CREB3L1

Summary

CREB3L1 (cAMP responsive element binding protein 3 like 1, HGNC:18856) is a protein-coding gene on chromosome 11p11.2, encoding Cyclic AMP-responsive element-binding protein 3-like protein 1 (Q96BA8). Precursor of the transcription factor form (Processed cyclic AMP-responsive element-binding protein 3-like protein 1), which is embedded in the endoplasmic reticulum membrane with N-terminal DNA-binding and transcription activation domains oriented toward the cytosolic face of t….

The protein encoded by this gene is normally found in the membrane of the endoplasmic reticulum (ER). However, upon stress to the ER, the encoded protein is cleaved and the released cytoplasmic transcription factor domain translocates to the nucleus. There it activates the transcription of target genes by binding to box-B elements.

Source: NCBI Gene 90993 — RefSeq curated summary.

At a glance

• Gene–disease (curated): osteogenesis imperfecta type 16 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 14
• Clinical variants (ClinVar): 364 total — 9 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 26
• Transcription factor: yes — 11 downstream targets (CollecTRI)
• MANE Select transcript: NM_052854

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18856
Approved symbol	CREB3L1
Name	cAMP responsive element binding protein 3 like 1
Location	11p11.2
Locus type	gene with protein product
Status	Approved
Aliases	OASIS
Ensembl gene	ENSG00000157613
Ensembl biotype	protein_coding
OMIM	616215
Entrez	90993

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000527342, ENST00000530518, ENST00000534616, ENST00000534787, ENST00000616094, ENST00000621158, ENST00000862985, ENST00000862986

RefSeq mRNA: 5 — MANE Select: NM_052854 NM_001425266, NM_001425267, NM_001425268, NM_001425269, NM_052854

CCDS: CCDS53620

Canonical transcript exons

ENST00000621158 — 12 exons

Exon	Start	End
ENSE00001097948	46312851	46312919
ENSE00001097950	46312612	46312670
ENSE00003543559	46312325	46312474
ENSE00003716851	46316286	46316385
ENSE00003721524	46320264	46320528
ENSE00003723767	46311032	46311189
ENSE00003734014	46320710	46321409
ENSE00003740876	46307816	46308000
ENSE00003743698	46309989	46310067
ENSE00003744366	46277662	46278213
ENSE00003745067	46299935	46300163
ENSE00003749462	46317361	46317487

Expression profiles

Bgee: expression breadth ubiquitous, 231 present calls, max score 98.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 43.4535 / max 591.1983, expressed in 1245 samples.

FANTOM5 promoters (17 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114069	31.9258	1203
114071	5.9216	968
114068	0.8879	539
114070	0.8130	469
114084	0.7601	414
114079	0.4905	269
206266	0.3561	212
114085	0.3422	211
114082	0.2866	175
114078	0.2818	119

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nasal cavity epithelium	UBERON:0005384	98.10	gold quality
stromal cell of endometrium	CL:0002255	97.66	gold quality
ileal mucosa	UBERON:0000331	95.46	gold quality
left ventricle myocardium	UBERON:0006566	95.34	gold quality
body of pancreas	UBERON:0001150	95.13	gold quality
mucosa of paranasal sinus	UBERON:0005030	94.90	gold quality
pylorus	UBERON:0001166	94.88	gold quality
heart right ventricle	UBERON:0002080	94.77	gold quality
apex of heart	UBERON:0002098	93.82	gold quality
rectum	UBERON:0001052	93.43	gold quality
pancreatic ductal cell	CL:0002079	93.40	silver quality
cardia of stomach	UBERON:0001162	92.88	gold quality
trachea	UBERON:0003126	92.88	gold quality
mucosa of transverse colon	UBERON:0004991	92.67	gold quality
type B pancreatic cell	CL:0000169	92.66	gold quality
prostate gland	UBERON:0002367	92.47	gold quality
periodontal ligament	UBERON:0008266	92.34	gold quality
olfactory bulb	UBERON:0002264	92.26	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	91.99	gold quality
cardiac ventricle	UBERON:0002082	91.96	gold quality
mucosa of sigmoid colon	UBERON:0004993	91.94	gold quality
heart left ventricle	UBERON:0002084	91.89	gold quality
body of stomach	UBERON:0001161	91.88	gold quality
stomach	UBERON:0000945	91.87	gold quality
colonic mucosa	UBERON:0000317	91.76	gold quality
decidua	UBERON:0002450	91.34	gold quality
pancreas	UBERON:0001264	91.15	gold quality
endocervix	UBERON:0000458	91.04	gold quality
gall bladder	UBERON:0002110	90.87	gold quality
minor salivary gland	UBERON:0001830	90.84	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	55.79
E-CURD-114	yes	54.30
E-GEOD-125970	yes	24.73
E-ANND-3	yes	20.72
E-CURD-112	yes	17.96
E-MTAB-9388	yes	11.11
E-MTAB-8410	yes	10.01
E-MTAB-10290	no	249.64

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

11 targets.

Target	Regulation
AVP
CHST3	Repression
COL1A1	Unknown
FGF2	Repression
FGFBP1	Repression
GFAP
HSPA5	Activation
NOS2	Activation
OXT	Activation
SDCBP
SLC1A4	Repression

JASPAR motifs

Motif	Name	Family
MA0839.1	CREB3L1	CREB-related factors
MA0839.2	CREB3L1	CREB-related factors

JASPAR matrix evidence (PMIDs): PMID:21041443

miRNA regulators (miRDB)

96 targeting CREB3L1, 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-4481	100.00	66.42	1669
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-4492	99.87	68.25	3611
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-4447	99.85	67.81	2900
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-92A-2-5P	99.75	67.01	2164

Literature-anchored findings (GeneRIF, showing 40)

• a transcriptional activator of CREB/ATF family with a transmembrane domain (PMID:12054625)
• Presence of FUS/CREB3L2 and FUS/CREB3L1 in low-grade fibromyxoid sarcoma and sclerosing epithelioid fibrosarcoma suggests these neoplasms may be related. (PMID:17721195)
• The human Creb3L1 can activate SPCG transcription in a heterologous system(Drosophila embryos), which suggests a general and direct role for this family of bZip transcription factors in mediating high-level secretory capacity. (PMID:21041443)
• FUS-CREB3L2/L1-positive sarcomas show a specific gene expression profile with upregulation of CD24 and FOXL1. (PMID:21536545)
• CREB3L1 may play an important role in limiting virus spread by inhibiting proliferation of virus-infected cells. (PMID:21767813)
• Upon infection with diverse DNA and RNA viruses, CREB3L1 was proteolytically cleaved, allowing its NH(2) terminus to enter the nucleus and induce multiple genes encoding inhibitors of the cell cycle to block cell proliferation of infected cells. (PMID:21767813)
• Rapid amplification of cDNA ends revealed exon 6 of the cAMP-responsive element binding protein 3-like 1 gene (CREB3L1) fused in-frame to the EWSR1 exon 11. (PMID:21987447)
• OASIS is notably unstable proteins that are easily degraded via the ubiquitin-proteasome pathway under normal conditions. (PMID:22705851)
• CREB3L1 expression may be a useful biomarker in identifying cancer cells sensitive to doxorubicin. (PMID:23256041)
• OASIS is important for the ER stress response and maintenance of some extracellular matrix proteins in human glioma cells. (PMID:23335989)
• a novel regulatory mechanism for VEGFA transcription by OASIS in human retinal pigment epithelial cells (PMID:23383089)
• We report 2 cases of Low-grade fibromyxoid sarcoma serendipitously found to harbor a novel alternative EWSR1-CREB3L1 gene fusion. (PMID:23588368)
• Fbxw7 controls osteogenesis and chondrogenesis by targeting OASIS and BBF2H7, respectively, for degradation. (PMID:23955342)
• CREB3L1 plays an important role in suppressing tumorigenesis and that loss of expression is required for the development of a metastatic phenotype. (PMID:24126059)
• Temporally regulates the differentiation from neural precursor cells into astrocytes [review] (PMID:24242870)
• EWSR1-CREB3L1 gene fusions are predominant over FUS and CREB3L2 rearrangements in pure sclerosing epithelioid fibrosarcoma. (PMID:24441665)
• Case Report: low-grade fibromyxoid sarcoma of the kidney found to harbor the EWSR1-CREB3L1 gene fusion. (PMID:24896634)
• Cleavage of CREB3L1 releases its NH2-terminal domain from membranes, allowing it to enter the nucleus where it binds to Smad4 to activate transcription of genes encoding proteins required for assembly of collagen-containing extracellular matrix. (PMID:25310401)
• Case Reports: genetically confirmed primary renal sclerosing epithelioid fibrosarcoma with EWSR1-CREB3L1 gene fusion. (PMID:25353281)
• CREB3L1 mRNA expression is downregulated in human bladder cancer.CREB3L1 is epigenetically silenced in human bladder cancer facilitating tumor cell spreading and migration in vitro. (PMID:25625847)
• CREB3L1 was expressed in 19% of RCC, which is generally resistant to doxorubicin, but in 70% of diffuse large B-cell lymphoma that is sensitive to doxorubicin. (PMID:26110425)
• Our data further strengthens the role for CREB3L1 as a metastasis suppressor in breast cancer and demonstrates that epigenetic silencing is a major regulator of the loss of CREB3L1 expression (PMID:26810754)
• The results suggest that CREB3L1 is required for decidualization in mice and humans and may be linked to the pathogenesis of endometriosis in a progesterone-dependent manner. (PMID:26917262)
• These findings indicate that the miR-146a-CREB3L1-FGFBP1 signaling axis plays an important role in the regulation of angiogenesis in human umbilical vein endothelial cells. (PMID:27121396)
• Ceramide inverts the membrane orientation of TMS4SF20, creating a form of TM4SF20 that stimulates the cleavage of CREB3L1. (PMID:27499293)
• Identification of novel prostate cancer drivers, ERF, CREB3L1, and POU2F2, using RegNetDriver, a framework for integration of genetic and epigenetic alterations with tissue-specific regulatory network. (PMID:28750683)
• ConclusionThis report confirms that CREB3L1 is an OI-related gene and suggests the pathogenic mechanism of CREB3L1-associated OI involves the altered regulation of proteins involved in cellular secretion. (PMID:28817112)
• Our findings support a model in which CREB3L1 acts as a downstream effector of TSH to regulate the expression of cargo proteins, and simultaneously increases the synthesis of transport factors and the expansion of the Golgi to synchronize the rise in cargo load with the amplified capacity of the secretory pathway (PMID:29093023)
• There was a relationship between the expression levels of both proteins and survival time. CREB3L1 and PTN expression levels serve as biomarkers with utility in grading gliomas. Absence of CREB3L1 and presence of PTN in brain glioma cells correlate with survival time of the glioma patients. (PMID:29531016)
• These results suggest that CREB3L1 expression level may be used as a biomarker to identify TNBC patients who are more likely to benefit from doxorubicin-based chemotherapy. (PMID:30103710)
• Here, we presenta Turkish family, in which molecular analysis of the proband revealeda previously unreported homozygous missense variant(c.911C>T,p.(Ala304Val))of the CREB3L1 (PMID:30657919)
• Study reports a novel homozygous CREB3L1 mutation in a large Indonesian family with osteogenesis imperfecta (OI); the homozygous affected members have survived to adulthood and they present a more severe phenotype than previously reported, expanding the clinical spectrum of OI for this gene. (PMID:31207160)
• Mutations in COL1A1/A2 and CREB3L1 are associated with oligodontia in osteogenesis imperfecta. (PMID:32234057)
• Transcription factor old astrocyte specifically induced substance is a novel regulator of kidney fibrosis. (PMID:33150680)
• A group of sclerosing epithelioid fibrosarcomas with low-level amplified EWSR1-CREB3L1 fusion gene in children. (PMID:34990868)
• Clinical and biological relevance of CREB3L1 in Philadelphia chromosome-negative myeloproliferative neoplasms. (PMID:35689957)
• Reduced CREB3L1 expression in triple negative and luminal a breast cancer cells contributes to enhanced cell migration, anchorage-independent growth and metastasis. (PMID:35802566)
• CREB3L1 promotes tumor growth and metastasis of anaplastic thyroid carcinoma by remodeling the tumor microenvironment. (PMID:36192735)
• KIF26B and CREB3L1 Derived from Immunoscore Could Inhibit the Progression of Ovarian Cancer. (PMID:38380081)
• Dimerization of hub protein DYNLL1 and bZIP transcription factor CREB3L1 enhances transcriptional activation of CREB3L1 target genes like arginine vasopressin. (PMID:38960286)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	creb3l1	ENSDARG00000015793
mus_musculus	Creb3l1	ENSMUSG00000027230
rattus_norvegicus	Creb3l1	ENSRNOG00000005413
drosophila_melanogaster	CrebA	FBGN0004396
drosophila_melanogaster	Atf6	FBGN0033010
drosophila_melanogaster	CrebB	FBGN0265784
caenorhabditis_elegans		WBGENE00000222
caenorhabditis_elegans		WBGENE00000793
caenorhabditis_elegans		WBGENE00016162

Paralogs (9): CREB3L3 (ENSG00000060566), CREM (ENSG00000095794), CREB3 (ENSG00000107175), ATF6 (ENSG00000118217), CREB1 (ENSG00000118260), ATF1 (ENSG00000123268), CREB3L4 (ENSG00000143578), CREB3L2 (ENSG00000182158), ATF6B (ENSG00000213676)

Protein

Protein identifiers

Cyclic AMP-responsive element-binding protein 3-like protein 1 — Q96BA8 (reviewed: Q96BA8)

Alternative names: Old astrocyte specifically-induced substance

All UniProt accessions (3): Q96BA8, E9PK33, H0YEU7

UniProt curated annotations — full annotation on UniProt →

Function. Precursor of the transcription factor form (Processed cyclic AMP-responsive element-binding protein 3-like protein 1), which is embedded in the endoplasmic reticulum membrane with N-terminal DNA-binding and transcription activation domains oriented toward the cytosolic face of the membrane. In response to ER stress or DNA damage, transported to the Golgi, where it is cleaved in a site-specific manner by resident proteases S1P/MBTPS1 and S2P/MBTPS2. The released N-terminal cytosolic domain is translocated to the nucleus where it activates transcription of specific target genes involved in the cell-cycle progression inhibition. Transcription factor involved in cell type specific DNA damage and unfolded protein response (UPR). Binds the DNA consensus sequence 5’-GTGXGCXGC-3’. Plays a critical role in bone formation through the transcription of COL1A1, and possibly COL1A2, and the secretion of bone matrix proteins. Directly binds to the UPR element (UPRE)-like sequence in an osteoblast-specific COL1A1 promoter region and induces its transcription. Does not regulate COL1A1 in other tissues, such as skin. Required to protect astrocytes from ER stress-induced cell death. In astrocytes, binds to the cAMP response element (CRE) of the BiP/HSPA5 promoter and participate in its transcriptional activation. In astrocytes and osteoblasts, upon DNA damage, inhibits cell-cycle progression after G2/M phase by binding to promoters and activating transcription of genes encoding cell-cycle inhibitors, such as p21/CDKN1A. Required for TGFB1 to activate genes involved in the assembly of collagen extracellular matrix. (Microbial infection) May play a role in limiting virus spread by inhibiting proliferation of virus-infected cells. Upon infection with diverse DNA and RNA viruses, inhibits cell-cycle progression by binding to promoters and activating transcription of genes encoding cell-cycle inhibitors, such as p21/CDKN1A.

Subunit / interactions. Interacts with SMAD4, the interaction takes place upon TGFB1 induction and SMAD4 acts as a CREB3L1 coactivator to induce the expression of genes involved in assembly of collagen extracellular matrix.

Subcellular location. Endoplasmic reticulum membrane Nucleus.

Tissue specificity. Expressed in several tissues, with highest levels in pancreas and prostate. Expressed at relatively lower levels in brain.

Post-translational modifications. Upon ER stress or DNA damage, translocated to the Golgi apparatus, where it is processed by regulated intramembrane proteolysis (RIP) to release the cytosol-facing N-terminal transcription factor domain. The cleavage is performed sequentially by site-1 and site-2 proteases (S1P/MBTPS1 and S2P/MBTPS2). RIP is induced by TGFB1 and ceramide. N-glycosylated. Ubiquitinated by HRD1/SYVN1; undergoes ‘Lys-48’-linked ubiquitination, followed by rapid proteasomal degradation under normal conditions. Upon ER stress, SYVN1 E3 ubiquitin-protein ligase dissociates from its substrate, ubiquitination does not occur and CREB3L1 is stabilized.

Disease relevance. Osteogenesis imperfecta 16 (OI16) [MIM:616229] An autosomal recessive form of osteogenesis imperfecta, a disorder of bone formation characterized by low bone mass, bone fragility and susceptibility to fractures after minimal trauma. Disease severity ranges from very mild forms without fractures to intrauterine fractures and perinatal lethality. Extraskeletal manifestations, which affect a variable number of patients, are dentinogenesis imperfecta, hearing loss, and blue sclerae. OI16 is a severe form. The disease may be caused by variants affecting the gene represented in this entry. OI16 affected patients show a genomic deletion encompassing CREB3L1 and the first exon of DGKZ. The absence of this exon does not affect all DGKZ isoforms, some are still produced at normal level. It cannot be ruled out that DGKZ could contribute to the phenotype, but in view of its role in bone formation, CREB3L1 is a strong OI16-causing candidate. This hypothesis is corroborated by the observation of CREB3L1 knockout mice which exhibit features reminiscent of severe human osteogenesis imperfecta.

Similarity. Belongs to the bZIP family. ATF subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96BA8-1	1	yes
Q96BA8-2	2, OASISv1

RefSeq proteins (5): NP_001412195, NP_001412196, NP_001412197, NP_001412198, NP_443086* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004827	bZIP	Domain
IPR046347	bZIP_sf	Homologous_superfamily

Pfam: PF00170

UniProt features (30 total): region of interest 6, mutagenesis site 5, compositionally biased region 4, chain 2, short sequence motif 2, glycosylation site 2, topological domain 2, site 1, cross-link 1, splice variant 1, sequence variant 1, sequence conflict 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96BA8-F1	55.66	0.13

Functional residue map

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

Catalytic / active sites (1): 426–427 (cleavage; by mbtps1)

Post-translational modifications (1): 184

Glycosylation sites (2): 492, 513

Mutagenesis-validated functional residues (5):

Position	Phenotype
392	abolishes proteolytic cleavage by mbtps2; when associated with a-395.
392	abolishes proteolytic cleavage by mbtps2.
395	abolishes proteolytic cleavage by mbtps2; when associated with a-392.
423	abolishes proteolytic cleavage by mbtps1.
426	abolishes proteolytic cleavage by mbtps1.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8874211	CREB3 factors activate genes

MSigDB gene sets: 340 (showing top): GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, SP3_Q3, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, ROVERSI_GLIOMA_COPY_NUMBER_UP, GOBP_OSTEOBLAST_DIFFERENTIATION, AP4_Q6, CAGCTG_AP4_Q5, GGCNKCCATNK_UNKNOWN, GOBP_CELLULAR_RESPONSE_TO_TOPOLOGICALLY_INCORRECT_PROTEIN, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_NEGATIVE_REGULATION_OF_FIBROBLAST_GROWTH_FACTOR_RECEPTOR_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS

GO Biological Process (16): osteoblast differentiation (GO:0001649), regulation of transcription by RNA polymerase II (GO:0006357), mitotic G2 DNA damage checkpoint signaling (GO:0007095), negative regulation of gene expression (GO:0010629), endoplasmic reticulum unfolded protein response (GO:0030968), positive regulation of collagen biosynthetic process (GO:0032967), response to endoplasmic reticulum stress (GO:0034976), negative regulation of fibroblast growth factor receptor signaling pathway (GO:0040037), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of transcription by RNA polymerase II (GO:0045944), extracellular matrix constituent secretion (GO:0070278), negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway (GO:1902236), negative regulation of sprouting angiogenesis (GO:1903671), negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of DNA-templated transcription (GO:0006355), response to unfolded protein (GO:0006986)

GO Molecular Function (11): transcription cis-regulatory region binding (GO:0000976), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), chromatin binding (GO:0003682), cAMP response element binding (GO:0035497), SMAD binding (GO:0046332), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (7): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Unfolded Protein Response (UPR)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of DNA-templated transcription	3
transcription by RNA polymerase II	3
regulation of transcription by RNA polymerase II	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of gene expression	2
DNA-templated transcription	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
ossification	1
cell differentiation	1
mitotic G2 phase	1
mitotic DNA damage checkpoint signaling	1
mitotic G2/M transition checkpoint	1
gene expression	1
negative regulation of macromolecule biosynthetic process	1
cellular response to unfolded protein	1
response to endoplasmic reticulum stress	1
intracellular signal transduction	1
positive regulation of biosynthetic process	1
positive regulation of collagen metabolic process	1
collagen biosynthetic process	1
regulation of collagen biosynthetic process	1
cellular response to stress	1
fibroblast growth factor receptor signaling pathway	1
negative regulation of signal transduction	1
regulation of fibroblast growth factor receptor signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
negative regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
extracellular matrix organization	1
secretion by cell	1
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	1
regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	1
negative regulation of response to endoplasmic reticulum stress	1
negative regulation of intrinsic apoptotic signaling pathway	1
sprouting angiogenesis	1
negative regulation of angiogenesis	1

Protein interactions and networks

STRING

1036 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CREB3L1	ATF6	P18850	739
CREB3L1	TMEM38B	Q9NVV0	734
CREB3L1	MBTPS2	O43462	719
CREB3L1	SEC24D	O94855	716
CREB3L1	FUS	P35637	708
CREB3L1	CRTAP	O75718	693
CREB3L1	FKBP10	Q96AY3	657
CREB3L1	P3H1	Q32P28	648
CREB3L1	IFITM5	A6NNB3	628
CREB3L1	MBTPS1	Q14703	601
CREB3L1	SERPINH1	P29043	555
CREB3L1	PLOD2	O00469	550
CREB3L1	EWSR1	Q01844	541
CREB3L1	SERPINF1	P36955	532
CREB3L1	PPIB	P23284	528

IntAct

832 interactions, top by confidence:

A	B	Type	Score
CREB3L1	SLC30A8	psi-mi:“MI:0915”(physical association)	0.810
SLC30A8	CREB3L1	psi-mi:“MI:0915”(physical association)	0.810
PLP1	CREB3L1	psi-mi:“MI:0915”(physical association)	0.810
CREB3L1	TMEM218	psi-mi:“MI:0915”(physical association)	0.780
CREB3L1	GPR25	psi-mi:“MI:0915”(physical association)	0.780
TSPO	CREB3L1	psi-mi:“MI:0915”(physical association)	0.780
CREB3L1	TMEM147	psi-mi:“MI:0915”(physical association)	0.780
TMEM218	CREB3L1	psi-mi:“MI:0915”(physical association)	0.780
CREB3L1	TSPO	psi-mi:“MI:0915”(physical association)	0.780
CREB3L1	MFSD5	psi-mi:“MI:0915”(physical association)	0.720
CREB3L1	SLC35B4	psi-mi:“MI:0915”(physical association)	0.720
FXYD6	CREB3L1	psi-mi:“MI:0915”(physical association)	0.720
SLC35B4	CREB3L1	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (279): CREB3L1 (Two-hybrid), CREB3L1 (Two-hybrid), CREB3L1 (Two-hybrid), CREB3L1 (Two-hybrid), CREB3L1 (Two-hybrid), CREB3L1 (Two-hybrid), CREB3L1 (Two-hybrid), CREB3L1 (Two-hybrid), CREB3L1 (Two-hybrid), CREB3L1 (Two-hybrid), CREB3L1 (Two-hybrid), CREB3L1 (Two-hybrid), CREB3L1 (Two-hybrid), CREB3L1 (Two-hybrid), SLC30A8 (Two-hybrid)

ESM2 similar proteins: A0A0G2JTY4, A2VD01, A5PMU4, A8E4V2, D2HNW6, E1BEQ5, O54972, O95644, P16236, P59281, P70365, P97305, Q12968, Q13191, Q13469, Q13905, Q15788, Q1LY51, Q2VPU4, Q3LRZ1, Q3TTA7, Q3U182, Q4PJW2, Q4VCS5, Q60591, Q61122, Q66IV1, Q68FF7, Q6DFR2, Q6GQL0, Q6NYU6, Q6ZNC4, Q80TM6, Q80VG1, Q8HWS3, Q8IXK0, Q8IY63, Q8K4S7, Q8N228, Q8VHG2

Diamond homologs: A1L224, A2VD01, O43889, O44743, P29747, Q08CW8, Q1LYG4, Q3SYZ3, Q4JFH9, Q502F0, Q5FVM5, Q5RCM9, Q5UEM7, Q5UEM8, Q61817, Q66HA2, Q68CJ9, Q6QDP7, Q70SY1, Q8BH52, Q8SQ19, Q8TEY5, Q91XE9, Q96BA8, Q9D2A5, Q9Z125, Q54Y73, P15337, P16220, P18846, P27699, P27925, P51984, P51985, P79145, P81269, Q01147, Q03060, Q03061, Q08DA8

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
MBTPS1	up-regulates	CREB3L1	cleavage
MBTPS2	up-regulates	CREB3L1	cleavage
Unfolded_Proteins	up-regulates	CREB3L1
CREB3L1	“up-regulates quantity by expression”	OXT	“transcriptional regulation”
CREB3L1	“up-regulates activity”	CREB3L1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	6
Uncertain significance	150
Likely benign	150
Benign	31

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
1687286	NM_052854.4(CREB3L1):c.1186G>T (p.Glu396Ter)	Pathogenic
1914965	NM_052854.4(CREB3L1):c.878del (p.Arg293fs)	Pathogenic
2857894	NM_052854.4(CREB3L1):c.1226del (p.Leu409fs)	Pathogenic
3644421	NM_052854.4(CREB3L1):c.1060C>T (p.Gln354Ter)	Pathogenic
3695284	NM_052854.4(CREB3L1):c.420del (p.Leu141fs)	Pathogenic
4796547	NM_052854.4(CREB3L1):c.1267C>T (p.Arg423Ter)	Pathogenic
559483	NM_052854.4(CREB3L1):c.928AAG[2] (p.Lys312del)	Pathogenic
559484	NM_052854.4(CREB3L1):c.1284C>A (p.Tyr428Ter)	Pathogenic
982569	NM_052854.4(CREB3L1):c.911C>T (p.Ala304Val)	Pathogenic
1324170	NM_052854.4(CREB3L1):c.753+1G>A	Likely pathogenic
3359262	NM_052854.4(CREB3L1):c.1259-7_1267del	Likely pathogenic
3895517	NM_052854.4(CREB3L1):c.595+2T>A	Likely pathogenic
4081293	NM_052854.4(CREB3L1):c.89del (p.Phe30fs)	Likely pathogenic
4279085	NM_052854.4(CREB3L1):c.1042C>T (p.Gln348Ter)	Likely pathogenic
930601	NM_052854.4(CREB3L1):c.774del (p.Pro259fs)	Likely pathogenic

SpliceAI

1668 predictions. Top by Δscore:

Variant	Effect	Δscore
11:46278210:TGCGG:T	donor_loss	1.0000
11:46278211:GCG:G	donor_gain	1.0000
11:46278212:CGGT:C	donor_loss	1.0000
11:46278213:GGTA:G	donor_loss	1.0000
11:46278214:G:GG	donor_gain	1.0000
11:46278215:T:G	donor_loss	1.0000
11:46299934:GC:G	acceptor_gain	1.0000
11:46300162:AGGTA:A	donor_loss	1.0000
11:46300163:GGT:G	donor_loss	1.0000
11:46300164:G:GG	donor_gain	1.0000
11:46307814:A:AG	acceptor_gain	1.0000
11:46307815:G:GG	acceptor_gain	1.0000
11:46309983:CCTCA:C	acceptor_loss	1.0000
11:46309984:CTCA:C	acceptor_loss	1.0000
11:46309985:TCAG:T	acceptor_loss	1.0000
11:46309986:CA:C	acceptor_loss	1.0000
11:46309987:A:AG	acceptor_gain	1.0000
11:46309987:AG:A	acceptor_gain	1.0000
11:46309988:G:GG	acceptor_gain	1.0000
11:46309988:GG:G	acceptor_gain	1.0000
11:46310065:CGGG:C	donor_loss	1.0000
11:46310066:GG:G	donor_gain	1.0000
11:46310067:GG:G	donor_gain	1.0000
11:46310068:G:GG	donor_gain	1.0000
11:46310069:T:G	donor_loss	1.0000
11:46312322:C:G	acceptor_gain	1.0000
11:46312323:A:AG	acceptor_gain	1.0000
11:46312324:G:GC	acceptor_gain	1.0000
11:46312324:GA:G	acceptor_gain	1.0000
11:46312324:GAA:G	acceptor_gain	1.0000

AlphaMissense

3412 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:46312356:T:A	L262Q	1.000
11:46312369:G:C	E266D	1.000
11:46312369:G:T	E266D	1.000
11:46312374:G:C	R268P	1.000
11:46312380:T:A	L270Q	1.000
11:46312380:T:C	L270P	1.000
11:46312385:G:C	A272P	1.000
11:46312443:T:C	L291S	1.000
11:46312445:A:G	K292E	1.000
11:46312447:G:C	K292N	1.000
11:46312447:G:T	K292N	1.000
11:46312452:T:A	V294D	1.000
11:46312458:G:C	R296T	1.000
11:46312458:G:T	R296M	1.000
11:46312459:G:C	R296S	1.000
11:46312459:G:T	R296S	1.000
11:46312460:A:G	K297E	1.000
11:46312462:A:C	K297N	1.000
11:46312462:A:T	K297N	1.000
11:46312464:T:A	I298N	1.000
11:46312464:T:C	I298T	1.000
11:46312464:T:G	I298S	1.000
11:46312466:A:G	K299E	1.000
11:46312467:A:T	K299M	1.000
11:46312468:G:C	K299N	1.000
11:46312468:G:T	K299N	1.000
11:46312469:A:C	N300H	1.000
11:46312469:A:G	N300D	1.000
11:46312470:A:C	N300T	1.000
11:46312470:A:G	N300S	1.000

dbSNP variants (sampled 300 via entrez): RS1000040913 (11:46301721 G>T), RS1000054123 (11:46318203 G>A), RS1000095621 (11:46295345 C>G), RS1000147352 (11:46307388 C>A), RS1000147941 (11:46295013 T>C), RS1000225181 (11:46281280 G>C), RS1000232231 (11:46288563 C>G), RS1000364506 (11:46318433 G>A), RS1000406499 (11:46312998 C>A,G,T), RS1000600369 (11:46299675 A>C), RS1000614097 (11:46287392 G>A,T), RS1000663950 (11:46301408 C>A,G,T), RS1000704417 (11:46305963 T>C), RS1000756512 (11:46313256 G>A), RS1000842972 (11:46317570 A>G)

Disease associations

OMIM: gene MIM:616215 | disease phenotypes: MIM:616229, MIM:166200

GenCC curated gene-disease

Disease	Classification	Inheritance
osteogenesis imperfecta type 16	Strong	Autosomal recessive
osteogenesis imperfecta type 3	Supportive	Autosomal dominant

Mondo (4): osteogenesis imperfecta type 16 (MONDO:0014544), teratoma (MONDO:0002601), osteogenesis imperfecta (MONDO:0019019), osteogenesis imperfecta type 3 (MONDO:0009804)

Orphanet (1): Osteogenesis imperfecta (Orphanet:666)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000308	Microretrognathia
HP:0000365	Hearing impairment
HP:0000405	Conductive hearing impairment
HP:0000592	Blue sclerae
HP:0000774	Narrow chest
HP:0000926	Platyspondyly
HP:0000938	Osteopenia
HP:0000978	Bruising susceptibility
HP:0001382	Joint hypermobility
HP:0001518	Small for gestational age
HP:0002645	Wormian bones
HP:0002757	Recurrent fractures
HP:0002953	Vertebral compression fracture
HP:0003010	Prolonged bleeding time
HP:0003026	Short long bone
HP:0003027	Mesomelia
HP:0003577	Congenital onset
HP:0003863	Angulated humerus
HP:0004322	Short stature
HP:0005474	Decreased calvarial ossification
HP:0006487	Bowing of the long bones
HP:0006640	Multiple rib fractures
HP:0008905	Rhizomelia
HP:0009804	Tooth agenesis
HP:0034198	Second trimester onset

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST004521_122	Autism spectrum disorder or schizophrenia	3.000000e-13
GCST004521_165	Autism spectrum disorder or schizophrenia	3.000000e-08
GCST005186_10	Fasting blood glucose	2.000000e-07
GCST006612_102	LDL cholesterol	3.000000e-08
GCST006803_20	Schizophrenia	3.000000e-13
GCST007267_5	Systolic blood pressure	4.000000e-13
GCST007825_4	Alzheimer’s disease or fasting glucose levels (pleiotropy)	3.000000e-16
GCST007928_33	Medication use (diuretics)	3.000000e-08
GCST008363_82	Offspring birth weight	4.000000e-09
GCST008474_12	Peripheral artery disease	8.000000e-10
GCST010241_48	Apolipoprotein A1 levels	5.000000e-15
GCST010242_134	HDL cholesterol levels	2.000000e-12
GCST012020_205	Serum metabolite levels	3.000000e-14
GCST012020_206	Serum metabolite levels	2.000000e-13

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0006335	systolic blood pressure
EFO:0009928	Diuretic use measurement
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004612	high density lipoprotein cholesterol measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D010013	Osteogenesis Imperfecta	C05.116.099.708.685; C16.320.737; C17.300.200.540
D013724	Teratoma	C04.557.465.910
C536044	Osteogenesis imperfecta, type 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Smoke	increases abundance, increases expression, decreases expression	3
Calcitriol	decreases expression, increases expression, affects cotreatment	2
Estradiol	affects cotreatment, increases expression, decreases expression	2
aristolochic acid I	increases expression	1
sotorasib	affects cotreatment, decreases expression	1
bisphenol A	increases expression	1
methylselenic acid	decreases expression	1
sodium arsenite	increases expression	1
manganese chloride	increases abundance, increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
tetraethoxysilane	decreases reaction, increases methylation, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
obeticholic acid	decreases expression	1
abrine	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	decreases expression, affects cotreatment	1
Decitabine	decreases reaction, increases methylation	1
Sunitinib	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	decreases expression, increases abundance	1
Chelating Agents	decreases expression, affects binding	1
Cisplatin	affects cotreatment, decreases expression	1
Copper	affects binding, decreases expression	1
Diethylhexyl Phthalate	increases expression	1
Doxorubicin	decreases expression	1
Manganese	increases abundance, increases expression	1
Phthalic Acids	increases methylation	1
Testosterone	increases expression, affects cotreatment	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E0AV	Ubigene HeLa CREB3L1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00131469	PHASE4	COMPLETED	Study of Teriparatide (FORTEO) to Treat Adults With Osteogenesis Imperfecta
NCT00159419	PHASE4	COMPLETED	Bisphosphonate Therapy for Osteogenesis Imperfecta
NCT01713231	PHASE4	COMPLETED	Effect of High-Dose Vitamin D on Bone Density in Osteogenesis Imperfecta
NCT02303873	PHASE4	COMPLETED	Efficacy and Safety of Alendronate in Chinese Children or Adolescents With Osteogenesis Imperfecta
NCT03735537	PHASE4	COMPLETED	Treatment of Osteogenesis Imperfecta With Parathyroid Hormone and Zoledronic Acid
NCT04152551	PHASE4	RECRUITING	Effects of Bisphosphonates on OI-Related Hearing Loss
NCT00104676	PHASE3	COMPLETED	Combination Chemotherapy in Treating Patients With Stage II or Stage III Germ Cell Tumors
NCT02375204	PHASE3	ACTIVE_NOT_RECRUITING	Standard-Dose Combination Chemotherapy or High-Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients with Relapsed or Refractory Germ Cell Tumors
NCT00001305	PHASE3	COMPLETED	Growth Hormone Therapy in Osteogenesis Imperfecta
NCT00005901	PHASE3	COMPLETED	Pamidronate to Treat Osteogenesis Imperfecta in Children
NCT00106028	PHASE3	COMPLETED	Safety and Efficacy of Risedronate in the Treatment of Osteogenesis Imperfecta in Children
NCT00982124	PHASE3	COMPLETED	An Efficacy and Safety Trial of Intravenous Zoledronic Acid in Infants Less Than One Year of Age, With Severe Osteogenesis Imperfecta
NCT02352753	PHASE3	TERMINATED	Multicenter,Single-arm Study to Evaluate Efficacy, Safety, & Pharmacokinetics of Denosumab in Children w/ OI
NCT03638128	PHASE3	TERMINATED	Open-label Extension of Study 20130173 of Denosumab in Children and Young Adults With Osteogenesis Imperfecta
NCT05768854	PHASE3	ACTIVE_NOT_RECRUITING	Setrusumab vs Bisphosphonates in Pediatric Subjects With Osteogenesis Imperfecta
NCT05972551	PHASE3	ACTIVE_NOT_RECRUITING	Study to Evaluate Efficacy and Safety of Romosozumab Compared With Bisphosphonates in Children and Adolescents With Osteogenesis Imperfecta
NCT06636071	PHASE3	ACTIVE_NOT_RECRUITING	Setrusumab in Pediatric Japanese Subjects With Osteogenesis Imperfecta
NCT07366086	PHASE3	RECRUITING	Pediatric Safety Follow-up Study of Prior Treatment With Romosozumab for Osteogenesis Imperfecta
NCT03118570	PHASE2	COMPLETED	A Study in Adult Patients With Type I, III or IV Osteogenesis Imperfecta Treated With BPS804
NCT00002931	PHASE2	COMPLETED	Combination Chemotherapy Plus Peripheral Stem Cell Transplantation in Treating Patients With Relapsed Germ Cell Cancer
NCT00301782	PHASE2	COMPLETED	Combination Chemotherapy in Treating Male Patients With Germ Cell Tumors
NCT00432094	PHASE2	COMPLETED	Autologous Peripheral Blood Stem Cell Transplant for Germ Cell Tumors
NCT00453232	PHASE2	COMPLETED	Combination Chemotherapy and Pegfilgrastim in Treating Men With Metastatic Germ Cell Tumors
NCT00453310	PHASE2	COMPLETED	Sunitinib in Treating Patients With Metastatic Germ Cell Tumors That Have Relapsed or Not Responded to Treatment
NCT00470366	PHASE2	COMPLETED	Combination Chemotherapy and Pegfilgrastim in Treating Patients With Previously Untreated Germ Cell Tumors
NCT02300987	PHASE2	COMPLETED	A Randomized, Blinded, Placebo-controlled, Phase II Trial of LEE011 in Patients With Relapsed, Refractory, Incurable Teratoma With Recent Progression
NCT00063479	PHASE2	COMPLETED	Bisphosphonate Treatment of Osteogenesis Imperfecta
NCT00131118	PHASE2	COMPLETED	Zoledronic Acid in Children (1 -17 Years) With Severe Osteogenesis Imperfecta
NCT01417091	PHASE2	COMPLETED	Safety, Pharmacokinetics and Pharmacodynamics of BPS804 in Osteogenesis Imperfecta
NCT01679080	PHASE2	TERMINATED	The Effect of Treatment With Teriparatide and Zoledronic Acid in Patients With Osteogenesis Imperfecta
NCT01799798	PHASE2	COMPLETED	Translational Therapy in Patients With Osteogenesis Imperfecta - A Pilot Trial on Treatment With the Rankl-Antibody Denosumab
NCT03208582	PHASE2	COMPLETED	Do Bisphosphonates Alter the Skeletal Response to Mechanical Stimulation in Children With Osteogenesis Imperfecta?
NCT03216486	PHASE2	WITHDRAWN	An Exploratory Study of BPS804 Treatment in Adult Patients With Type I, III or IV Osteogenesis Imperfecta
NCT05312697	PHASE2	TERMINATED	Long-term Extension Study of Setrusumab in Adults With Type I, III, or IV Osteogenesis Imperfecta
NCT07062588	PHASE2	RECRUITING	Osteogenesis Imperfecta Trial of AGA2115 for ADUlts With COL1A1 and/or COL1A2 GeNetic Variations (IDUN)
NCT07557446	PHASE2	NOT_YET_RECRUITING	A Dose REgimen-Finding Study of AGA2115 in Chinese Patients With Osteogenesis ImpeRfecta (EIR)
NCT01061099	PHASE1	COMPLETED	Repeated Infusions of Mesenchymal Stromal Cells in Children With Osteogenesis Imperfecta
NCT00705120	PHASE1	COMPLETED	Treatment of Severe Osteogenesis Imperfecta by Allogeneic Bone Marrow Transplantation
NCT02172885	PHASE1	COMPLETED	Mesenchymal Stem Cell Based Therapy for the Treatment of Osteogenesis Imperfecta
NCT03064074	PHASE1	COMPLETED	Safety of Fresolimumab in the Treatment of Osteogenesis Imperfecta