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): 130 total — 3 pathogenic, 1 likely-pathogenic
• GTEx eGene: eQTL in 16 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 52
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.63 (unconstrained)
• 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: 19 — 17 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

MANE Select: ENST00000539261

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

ENST00000539261, ENST00000228938, ENST00000507170, ENST00000545199, ENST00000905127, ENST00001032221, ENST00001032222, ENST00001095042, ENST00001095043, ENST00001095044, ENST00001095045, ENST00001095046, ENST00001095047, ENST00001095048, ENST00001095049, ENST00001095050, ENST00001095051, ENST00001095052, ENST00001137412

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.

Highest expression (Bgee): ascending aorta, thoracic aorta, descending thoracic aorta, coronary artery, aorta.

Genetic regulation across tissues (GTEx eQTL / sQTL)

MGP is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 16 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

17 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	eqtl	5.6e-16	-0.24	12:14899824:G:A
Lung	eqtl	1.4e-12	+0.21	12:14924022:A:G
Artery Aorta	eqtl	1.1e-06	-0.18	12:14924593:A:T
Artery Tibial	eqtl	1.7e-06	+0.12	12:14921396:A:C
Thyroid	eqtl	6.8e-06	-0.17	12:14899824:G:A
Adipose Subcutaneous	eqtl	5.6e-05	+0.15	12:14935977:C:T
Skin Not Sun Exposed Suprapubic	eqtl	1.8e-04	-0.12	12:14857929:G:C
Skin Sun Exposed Lower leg	eqtl	2.5e-04	-0.11	12:14857673:A:G
Adrenal Gland	eqtl	2.6e-04	-0.32	12:14869097:C:T
Esophagus Muscularis	eqtl	1.0e-03	-0.17	12:14861054:A:T
Adipose Visceral Omentum	eqtl	3.7e-03	-0.14	12:14857673:A:G
Cells Cultured fibroblasts	eqtl	8.1e-03	-0.11	12:14853896:A:G
Esophagus Mucosa	eqtl	1.6e-02	-0.12	12:14904925:C:T
Brain Caudate basal ganglia	eqtl	1.7e-02	-0.25	12:14803397:C:T
Stomach	eqtl	2.2e-02	-0.28	12:14569344:A:T
Lung	sqtl	3.1e-02	-0.62	12:14221733:A:G
Brain Cerebellum	eqtl	4.2e-02	-0.33	12:13970151:C:T

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
129867	270.3359	999

Top tissues by expression

showing 100 of 301 tissues 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
right adrenal gland	UBERON:0001233	99.80	gold quality
left adrenal gland cortex	UBERON:0035825	99.80	gold quality
tendon	UBERON:0000043	99.79	gold quality
adrenal cortex	UBERON:0001235	99.79	gold quality
myometrium	UBERON:0001296	99.79	gold quality
thyroid gland	UBERON:0002046	99.78	gold quality
adenohypophysis	UBERON:0002196	99.78	gold quality
peritoneum	UBERON:0002358	99.78	gold quality
omental fat pad	UBERON:0010414	99.78	gold quality
endocervix	UBERON:0000458	99.77	gold quality
superficial temporal artery	UBERON:0001614	99.76	gold quality
adipose tissue of abdominal region	UBERON:0007808	99.76	gold quality
right adrenal gland cortex	UBERON:0035827	99.75	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.72	gold quality
mammary gland	UBERON:0001911	99.71	gold quality
thoracic mammary gland	UBERON:0005200	99.71	gold quality
upper lobe of left lung	UBERON:0008952	99.71	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.71	gold quality
lower esophagus	UBERON:0013473	99.70	gold quality
right lung	UBERON:0002167	99.69	gold quality
upper lobe of lung	UBERON:0008948	99.69	gold quality
muscle layer of sigmoid colon	UBERON:0035805	99.68	gold quality
right ovary	UBERON:0002118	99.65	gold quality
heart right ventricle	UBERON:0002080	99.64	gold quality
apex of heart	UBERON:0002098	99.61	gold quality
pituitary gland	UBERON:0000007	99.60	gold quality
smooth muscle tissue	UBERON:0001135	99.59	gold quality
nipple	UBERON:0002030	99.59	gold quality
epithelium of mammary gland	UBERON:0003244	99.58	gold quality
fundus of stomach	UBERON:0001160	99.57	gold quality
decidua	UBERON:0002450	99.57	gold quality
skin of hip	UBERON:0001554	99.56	gold quality
caput epididymis	UBERON:0004358	99.54	gold quality
adult organism	UBERON:0007023	99.54	gold quality
nerve	UBERON:0001021	99.51	gold quality
tibial nerve	UBERON:0001323	99.51	gold quality
left ovary	UBERON:0002119	99.47	gold quality
parotid gland	UBERON:0001831	99.46	gold quality
parietal pleura	UBERON:0002400	99.40	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.40	gold quality
minor salivary gland	UBERON:0001830	99.38	gold quality
saliva-secreting gland	UBERON:0001044	99.37	gold quality
pleura	UBERON:0000977	99.34	gold quality
corpus epididymis	UBERON:0004359	99.31	gold quality
lower lobe of lung	UBERON:0008949	99.26	gold quality
renal medulla	UBERON:0000362	99.20	gold quality
colonic epithelium	UBERON:0000397	99.19	gold quality
ectocervix	UBERON:0012249	99.19	gold quality
olfactory bulb	UBERON:0002264	99.18	gold quality
visceral pleura	UBERON:0002401	99.17	gold quality
urinary bladder	UBERON:0001255	99.14	gold quality
skin of leg	UBERON:0001511	99.11	gold quality
adipose tissue	UBERON:0001013	99.10	gold quality
adrenal gland	UBERON:0002369	99.09	gold quality
rectum	UBERON:0001052	99.01	gold quality
connective tissue	UBERON:0002384	99.01	gold quality
skin of abdomen	UBERON:0001416	98.99	gold quality
penis	UBERON:0000989	98.96	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.94	gold quality
body of pancreas	UBERON:0001150	98.92	gold quality
caecum	UBERON:0001153	98.87	gold quality
cardiac ventricle	UBERON:0002082	98.86	gold quality
heart left ventricle	UBERON:0002084	98.84	gold quality
pylorus	UBERON:0001166	98.83	gold quality
heart	UBERON:0000948	98.80	gold quality
diaphragm	UBERON:0001103	98.80	gold quality
tibia	UBERON:0000979	98.77	gold quality
upper leg skin	UBERON:0004262	98.76	gold quality
right uterine tube	UBERON:0001302	98.73	gold quality
cardiac atrium	UBERON:0002081	98.70	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

HPA expression

RNA tissue specificity: Tissue enriched

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Breast	tissue	3496.1	low
Salivary gland	tissue	1985.4	low
Vagina	tissue	1291.8	not detected
Smooth muscle	tissue	1221.9	not detected
Seminal vesicle	tissue	1069.9	not detected
Gallbladder	tissue	1014.3	not detected
Adrenal gland	tissue	904.4	not detected
Pituitary gland	tissue	896.7
Urinary bladder	tissue	871.2	not detected
Heart muscle	tissue	759.3	not detected
Adipose tissue	tissue	742.4	not detected
Epididymis	tissue	710.2	not detected
Lung	tissue	578.4	not detected
Endometrium 1	tissue	572.9	not detected
Prostate	tissue	558.7	medium
Cervix	tissue	478.8	not detected
Superior colliculi	tissue	413.8
Kidney	tissue	366.9	not detected
Choroid plexus	tissue	329.6
Colon	tissue	307.4	not detected
Rectum	tissue	259.7	not detected
Thyroid gland	tissue	258.3	not detected
Fallopian tube	tissue	257.8	not detected
Tongue	tissue	256.2
Ovary	tissue	245.2	not detected
Esophagus	tissue	204.9	not detected
Placenta	tissue	191.2	not detected
Pancreas	tissue	179.5	not detected
Spinal cord	tissue	177.7
Appendix	tissue	176.6	not detected
Substantia nigra	tissue	140.5
Small intestine	tissue	136.8	not detected
Testis	tissue	132.1	not detected
Frontal cortex	tissue	104.9
Parathyroid gland	tissue	102.7	not detected
Lymph node	tissue	100.1	not detected
Thymus	tissue	92.9
Duodenum	tissue	65.5	not detected
Spleen	tissue	63.3	not detected
Tonsil	tissue	61.7	not detected
Caudate putamen	tissue	59.1
Skeletal muscle	tissue	53.4	not detected
Stomach 1	tissue	51.6	not detected
Skin 1	tissue	46.7	not detected
Pons	tissue	42.0
Thalamus	tissue	39.3
Liver	tissue	39.3	not detected
Medulla oblongata	tissue	38.2
Midbrain	tissue	31.8
Hippocampal formation	tissue	31.6
Entorhinal cortex	tissue	31.6
Olfactory bulb	tissue	30.6
Hypothalamus	tissue	25.7
Septum	tissue	23.8
Periaqueductal gray	tissue	16.7
Cerebral cortex	tissue	15.7	not detected
Temporal cortex	tissue	15.7
Motor cortex	tissue	14.3
Retrosplenial and cingulate cortex	tissue	12.3
Hippocampus	tissue	12.0	not detected

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Blood vessel (15727.7), Dorsal spinal cord (177.7), Ventral spinal cord (82.5), Anterior insular cortex, dorsal (55.7), Nucleus basalis of Meynert (48.0).

Regulation

Is transcription factor: no

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

miRNA regulators (miRDB)

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

showing 30 of 53 miRNAs:

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

gnomAD constraint: pLI 0.000638, LOEUF 1.63, missense Z 0.24 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000539261 — one region, missense o/e 0.96. 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

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:96976) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 41 distinct phenotype terms.

Mouse phenotype (MP)	Records
calcified artery	2
decreased bone mineral density	1
abnormal kidney vasculature morphology	1
abnormal lung morphology	1
decreased body height	1
decreased body size	1
internal hemorrhage	1
postnatal growth retardation	1
premature death	1
abnormal artery morphology	1
increased heart rate	1
small kidney	1
abnormal bone remodeling	1
abnormal long bone epiphyseal plate morphology	1
abnormal tracheal cartilage morphology	1
abnormal aorta elastic fiber morphology	1
decreased width of hypertrophic chondrocyte zone	1
small lung	1
abnormal long bone epiphyseal plate proliferative zone	1
increased kidney weight	1
abnormal lung vasculature morphology	1
decreased bone mass	1
abnormal osteoblast physiology	1
abnormal renal glomerulus morphology	1
arteriovenous malformation	1

+16 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
Bos taurus	P07507	93.2%	Diamond
Sus scrofa	Q8MJ39	93.2%	Diamond
Oryctolagus cuniculus	P47841	87.9%	Diamond
Pongo abelii	Q5RDP6	85.4%	Diamond
Galeorhinus galeus	P56620	76.7%	Diamond
Chinchilla lanigera	Q6QN06	75.7%	Diamond
Gallus gallus	O42413	57.0%	Diamond
Argyrosomus regius	Q800Y2	39.6%	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
ARHGDIB	protein-coding	397
PDE6H	protein-coding	5149
ERP27	protein-coding	121506
ART4	protein-coding	420
C12orf60	protein-coding	144608
SMCO3	protein-coding	440087
WBP11	protein-coding	51729
H2AJ	protein-coding	55766

Protein

Protein identifiers

Matrix Gla protein — P08493 (reviewed: P08493)

Alternative names: Cell growth-inhibiting gene 36 protein

All UniProt accessions (2): H0YGZ6, P08493

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 by resolution:

PDB	Title	Method	Resolution (Å)
9L24	cryo-EM structure of Vitamin K-dependent gamma-carboxylase complexed with Matrix Gla …	ELECTRON MICROSCOPY	3.1
9WFC	Cryo-EM structure of GGCX-MGP complex	ELECTRON MICROSCOPY	3.33
9NUB	NMR solution structure of unmodified human matrix Gla protein	SOLUTION NMR

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Predicted secreted proteins, Predicted intracellular proteins, Disease related genes, Human disease related genes, Congenital malformations, Other congenital malformations

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH approved

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)

Type	Positions
4-carboxyglutamate	67, 71, 21, 56, 60
Phosphoserine	22, 25, 28

Disulfide bonds (1)

Type	Positions
Disulfide bond	73–79

Function

Pathways and Gene Ontology

Reactome pathways

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

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 (3): extracellular matrix (GO:0031012), extracellular exosome (GO:0070062), extracellular region (GO:0005576)

GO top-level categories

20 GO namespaces:

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

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 2 of 13 annotations. The rest are phylogenetic / computational / electronic (IEA).

2 experimentally-supported GO terms:

GO term	NS	Evidence
extracellular exosome	CC	high-throughput assay
extracellular matrix	CC	high-throughput assay

Protein interactions and networks

STRING

showing 15 of 1,676 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MGP	GGCX	P38435	949
MGP	AHSG	P02765	893
MGP	BGLAP	P02818	890
MGP	ABCC6	P78420	882
MGP	VKORC1	Q9BQB6	848
MGP	SPP1	P10451	830
MGP	UCMA	Q8WVF2	742
MGP	SPP2	Q13103	720
MGP	TNFRSF11B	O00300	655
MGP	RUNX2	Q13950	653
MGP	BMP2	P12643	640
MGP	ELN	P15502	639
MGP	F2	P00734	616
MGP	PTH	P01270	597
MGP	CASR	P41180	590

IntAct

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

1 partners by confidence:

Partner	Interaction type	MIscore	Records
CFTR	physical association	0.370	1

BioGRID (5 interactions; top human partners by supporting records): BMP2 (Affinity Capture-Western), CFTR (PCA), HTN3 (Affinity Capture-MS), LATS1 (Affinity Capture-MS), TIMM10 (Affinity Capture-MS)

Disease & clinical

Genetic variants

Variant evidence for MGP: 130 ClinVar records (4 pathogenic / likely pathogenic); 4 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	44
Likely benign	53
Benign	12

Top pathogenic / likely-pathogenic (4)

Showing all 4 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
1987659	NM_000900.5(MGP):c.94+2T>C	Likely pathogenic	criteria provided, single submitter	1
14341	NM_000900.5(MGP):c.43del (p.Ala14_Val15insTer)	Pathogenic	no assertion criteria provided	1
14342	NM_000900.5(MGP):c.62-2A>G	Pathogenic	no assertion criteria provided	1
14343	NM_000900.5(MGP):c.87T>A (p.Tyr29Ter)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore MGP’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 24 predictions of 229):

Position(s)	Effect	Δscore	Sites
12:14882281	acceptor_loss	1.0000
12:14882288	acceptor_gain	1.0000
12:14883049	acceptor_gain	1.0000
12:14884246–14884247	acceptor_loss	1.0000	5
12:14884252	acceptor_gain	1.0000
12:14882281–14882282	acceptor_loss	0.9900	3
12:14884211–14884212	donor_loss	0.9900	5
12:14884246	acceptor_loss	0.9900
12:14885729–14885730	donor_loss	0.9900	5
12:14882282	acceptor_loss	0.9800

AlphaMissense

208 missense substitutions predicted likely pathogenic (of 670 scored), across 57 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
C73	7	0.991	0.997
C79	7	0.989	0.996
F96	7	0.977	0.990
F43	7	0.943	0.985
E71	7	0.929	0.964
S25	7	0.903	0.984
F34	7	0.894	0.970
E67	7	0.875	0.957
D75	7	0.771	0.871
E24	7	0.767	0.883
E27	7	0.745	0.865
K63	6	0.972	0.993
A91	6	0.856	0.990
R70	6	0.831	0.917
E30	6	0.703	0.801
G87	5	0.974	0.992
Y95	5	0.927	0.967
Y92	5	0.885	0.973
Y82	5	0.876	0.944
A40	5	0.814	0.949

HPA cancer prognostics

RNA cancer specificity: Cancer enriched (Breast Invasive Carcinoma)

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

1 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Papillary Cell Carcinoma (TCGA)	unfavorable	0.000203

Disease associations

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

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
Keutel syndrome	Definitive	Autosomal recessive	5
skeletal dysplasia	Strong	Autosomal dominant

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
Keutel syndrome	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (4 panels, 4 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

4 panels:

Panel	Rating
DDG2P	green
Fetal anomalies	green
Paediatric disorders	green
Skeletal dysplasia	green

Mondo (2): Keutel syndrome (MONDO:0009495), skeletal dysplasia (MONDO:0018230)

Orphanet (1): Keutel syndrome (Orphanet:85202)

HPO phenotypes

52 phenotypes (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
HP:0004334	Dermal atrophy
HP:0004415	Pulmonary artery stenosis
HP:0004969	Peripheral pulmonary artery stenosis
HP:0004971	Pulmonary artery hypoplasia
HP:0005103	Calcification of the auricular cartilage
HP:0005268	Miscarriage
HP:0005275	Cartilaginous ossification of nose
HP:0005280	Depressed nasal bridge
HP:0006118	Shortening of all distal phalanges of the fingers
HP:0006140	Premature fusion of phalangeal epiphyses
HP:0006536	Airway obstruction
HP:0006646	Costal cartilage calcification
HP:0008747	Cartilaginous ossification of larynx
HP:0009778	Short thumb
HP:0009882	Short distal phalanx of finger
HP:0010109	Short hallux
HP:0010655	Epiphyseal stippling
HP:0011108	Recurrent sinusitis
HP:0011109	Chronic sinusitis
HP:0011800	Midface retrusion
HP:0100593	Calcification of cartilage
HP:0100682	Tracheal atresia

GWAS associations

4 associations:

Study	Trait	p-value
GCST006979_989	Heel bone mineral density	7e-17
GCST009596_4	Osteoarthritis of the hand	2e-15
GCST90010717_1	Finger osteoarthritis severity (hand Klsum)	5e-14
GCST90010716_1	Hand osteoarthritis severity (hand Klsum)	3e-12

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0009270	heel bone mineral density

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
C536167	Keutel syndrome *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects cotreatment, decreases expression, increases expression, decreases reaction	6
bisphenol A	increases expression, affects cotreatment	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	decreases expression, affects cotreatment, increases expression	2
tert-Butylhydroperoxide	decreases expression	2
Raloxifene Hydrochloride	decreases reaction, increases expression, decreases expression	2
bisphenol F	increases expression	1
trichostatin A	affects expression, decreases reaction	1
afimoxifene	decreases expression	1
sodium arsenite	affects splicing, decreases expression	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)

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

7 trials:

NCT	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