceptor_gain	0.9900
12:14882282:T:A	acceptor_loss	0.9900
12:14883049:T:TC	acceptor_gain	0.9900
12:14884207:A:AC	donor_gain	0.9900
12:14884208:C:CC	donor_gain	0.9900
12:14884209:T:TA	donor_loss	0.9900
12:14884210:TAC:T	donor_loss	0.9900
12:14884211:A:T	donor_loss	0.9900
12:14884241:TGATT:T	acceptor_gain	0.9900

AlphaMissense

670 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:14882233:C:T	C73Y	0.997
12:14882215:C:G	C79S	0.996
12:14882216:A:T	C79S	0.996
12:14882233:C:G	C73S	0.996
12:14882234:A:T	C73S	0.996
12:14882215:C:T	C79Y	0.995
12:14882232:A:C	C73W	0.994
12:14882214:G:C	C79W	0.993
12:14882215:C:A	C79F	0.993
12:14882233:C:A	C73F	0.993
12:14882262:C:A	K63N	0.993
12:14882262:C:G	K63N	0.993
12:14882191:C:A	G87V	0.992
12:14882216:A:G	C79R	0.992
12:14882234:A:G	C73R	0.992
12:14882164:A:C	F96C	0.990
12:14882179:G:T	A91D	0.990
12:14882163:G:C	F96L	0.987
12:14882163:G:T	F96L	0.987
12:14882165:A:G	F96L	0.987
12:14882203:G:T	A83D	0.986
12:14883014:A:C	F43C	0.985
12:14882191:C:T	G87E	0.984
12:14884232:G:C	S25R	0.984
12:14884232:G:T	S25R	0.984
12:14884234:T:G	S25R	0.984
12:14882204:C:G	A83P	0.983
12:14883013:G:C	F43L	0.983
12:14883013:G:T	F43L	0.983
12:14883015:A:G	F43L	0.983

dbSNP variants (sampled 300 via entrez): RS1000191257 (12:14880680 C>T), RS1000565279 (12:14886249 G>C), RS1000596596 (12:14886566 C>T), RS1001330630 (12:14884775 G>C), RS1001598444 (12:14885021 G>A), RS1001684975 (12:14884643 G>A,C), RS1001969478 (12:14882866 C>A,T), RS1002423427 (12:14883183 A>G), RS1002760168 (12:14887507 A>G), RS1003624592 (12:14881802 A>G), RS1004039019 (12:14881161 C>T), RS1004386581 (12:14883981 G>A), RS1004436538 (12:14886180 T>C), RS1004764332 (12:14884721 A>G), RS1005354091 (12:14881833 A>C)

Disease associations

OMIM: gene MIM:154870 | disease phenotypes: MIM:245150

GenCC curated gene-disease

Disease	Classification	Inheritance
Keutel syndrome	Definitive	Autosomal recessive
skeletal dysplasia	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Keutel syndrome	Definitive	AR

Mondo (3): spondyloepiphyseal dysplasia (MONDO:0016761), Keutel syndrome (MONDO:0009495), skeletal dysplasia (MONDO:0018230)

Orphanet (3): Spondyloepiphyseal dysplasia and spondyloepimetaphyseal dysplasia (Orphanet:253), Keutel syndrome (Orphanet:85202), OBSOLETE: Spondyloepimetaphyseal dysplasia (Orphanet:252)

HPO phenotypes

52 total (30 of 52 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000246	Sinusitis
HP:0000272	Malar flattening
HP:0000276	Long face
HP:0000340	Sloping forehead
HP:0000365	Hearing impairment
HP:0000400	Macrotia
HP:0000403	Recurrent otitis media
HP:0000430	Underdeveloped nasal alae
HP:0000431	Wide nasal bridge
HP:0000445	Wide nose
HP:0000648	Optic atrophy
HP:0000822	Hypertension
HP:0001027	Soft, doughy skin
HP:0001250	Seizure
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001507	Growth abnormality
HP:0001596	Alopecia
HP:0001611	Hypernasal speech
HP:0001629	Ventricular septal defect
HP:0001642	Pulmonic stenosis
HP:0002002	Deep philtrum
HP:0002092	Pulmonary arterial hypertension
HP:0002097	Emphysema
HP:0002205	Recurrent respiratory infections
HP:0002514	Cerebral calcification
HP:0002787	Tracheal calcification
HP:0002837	Recurrent bronchitis
HP:0004322	Short stature

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST006979_889	Heel bone mineral density	7.000000e-17
GCST009596_4	Osteoarthritis of the hand	2.000000e-15
GCST90010716_1	Hand osteoarthritis severity (hand Klsum)	3.000000e-12
GCST90010717_1	Finger osteoarthritis severity (hand Klsum)	5.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536167	Keutel syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	decreases reaction, affects cotreatment, decreases expression, increases expression	6
bisphenol A	affects cotreatment, increases expression	3
Nickel	affects expression, decreases expression, decreases reaction	3
bisphenol S	increases expression, increases methylation	2
Arsenic Trioxide	decreases expression, increases expression	2
Progesterone	decreases expression, increases expression	2
Tretinoin	increases expression	2
Valproic Acid	affects cotreatment, increases expression, decreases expression	2
tert-Butylhydroperoxide	decreases expression	2
Raloxifene Hydrochloride	decreases expression, decreases reaction, increases expression	2
bisphenol F	increases expression	1
trichostatin A	affects expression, decreases reaction	1
afimoxifene	decreases expression	1
sodium arsenite	decreases expression, affects splicing	1
tetrathiomolybdate	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
coumarin	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
paricalcitol	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
corosolic acid	increases expression	1
entinostat	increases expression	1
bazedoxifene	decreases expression	1
2,2’,4,4’,5-brominated diphenyl ether	decreases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
incobotulinumtoxinA	increases expression	1
3-hydroxy-4-prenyl-5-methoxystilbene-2-carboxylic acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00001754	Not specified	COMPLETED	Study of Skeletal Disorders and Short Stature
NCT02762318	Not specified	TERMINATED	Identification and Characterization of Bone-related Genetic Variants in Families
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT05247645	Not specified	RECRUITING	Data Collection of Patients With Rare Bone Diseases
NCT05876416	Not specified	RECRUITING	Decoding the Genetic Landscape of Skeletal Diseases
NCT05991609	Not specified	ACTIVE_NOT_RECRUITING	Extreme Morphology and Metabolic Health
NCT06002373	Not specified	UNKNOWN	Assessment of Artificial Intelligence for Treatment Decision Recommendation of Adult Skeletal Class III Patients