GREM1

Summary

GREM1 (gremlin 1, DAN family BMP antagonist, HGNC:2001) is a protein-coding gene on chromosome 15q13.3, encoding Gremlin-1 (O60565). Cytokine that may play an important role during carcinogenesis and metanephric kidney organogenesis, as a BMP antagonist required for early limb outgrowth and patterning in maintaining the FGF4-SHH feedback loop.

This gene encodes a member of the BMP (bone morphogenic protein) antagonist family. Like BMPs, BMP antagonists contain cystine knots and typically form homo- and heterodimers. The CAN (cerberus and dan) subfamily of BMP antagonists, to which this gene belongs, is characterized by a C-terminal cystine knot with an eight-membered ring. The antagonistic effect of the secreted glycosylated protein encoded by this gene is likely due to its direct binding to BMP proteins. As an antagonist of BMP, this gene may play a role in regulating organogenesis, body patterning, and tissue differentiation. In mouse, this protein has been shown to relay the sonic hedgehog (SHH) signal from the polarizing region to the apical ectodermal ridge during limb bud outgrowth. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 26585 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary mixed polyposis syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 16
• Clinical variants (ClinVar): 473 total — 2 pathogenic
• Phenotypes (HPO): 18
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_013372

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2001
Approved symbol	GREM1
Name	gremlin 1, DAN family BMP antagonist
Location	15q13.3
Locus type	gene with protein product
Status	Approved
Aliases	DRM, gremlin, DAND2, HMPS
Ensembl gene	ENSG00000166923
Ensembl biotype	protein_coding
OMIM	603054
Entrez	26585

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000560677, ENST00000560830, ENST00000651154, ENST00000652365, ENST00000908783, ENST00000908784

RefSeq mRNA: 4 — MANE Select: NM_013372 NM_001191322, NM_001191323, NM_001368719, NM_013372

CCDS: CCDS10029, CCDS53927

Canonical transcript exons

ENST00000300177 — 0 exons

Expression profiles

Bgee: expression breadth ubiquitous, 126 present calls, max score 99.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 243.8537 / max 8178.6602, expressed in 1064 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
145708	241.9259	1063
145740	0.6744	231
145714	0.4068	209
145709	0.3051	197
145710	0.1915	122
207456	0.1835	104
145739	0.1664	93

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	99.82	gold quality
gall bladder	UBERON:0002110	99.28	gold quality
mucosa of stomach	UBERON:0001199	99.23	gold quality
vermiform appendix	UBERON:0001154	98.55	gold quality
rectum	UBERON:0001052	94.52	gold quality
ectocervix	UBERON:0012249	93.90	gold quality
colonic epithelium	UBERON:0000397	93.30	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.11	gold quality
vagina	UBERON:0000996	92.01	gold quality
endocervix	UBERON:0000458	91.59	gold quality
uterine cervix	UBERON:0000002	91.16	gold quality
duodenum	UBERON:0002114	90.08	gold quality
small intestine	UBERON:0002108	90.00	gold quality
small intestine Peyer’s patch	UBERON:0003454	89.61	gold quality
islet of Langerhans	UBERON:0000006	89.48	gold quality
smooth muscle tissue	UBERON:0001135	88.08	gold quality
intestine	UBERON:0000160	87.74	gold quality
muscle layer of sigmoid colon	UBERON:0035805	87.56	gold quality
lower esophagus	UBERON:0013473	87.34	gold quality
lower esophagus muscularis layer	UBERON:0035833	87.29	gold quality
colon	UBERON:0001155	86.99	gold quality
fundus of stomach	UBERON:0001160	85.65	gold quality
omental fat pad	UBERON:0010414	85.64	gold quality
body of stomach	UBERON:0001161	85.59	gold quality
transverse colon	UBERON:0001157	85.32	gold quality
stomach	UBERON:0000945	85.25	gold quality
esophagus	UBERON:0001043	84.56	gold quality
corpus callosum	UBERON:0002336	82.77	gold quality
putamen	UBERON:0001874	82.22	gold quality
lymph node	UBERON:0000029	82.16	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-111727	yes	920.16
E-GEOD-124858	yes	825.73
E-ANND-3	yes	4.11

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
CDKN1A	Activation

Upstream regulators (CollecTRI, top): FLCN, GLI1, SMAD3, TP53

miRNA regulators (miRDB)

130 targeting GREM1, 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-4262	100.00	73.26	3931
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-4753-3P	99.90	71.03	3786

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• Drm/Gremlin transcriptionally activates p21(Cip1) via a novel mechanism and inhibits neoplastic transformation. (PMID:12135612)
• Review. Gremlin, a developmental regulator of bone morphogenetic proteins (BMPs), has recently been implicated in processes such as glomerulosclerosis, tubulointerstitial fibrosis and cellular hypertrophy. (PMID:12885271)
• our findings suggest that CRAC1 is unlikely to be implicated in the development of colorectal cancer in general or, if involved, it is through small somatic mutations or other loss of function mechanisms rather than allele loss. (PMID:12885466)
• Data demonstrate for the first time that Drm physically and functionally interacts with Slit proteins to act as a negative regulator for monocyte chemotaxis. (PMID:15528323)
• transgenic mice overexpressing gremlin in the bone microenvironment have decreased osteoblast number and function leading to osteopenia and spontaneous fractures. (PMID:15539560)
• TFG-beta is an inducer of gremlin expression in diabetic nephropathy. (PMID:15957132)
• gremlin 1 is overexpressed in human cancers and interacts with YWHAH protein (PMID:16545136)
• gremlin and insulin-like growth factor-binding proteins have roles in liver fibrogenesis (PMID:16606614)
• GREMLIN 1 was expressed in the stroma of human basal cell carcinoma (BCC) tumors but not in normal skin in vivo. Bone morphogenetic protein (BMP) 2 and 4 are expressed by BCC cells. (PMID:17003113)
• BMP4 and Gremlin are regulators of myogenic progenitor proliferation. (PMID:17015616)
• May play role infibrous process in crescentic nephritis, both in glomerular crescentic and tubular epithelial cells. May be important in mediating some of the pathological effects of TGF-beta. (PMID:17403698)
• in human bronchial epithelial cells asbestos-induced gremlin expression could be prevented by inhibitors of the TGF-beta receptor and also by inhibitors of the mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase pathways (PMID:17975199)
• Notch pathway gene expression is elevated in diabetic nephropathy, co-incident with Gremlin, and may contribute to the pathogenesis of this dise (PMID:17980714)
• Study mapped a high-penetrance gene (CRAC1; also known as HMPS) associated with colorectal cancer in the Ashkenazi population to a 0.6-Mb region on chromosome 15. (PMID:18084292)
• Elevated levels of gremlin-1 in eutopic endometrium and peripheral serum in patients with endometriosis. (PMID:18314105)
• the mechanisms of pulmonary hypertension and vascular loss in chronic lung disease and identifies gremlin 1 as a potentially important mediator of vascular changes in hypoxic pulmonary hypertension. (PMID:18469115)
• Grem1 enhances the determined path to cardiomyogenesis in a stage-specific manner, and inhibition of the BMP signaling pathway is involved in initial determination of Grem1-promoted cardiomyogenesis (PMID:18545679)
• Gremlin was expressed in optic nerve head (ONH) tissue & cells; gremlin levels were increased in lamina cribrosa region of glaucomatous ONH tissues; increased expression of gremlin in glaucoma ONH may exacerbate TGF-beta2 effects on ONH ECM metabolism (PMID:19031438)
• None of the single nucleotide polymorphisms studied in SMAD7, GREM1 or CRAC1 were associated with breast cancer risk in our study (PMID:19505925)
• the variants examined at GREM1 are not significant contributors to variation in albumin to creatinine ratio in Mexican Americans (PMID:19577778)
• Data suggest inhibition of BMP-7, by Drm (Gremlin), follistatin, and Noggin and upregulation of BMP-4 may play an integral role in the development of nonunions. (PMID:19597895)
• A role for GREM1 in clear cell renal cell carcinoma carcinogenesis and tumor angiogenesis. (PMID:20042676)
• Variant rs1129456 associates with diabetic nephropathy. (PMID:20150533)
• Chromosomal imbalances in the GREM1 FMN1 region in individuals with limb defects are reported here. (PMID:20610440)
• The results demonstrate that gremlin binds and activates VEGFR2, leading to VEGFR2-dependent angiogenic responses in vitro and in vivo (PMID:20660291)
• Gremlin-mediated BMP inhibition results in activation of epithelial cells and transient fibrosis, but also induction of epithelium-protective FGF10 (PMID:20705941)
• Genetic variation in GREM1 is associated with fibrosis in pulmonary sarcoidosis. (PMID:21214523)
• Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer (PMID:21655089)
• Gremlin is overexpressed in malignant mesothelioma and that aberrant activation of Gremlin may play a critical role in the tumorigenesis of this disease (PMID:21935575)
• Data show that Bmp4, Bmp7, Gremlin and Twisted gastrulation (Twsg1) are all expressed in the thymus and expression was clearly different for each gene investigated. (PMID:21978004)
• Gremlin1 gene is a potentially important gene for lean body mass variation. (PMID:22048656)
• This is the first demonstration linking differential expression of Gremlin with etiology of infertility in women. (PMID:22160428)
• Gremlin 1 (a bone morphogenetic protein-7 antagonist) plays a critical role in the modulation of reno-protective action of BMP-7 in epithelial-to-mesenchymal transition. (PMID:22525892)
• our study identified Gremlin 1, FRP, and Dkk-1 as natural brakes on hypertrophic differentiation in articular cartilage. (PMID:22576962)
• Our data support a tumor suppressor role of GREM1 in pancreatic neuroendocrine tumors. (PMID:22706573)
• Higher numbers of cirrhosis cases and HCCs showed gremlin expression, which correlated with the stage. Gremlin expression correlated with that of CK19 and FGF2 in hepatitis cases (PMID:22839096)
• Lung adenocarcinoma but not squamous cell carcinoma shows a significant increase in Gremlin expression by mRNA and protein level. Lung fibroblast and epithelial cell lines transfected with GREM1 show significantly increased cell proliferation. (PMID:22870311)
• In tubular epithelial cells Gremlin increased profibrotic genes and caused epithelial mesenchymal transition changes. (PMID:23548835)
• Enrichment map profiling of the cancer invasion front suggests regulation of colorectal cancer progression by the bone morphogenetic protein antagonist, gremlin-1. (PMID:23659962)
• Gene duplication upstream of GREM1 was screened for in all sixty-five SPS individuals with no carriers being identified. (PMID:23805267)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	grem1a	ENSDARG00000029546
danio_rerio		ENSDARG00000090720
danio_rerio	grem1b	ENSDARG00000104618
mus_musculus	Grem1	ENSMUSG00000074934
rattus_norvegicus	Grem1	ENSRNOG00000026053
caenorhabditis_elegans		WBGENE00009389

Paralogs (2): NBL1 (ENSG00000158747), GREM2 (ENSG00000180875)

Protein

Protein identifiers

Gremlin-1 — O60565 (reviewed: O60565)

Alternative names: Cell proliferation-inducing gene 2 protein, Cysteine knot superfamily 1, BMP antagonist 1, DAN domain family member 2, Down-regulated in Mos-transformed cells protein, Increased in high glucose protein 2

All UniProt accessions (3): O60565, A6XAA7, H0YLY2

UniProt curated annotations — full annotation on UniProt →

Function. Cytokine that may play an important role during carcinogenesis and metanephric kidney organogenesis, as a BMP antagonist required for early limb outgrowth and patterning in maintaining the FGF4-SHH feedback loop. Down-regulates the BMP4 signaling in a dose-dependent manner. Antagonist of BMP2; inhibits BMP2-mediated differentiation of osteoblasts (in vitro). Acts as inhibitor of monocyte chemotaxis. Can inhibit the growth or viability of normal cells but not transformed cells when is overexpressed.

Subunit / interactions. Homodimer; can also form homooligomers. Interacts with BMP2; can form higher oligomers with BMP2. Interacts with SLIT1 and SLIT2 in a glycosylation-dependent manner.

Subcellular location. Secreted.

Tissue specificity. Highly expressed in small intestine, fetal brain and colon. Expression is restricted to intestinal subepithelial myofibroblasts (ISEMFs) at the crypt base. In subjects with HMPS1, by contrast, GREM1 is expressed, not only in basal ISEMFs, but also at very high levels in epithelial cells (predominantly colonocytes), with expression extending most of the way up the sides of the crypt. Weakly expressed in brain, ovary, prostate, pancreas and skeletal muscle. In brain found in the region localized around the internal capsule in the large subcortical nuclei, including caudate, putamen, substantia nigra, thalamus and subthalamus. Predominantly expressed in normal cells including neurons, astrocytes and fibroblasts.

Disease relevance. Polyposis syndrome, mixed hereditary 1 (HMPS1) [MIM:601228] A disease characterized by apparent autosomal dominant inheritance of multiple types of colorectal polyp, with colorectal carcinoma occurring in a high proportion of affected individuals. Patients can develop polyps of multiple and mixed morphologies, including serrated lesions, Peutz-Jeghers polyps, juvenile polyps, conventional adenomas and colorectal carcinoma in the absence of any identifiable extra-colonic features. The disease is caused by variants affecting the gene represented in this entry. HMPS1 is caused by a duplication spanning the 3’ end of the SCG5 gene and a region upstream of the GREM1 locus. This duplication is associated with increased allele-specific GREM1 expression that may cause reduced bone morphogenetic protein (BMP) pathway activity. This mechanism also underlies tumorigenesis in juvenile polyposis of the large bowel.

Induction. By high glucose through TGFB1-mediated pathways in mesangial cell. Down-regulated in tumor cell lines.

Similarity. Belongs to the DAN family.

Isoforms (2)

UniProt ID	Names	Canonical?
O60565-1	1	yes
O60565-2	2

RefSeq proteins (4): NP_001178251, NP_001178252, NP_001355648, NP_037504* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004133	DAN_dom	Domain
IPR006207	Cys_knot_C	Domain
IPR017159	Gremlin-1/2	Family
IPR029034	Cystine-knot_cytokine	Homologous_superfamily

Pfam: PF03045

UniProt features (18 total): strand 6, disulfide bond 4, signal peptide 1, chain 1, helix 1, turn 1, domain 1, region of interest 1, glycosylation site 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5AEJ	X-RAY DIFFRACTION	1.9
8B7H	X-RAY DIFFRACTION	1.95

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60565-F1	74.57	0.41

Antibody-complex structures (SAbDab): 1 — 8B7H

Functional residue map

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

Disulfide bonds (4): 94–144, 108–158, 118–176, 122–178

Glycosylation sites (1): 42

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9830674	Formation of the ureteric bud

MSigDB gene sets: 528 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_METANEPHRIC_NEPHRON_MORPHOGENESIS, CREL_01, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, AAGCAAT_MIR137, GOBP_EPITHELIUM_DEVELOPMENT, FREAC2_01, GOBP_BONE_TRABECULA_MORPHOGENESIS, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_REGULATION_OF_MORPHOGENESIS_OF_A_BRANCHING_STRUCTURE

GO Biological Process (42): cell morphogenesis (GO:0000902), cell migration involved in sprouting angiogenesis (GO:0002042), positive regulation of receptor internalization (GO:0002092), mesenchymal to epithelial transition involved in metanephros morphogenesis (GO:0003337), signal transduction (GO:0007165), cell-cell signaling (GO:0007267), positive regulation of cell population proliferation (GO:0008284), proximal/distal pattern formation (GO:0009954), regulation of epithelial to mesenchymal transition (GO:0010717), collagen fibril organization (GO:0030199), embryonic limb morphogenesis (GO:0030326), negative regulation of bone mineralization (GO:0030502), negative regulation of BMP signaling pathway (GO:0030514), negative regulation of chondrocyte differentiation (GO:0032331), negative regulation of osteoblast proliferation (GO:0033689), obsolete sequestering of BMP from receptor via BMP binding (GO:0038098), negative regulation of apoptotic process (GO:0043066), negative regulation of osteoblast differentiation (GO:0045668), positive regulation of angiogenesis (GO:0045766), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of bone remodeling (GO:0046851), determination of dorsal identity (GO:0048263), regulation of focal adhesion assembly (GO:0051893), cardiac muscle cell differentiation (GO:0055007), limb development (GO:0060173), cardiac muscle cell myoblast differentiation (GO:0060379), negative regulation of SMAD protein signal transduction (GO:0060392), ureteric bud formation (GO:0060676), negative regulation of monocyte chemotaxis (GO:0090027), positive regulation of cell migration involved in sprouting angiogenesis (GO:0090050), negative regulation of canonical Wnt signaling pathway (GO:0090090), positive regulation of branching involved in ureteric bud morphogenesis (GO:0090190), negative regulation of osteoclast proliferation (GO:0090291), negative regulation of bone trabecula formation (GO:1900155), negative regulation of bone mineralization involved in bone maturation (GO:1900158), positive regulation of vascular endothelial growth factor signaling pathway (GO:1900748), positive regulation of non-canonical NF-kappaB signal transduction (GO:1901224), angiogenesis (GO:0001525), animal organ morphogenesis (GO:0009887)

GO Molecular Function (8): cytokine activity (GO:0005125), morphogen activity (GO:0016015), transmembrane receptor protein tyrosine kinase activator activity (GO:0030297), BMP binding (GO:0036122), protein homodimerization activity (GO:0042803), vascular endothelial growth factor receptor 2 binding (GO:0043184), receptor ligand activity (GO:0048018), protein binding (GO:0005515)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), cell surface (GO:0009986), extracellular matrix (GO:0031012), extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Kidney development	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell communication	2
signaling	2
negative regulation of cell differentiation	2
receptor ligand activity	2
signaling receptor activator activity	2
cellular anatomical structure	2
anatomical structure morphogenesis	1
sprouting angiogenesis	1
blood vessel endothelial cell migration	1
regulation of receptor internalization	1
receptor internalization	1
positive regulation of receptor-mediated endocytosis	1
metanephros morphogenesis	1
epithelial cell differentiation involved in kidney development	1
mesenchymal to epithelial transition	1
metanephric renal vesicle morphogenesis	1
cellular process	1
regulation of cellular process	1
cellular response to stimulus	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
regionalization	1
epithelial to mesenchymal transition	1
regulation of cell differentiation	1
extracellular matrix organization	1
limb morphogenesis	1
embryonic appendage morphogenesis	1
negative regulation of ossification	1
bone mineralization	1
regulation of bone mineralization	1
negative regulation of biomineral tissue development	1
BMP signaling pathway	1
regulation of BMP signaling pathway	1
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
chondrocyte differentiation	1
regulation of chondrocyte differentiation	1
negative regulation of cartilage development	1
negative regulation of cell population proliferation	1

Protein interactions and networks

STRING

1154 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GREM1	BMP2	P12643	988
GREM1	BMP4	P12644	901
GREM1	FMN1	Q68DA7	844
GREM1	SHH	Q15465	806
GREM1	NOG	Q13253	802
GREM1	FGF4	P08620	781
GREM1	BMP7	P18075	751
GREM1	SCG5	P01164	738
GREM1	TGFB2	P08112	735
GREM1	SOST	Q9BQB4	712
GREM1	POLD1	P28340	709
GREM1	MUTYH	Q9UIF7	701
GREM1	BMPR2	Q13873	685
GREM1	GALNT12	Q8IXK2	663
GREM1	CHRD	Q9H2X0	656

IntAct

20 interactions, top by confidence:

A	B	Type	Score
KDR	GREM1	psi-mi:“MI:0915”(physical association)	0.640
KDR	GREM1	psi-mi:“MI:0407”(direct interaction)	0.640
GREM1	YWHAH	psi-mi:“MI:0915”(physical association)	0.590
GREM1	YWHAH	psi-mi:“MI:0407”(direct interaction)	0.590
GREM1	KRTAP12-2	psi-mi:“MI:0915”(physical association)	0.560
GREM1	MDFI	psi-mi:“MI:0915”(physical association)	0.560
EBNA1	IGF2BP3	psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350
	SNAP23	psi-mi:“MI:0914”(association)	0.350
	HAX1	psi-mi:“MI:0914”(association)	0.350
GREM1	KRTAP12-2	psi-mi:“MI:0915”(physical association)	0.000
GREM1	MDFI	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (6): GREM1 (Affinity Capture-MS), GREM1 (Two-hybrid), KRTAP12-2 (Two-hybrid), GREM1 (Affinity Capture-MS), GREM1 (Proximity Label-MS), GREM1 (Affinity Capture-MS)

ESM2 similar proteins: A0MTF4, A4FUY1, A8MVS5, M3X9S6, O15444, O18796, O35793, O54693, O60565, O70326, O73754, O73755, P01344, P01346, P07456, P09535, P10764, P12034, P15656, P17085, P19438, P48540, P48807, P50555, P51459, Q02815, Q07731, Q14CZ8, Q20FD0, Q3TMX7, Q4PR21, Q5BJT4, Q640R3, Q68A91, Q6P6J9, Q70EL4, Q7TSQ1, Q7Z692, Q86Y78, Q8R0A6

Diamond homologs: O35793, O55233, O60565, O70326, O73753, O73754, O73755, O88273, O95813, P41271, P70041, Q06880, Q28H35, Q61477, Q6DF53, Q6NZ13, Q76LW6, Q800X4, Q8WNY1, Q90YC9, Q9H772, Q07G34, Q8N907, Q9PWB0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
miR-542-5p	“down-regulates quantity by destabilization”	GREM1	“post transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	236
Likely benign	167
Benign	62

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
832500	NC_000015.10:g.(?32679746)(32702555_?)dup	Pathogenic
832797	NC_000015.10:g.(?32679746)(32712736_?)dup	Pathogenic

SpliceAI

238 predictions. Top by Δscore:

Variant	Effect	Δscore
15:32730688:A:AG	acceptor_gain	1.0000
15:32730689:G:GG	acceptor_gain	1.0000
15:32730689:GT:G	acceptor_gain	1.0000
15:32730689:GTAT:G	acceptor_gain	1.0000
15:32718158:ACAG:A	donor_loss	0.9900
15:32718160:AGG:A	donor_loss	0.9900
15:32718162:GT:G	donor_loss	0.9900
15:32730685:TTTA:T	acceptor_loss	0.9900
15:32730686:TTAGT:T	acceptor_loss	0.9900
15:32730687:TAGT:T	acceptor_loss	0.9900
15:32730688:AGTAT:A	acceptor_gain	0.9900
15:32730689:G:A	acceptor_loss	0.9900
15:32730689:GTA:G	acceptor_gain	0.9900
15:32730689:GTATG:G	acceptor_gain	0.9900
15:32731291:G:GT	donor_gain	0.9900
15:32730672:T:A	acceptor_gain	0.9800
15:32730672:T:TA	acceptor_loss	0.9800
15:32731240:GAT:G	donor_gain	0.9800
15:32718162:G:GG	donor_gain	0.9700
15:32730674:T:TA	acceptor_gain	0.9700
15:32718157:GACAG:G	donor_gain	0.9600
15:32730692:T:G	acceptor_gain	0.9100
15:32730687:TAGTA:T	acceptor_gain	0.8800
15:32730691:AT:A	acceptor_gain	0.8600
15:32730686:TTA:T	acceptor_gain	0.8400
15:32730688:A:C	acceptor_gain	0.8400
15:32718571:C:T	donor_gain	0.8300
15:32730684:CTTTA:C	acceptor_gain	0.8300
15:32730685:TTTAG:T	acceptor_gain	0.8300
15:32730691:A:AG	acceptor_gain	0.8300

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000143337 (15:32744599 C>A), RS1000478470 (15:32741980 A>G), RS1000504037 (15:32718625 C>A), RS1000514304 (15:32735676 A>G), RS1000651642 (15:32735400 C>T), RS1000684642 (15:32722482 G>A), RS1000695125 (15:32721109 T>C), RS1000987228 (15:32726271 G>A,T), RS1001000489 (15:32720030 A>C), RS1001019737 (15:32725990 G>A,T), RS1001110300 (15:32717703 C>A), RS1001156940 (15:32729128 A>G), RS1001312054 (15:32717484 G>T), RS1001638588 (15:32726695 A>G), RS1001646116 (15:32736123 C>G)

Disease associations

OMIM: gene MIM:603054 | disease phenotypes: MIM:601228

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary mixed polyposis syndrome	Definitive	Autosomal dominant
polyposis syndrome, hereditary mixed, 1	Strong	Autosomal dominant
hereditary intestinal polyposis	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hereditary mixed polyposis syndrome	Definitive	AD

Mondo (6): familial colorectal cancer (MONDO:0023113), hereditary neoplastic syndrome (MONDO:0015356), hereditary mixed polyposis syndrome (MONDO:0011023), polyposis syndrome, hereditary mixed, 1 (MONDO:0042486), premature menopause (MONDO:0001119), (MONDO:0018188)

Orphanet (2): Inherited cancer-predisposing syndrome (Orphanet:140162), Hereditary mixed polyposis syndrome (Orphanet:157794)

HPO phenotypes

18 total (18 of 18 shown, HPO-id order):

HPO	Term
HP:0001892	Abnormal bleeding
HP:0002573	Hematochezia
HP:0002576	Intussusception
HP:0002890	Thyroid carcinoma
HP:0003003	Colon cancer
HP:0005227	Adenomatous colonic polyposis
HP:0005505	Refractory anemia
HP:0006771	Duodenal adenocarcinoma
HP:0007378	Neoplasm of the gastrointestinal tract
HP:0012114	Endometrial carcinoma
HP:0012125	Prostate cancer
HP:0012183	Hyperplastic colonic polyposis
HP:0012198	Juvenile colonic polyposis
HP:0040276	Adenocarcinoma of the colon
HP:0100245	Gastrointestinal desmoid tumor
HP:0100743	Neoplasm of the rectum
HP:0100896	Rectal polyposis
HP:0200063	Colorectal polyposis

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST000547_2	Orofacial clefts	1.000000e-06
GCST001161_3	Colorectal cancer	2.000000e-08
GCST001787_3	Colorectal cancer	5.000000e-07
GCST002411_3	Colorectal cancer	1.000000e-11
GCST002563_15	Hypospadias	6.000000e-10
GCST002919_15	Colorectal cancer	3.000000e-11
GCST003017_20	Colorectal cancer	1.000000e-08
GCST003989_5	Chin dimples	6.000000e-45
GCST003996_28	Monobrow	5.000000e-25
GCST007856_45	Colorectal cancer or advanced adenoma	1.000000e-13
GCST007856_61	Colorectal cancer or advanced adenoma	4.000000e-15
GCST007856_65	Colorectal cancer or advanced adenoma	7.000000e-09
GCST007856_67	Colorectal cancer or advanced adenoma	9.000000e-40
GCST007856_81	Colorectal cancer or advanced adenoma	6.000000e-37
GCST009391_847	Metabolite levels	6.000000e-06
GCST90014033_61	Haemorrhoidal disease	4.000000e-13

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0003959	cleft lip
EFO:0007906	synophrys measurement
EFO:0010400	triacylglycerol 46:0 measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008594	Menopause, Premature	C12.050.351.500.056.630.250; C12.100.250.056.630.250; G08.686.157.500.500; G08.686.841.249.500.500
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
C563365	Polyposis Syndrome, Hereditary Mixed, 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 0 entries

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, affects cotreatment, increases expression	8
Particulate Matter	increases abundance, increases expression, decreases expression, affects cotreatment	5
methylmercuric chloride	increases expression, affects cotreatment	4
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	affects methylation, affects cotreatment, increases abundance, increases expression	3
Estradiol	increases expression, decreases expression, affects expression, affects cotreatment	3
Tetrachlorodibenzodioxin	decreases reaction, increases expression, decreases expression	3
Asbestos, Crocidolite	decreases reaction, increases expression	3
aristolochic acid I	decreases expression, increases expression, decreases activity, decreases reaction, decreases response to substance	2
arsenite	affects binding, increases reaction, increases methylation	2
mercuric bromide	affects cotreatment, increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases reaction, increases expression, decreases expression	2
belinostat	increases expression, affects cotreatment	2
bisphenol AF	increases expression	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	increases expression, affects cotreatment	2
Air Pollutants	increases abundance, increases expression, decreases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	2
Calcitriol	decreases expression	2
Dexamethasone	affects cotreatment, decreases expression, decreases reaction, increases expression	2
Glucose	increases expression	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Progesterone	affects cotreatment, decreases expression	2
Silicon Dioxide	increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
bisphenol F	increases expression	1
testosterone enanthate	affects expression	1
bisphenol A	increases expression	1
deoxynivalenol	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7QX	Ubigene A-549 GREM1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT06447961	Not specified	RECRUITING	PSYLIVED: the Psychological Impacts of Living With an Inherited Colorectal Cancer Predisposition Syndrome
NCT00349817	Not specified	UNKNOWN	Genetics Education: Preparing Physicians for the Future
NCT02645084	Not specified	COMPLETED	Identifying Patients With Hereditary and Familial Colorectal Cancer by Using an Online Risk Tool
NCT03365986	Not specified	UNKNOWN	Systemic Screening for Hereditary Colorectal Cancer in China
NCT04197856	Not specified	ACTIVE_NOT_RECRUITING	Direct Information to At-risk Relatives
NCT04280666	Not specified	UNKNOWN	Next-generation Sequencing of Colorectal Cancer Somatic Cells to Guide Genetic Susceptibility Gene Mutations Screening.
NCT05495776	Not specified	RECRUITING	Prospective Multicenter Registry Study to Assess the Frequency of Lynch Syndrome Among Patients With Colorectal Cancer
NCT07307664	Not specified	RECRUITING	Increasing Germline Genetic Testing for Patients With Cancer
NCT00001496	Not specified	COMPLETED	Establishment of Normal Breast Epithelial Cell Lines From Patients at High Risk for Breast Cancer
NCT00001898	Not specified	COMPLETED	Microarray Analysis for Human Genetic Disease
NCT00026884	Not specified	RECRUITING	Collection of Serum and Tissue Samples From Patients With Biopsy-Proved or Suspected Malignant Disease
NCT02289326	Not specified	COMPLETED	Biomarker Monitoring in TP53 Mutation Carriers
NCT02958462	Not specified	RECRUITING	Pre-myeloid Cancer and Bone Marrow Failure Clinic Study
NCT03160274	Not specified	RECRUITING	Genetic Analysis of Pheochromocytomas, Paragangliomas and Associated Conditions
NCT03426878	Not specified	COMPLETED	Cancer Health Assessments Reaching Many
NCT03857594	Not specified	ACTIVE_NOT_RECRUITING	Integrative Sequencing In Germline and Hereditary Tumours
NCT03973450	Not specified	UNKNOWN	Epidemiology of Pituitary Tumours: Prevalence of Associated Neoplasia
NCT03979612	Not specified	UNKNOWN	Evaluation of the Adhesion to the GENEPY Network
NCT04261972	Not specified	ACTIVE_NOT_RECRUITING	Cell-free DNA in Hereditary And High-Risk Malignancies 1
NCT04494945	Not specified	RECRUITING	Identifying and Caring for Individuals With Inherited Cancer Syndrome
NCT04541654	Not specified	RECRUITING	Li-Fraumeni & TP53 (LiFT UP): Understanding and Progress
NCT04763915	Not specified	ACTIVE_NOT_RECRUITING	Improving Care After Inherited Cancer Testing