NBL1

Summary

NBL1 (NBL1, DAN family BMP antagonist, HGNC:7650) is a protein-coding gene on chromosome 1p36.13, encoding Neuroblastoma suppressor of tumorigenicity 1 (P41271). Possible candidate as a tumor suppressor gene of neuroblastoma.

This gene product is the founding member of the evolutionarily conserved CAN (Cerberus and DAN) family of proteins, which contain a domain resembling the CTCK (C-terminal cystine knot-like) motif found in a number of signaling molecules. These proteins are secreted, and act as BMP (bone morphogenetic protein) antagonists by binding to BMPs and preventing them from interacting with their receptors. They may thus play an important role during growth and development. Alternatively spliced transcript variants have been identified for this gene. Read-through transcripts between this locus and the upstream mitochondrial inner membrane organizing system 1 gene (GeneID 440574) have been observed.

Source: NCBI Gene 4681 — RefSeq curated summary.

At a glance

• GWAS associations: 12
• Clinical variants (ClinVar): 1 total
• MANE Select transcript: NM_005380

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7650
Approved symbol	NBL1
Name	NBL1, DAN family BMP antagonist
Location	1p36.13
Locus type	gene with protein product
Status	Approved
Aliases	D1S1733E, NB, DAN, NO3, DAND1
Ensembl gene	ENSG00000158747
Ensembl biotype	protein_coding
OMIM	600613
Entrez	4681

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 26 protein_coding

ENST00000289749, ENST00000375136, ENST00000425400, ENST00000427894, ENST00000428975, ENST00000439278, ENST00000439664, ENST00000451758, ENST00000548815, ENST00000602662, ENST00000615215, ENST00000618761, ENST00000621723, ENST00000622566, ENST00000899516, ENST00000899517, ENST00000899518, ENST00000899519, ENST00000899520, ENST00000899521, ENST00000899522, ENST00000933903, ENST00000968538, ENST00000968539, ENST00000968540, ENST00000968541

RefSeq mRNA: 10 — MANE Select: NM_005380 NM_001204084, NM_001204085, NM_001204086, NM_001204088, NM_001204089, NM_001278164, NM_001278165, NM_001278166, NM_005380, NM_182744

CCDS: CCDS41278, CCDS72720

Canonical transcript exons

ENST00000375136 — 4 exons

Exon	Start	End
ENSE00001159957	19656866	19658452
ENSE00001862341	19644311	19644446
ENSE00003817919	19655324	19655435
ENSE00003828997	19655012	19655200

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 99.49.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 63.3860 / max 379.9191, expressed in 1826 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1066	63.3860	1826
1077	55.0480	1676
1076	4.3141	1315
1078	0.7925	430
201389	0.7449	487
1074	0.3951	157
1075	0.2477	123
1073	0.0048	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endocervix	UBERON:0000458	99.49	gold quality
left ovary	UBERON:0002119	99.43	gold quality
right ovary	UBERON:0002118	99.41	gold quality
tendon of biceps brachii	UBERON:0008188	99.25	gold quality
ectocervix	UBERON:0012249	99.14	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.02	gold quality
mucosa of transverse colon	UBERON:0004991	99.01	gold quality
lower esophagus	UBERON:0013473	99.01	gold quality
gall bladder	UBERON:0002110	99.00	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.00	gold quality
prostate gland	UBERON:0002367	98.97	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.89	gold quality
mucosa of stomach	UBERON:0001199	98.88	gold quality
transverse colon	UBERON:0001157	98.85	gold quality
stromal cell of endometrium	CL:0002255	98.82	gold quality
urethra	UBERON:0000057	98.78	gold quality
left uterine tube	UBERON:0001303	98.76	gold quality
periodontal ligament	UBERON:0008266	98.71	gold quality
nipple	UBERON:0002030	98.70	gold quality
body of uterus	UBERON:0009853	98.66	gold quality
small intestine	UBERON:0002108	98.60	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.41	gold quality
vagina	UBERON:0000996	98.36	gold quality
ileal mucosa	UBERON:0000331	98.33	gold quality
lower esophagus mucosa	UBERON:0035834	98.32	gold quality
esophagus	UBERON:0001043	98.31	gold quality
skin of leg	UBERON:0001511	98.30	gold quality
skin of abdomen	UBERON:0001416	98.27	gold quality
right uterine tube	UBERON:0001302	98.24	gold quality
upper lobe of left lung	UBERON:0008952	98.22	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-CURD-126	yes	2052.20
E-MTAB-9906	yes	1202.17
E-MTAB-10287	yes	515.45
E-MTAB-6701	yes	122.68
E-HCAD-1	yes	93.63
E-HCAD-11	yes	48.57
E-MTAB-8410	yes	40.81
E-GEOD-134144	yes	39.05
E-CURD-46	yes	22.79
E-GEOD-135922	yes	19.66
E-ANND-3	yes	17.03
E-MTAB-8381	no	670.26
E-GEOD-124858	no	17.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

38 targeting NBL1, 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-1252-5P	100.00	69.80	2774
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-4786-3P	99.36	68.35	1390
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-6738-3P	99.03	67.14	1326
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-2355-5P	98.83	65.51	1589
HSA-MIR-6885-5P	98.71	64.33	902

Literature-anchored findings (GeneRIF, showing 10)

• expression dependent on p73 during cisplatin-induced cell death and osteoblast differentiation (PMID:12150978)
• Data demonstrate for the first time that Dan physically and functionally interacts with Slit proteins to act as a negative regulator for monocyte chemotaxis. (PMID:15528323)
• This study was to establish if NBL1 was a molecular marker for pancreatic cancer. (PMID:19995712)
• CDKN2A, GATA3, CREBBP, ITGA2, NBL1 and TGM4 were down-regulated in the prostate carcinoma glands compared to the corresponding normal glands (PMID:21743959)
• NBL1 is a secreted protein that is highly restricted to the prostate. Underexpression of NBL1 correlated with prostate cancer progression. (PMID:22948749)
• The DAN family proteins with regards to BMP inhibition and also highlights their emerging roles in the modulation of Wnt and VEGF signaling pathways. (PMID:24810382)
• inhibition toward BMP2 and BMP7, but not GDF5. Although NBL1(S67Y) was able to antagonize BMP7 as effectively as PRDC, NBL1(S67Y) was still 32-fold weaker than PRDC against BMP2. (PMID:25561725)
• The structure of Grem2-GDF5 complex has revealed a number of key findings for DAN-family mediated BMP2 inhibition. (PMID:27524626)
• Neuroblastoma suppressor of tumorigenicity 1 is a circulating protein associated with progression to end-stage kidney disease in diabetes. (PMID:35947673)
• Neuroblastoma suppressor of tumorigenicity 1 is associated with the severity of interstitial fibrosis and kidney function decline in IgA nephropathy. (PMID:37436574)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000102687
mus_musculus	Nbl1	ENSMUSG00000041120
rattus_norvegicus	Nbl1	ENSRNOG00000049402
caenorhabditis_elegans		WBGENE00009389

Paralogs (2): GREM1 (ENSG00000166923), GREM2 (ENSG00000180875)

Protein

Protein identifiers

Neuroblastoma suppressor of tumorigenicity 1 — P41271 (reviewed: P41271)

Alternative names: DAN domain family member 1, Protein N03, Zinc finger protein DAN

All UniProt accessions (8): A0A087WTY6, A3KFI1, A3KFI2, A3KFI3, A3KFI4, A3KFI5, P41271, E5RFZ1

UniProt curated annotations — full annotation on UniProt →

Function. Possible candidate as a tumor suppressor gene of neuroblastoma. May play an important role in preventing cells from entering the final stage (G1/S) of the transformation process.

Subunit / interactions. Homodimer.

Subcellular location. Secreted.

Tissue specificity. Most abundant in normal lung and meningioma.

Similarity. Belongs to the DAN family.

Isoforms (2)

UniProt ID	Names	Canonical?
P41271-1	1	yes
P41271-2	2

RefSeq proteins (10): NP_001191013, NP_001191014, NP_001191015, NP_001191017, NP_001191018, NP_001265093, NP_001265094, NP_001265095, NP_005371, NP_877421 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004133	DAN_dom	Domain
IPR006207	Cys_knot_C	Domain
IPR016728	Neuroblast_suppress_tumour_1	Family
IPR029034	Cystine-knot_cytokine	Homologous_superfamily

Pfam: PF03045

UniProt features (16 total): strand 6, disulfide bond 5, signal peptide 1, chain 1, domain 1, region of interest 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4YU8	X-RAY DIFFRACTION	1.8
4X1J	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P41271-F1	76.29	0.43

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 (5): 35–85, 49–99, 59–118, 63–120, 82–123

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 233 (showing top): VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, BENPORATH_ES_WITH_H3K27ME3, MYOGENIN_Q6, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, YAO_HOXA10_TARGETS_VIA_PROGESTERONE_UP, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_POSITIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_NEUROGENESIS, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_1, RIZKI_TUMOR_INVASIVENESS_3D_DN, GGGTGGRR_PAX4_03, CHANDRAN_METASTASIS_DN, GOBP_REGULATION_OF_LEUKOCYTE_MIGRATION

GO Biological Process (11): nervous system development (GO:0007399), negative regulation of BMP signaling pathway (GO:0030514), obsolete sequestering of BMP in extracellular matrix (GO:0035582), obsolete sequestering of BMP from receptor via BMP binding (GO:0038098), positive regulation of neuron differentiation (GO:0045666), determination of dorsal identity (GO:0048263), neuron projection morphogenesis (GO:0048812), negative regulation of monocyte chemotaxis (GO:0090027), signal transduction (GO:0007165), neuron differentiation (GO:0030182), obsolete sequestering of extracellular ligand from receptor (GO:0035581)

GO Molecular Function (5): morphogen activity (GO:0016015), BMP binding (GO:0036122), identical protein binding (GO:0042802), receptor ligand activity (GO:0048018), protein binding (GO:0005515)

GO Cellular Component (2): obsolete extracellular space (GO:0005615), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
system 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
neuron differentiation	1
positive regulation of cell differentiation	1
regulation of neuron differentiation	1
dorsal/ventral pattern formation	1
determination of dorsal/ventral asymmetry	1
neuron projection development	1
plasma membrane bounded cell projection morphogenesis	1
monocyte chemotaxis	1
negative regulation of leukocyte chemotaxis	1
negative regulation of mononuclear cell migration	1
regulation of monocyte chemotaxis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell differentiation	1
generation of neurons	1
receptor ligand activity	1
cytokine binding	1
protein binding	1
signaling receptor binding	1
signal transduction	1
signaling receptor activator activity	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

444 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NBL1	INCENP	Q9NQS7	903
NBL1	KCNJ6	P48051	879
NBL1	AURKB	Q96GD4	828
NBL1	ID3	Q02535	697
NBL1	TNFRSF1B	P20333	548
NBL1	CCL22	O00626	504
NBL1	CDCA8	Q53HL2	447
NBL1	MYCN	P04198	432
NBL1	SOSTDC1	Q6X4U4	432
NBL1	SPATS1	Q496A3	398
NBL1	SRC	P12931	389
NBL1	FBXO36	Q8NEA4	377
NBL1	SOST	Q9BQB4	371
NBL1	CER1	O95813	359
NBL1	CHRD	Q9H2X0	358

IntAct

13 interactions, top by confidence:

A	B	Type	Score
NBL1	NCS1	psi-mi:“MI:0915”(physical association)	0.560
NBL1	ZMIZ2	psi-mi:“MI:0915”(physical association)	0.560
NBL1	UBQLN1	psi-mi:“MI:0915”(physical association)	0.560
UBQLN1	NBL1	psi-mi:“MI:0915”(physical association)	0.560
ZMIZ2	NBL1	psi-mi:“MI:0915”(physical association)	0.560
NCS1	NBL1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (51): NCS1 (Two-hybrid), UBQLN1 (Two-hybrid), ZMIZ2 (Two-hybrid), MINOS1-NBL1 (Affinity Capture-RNA), MINOS1-NBL1 (Positive Genetic), MINOS1-NBL1 (Positive Genetic), MINOS1-NBL1 (Negative Genetic), MINOS1-NBL1 (Negative Genetic), MINOS1-NBL1 (Negative Genetic), MINOS1-NBL1 (Positive Genetic), MINOS1-NBL1 (Negative Genetic), MINOS1-NBL1 (Negative Genetic), MINOS1-NBL1 (Negative Genetic), MINOS1-NBL1 (Negative Genetic), MINOS1-NBL1 (Negative Genetic)

ESM2 similar proteins: A0MTF4, M3X9S6, O35757, O35793, O54693, O60565, O70326, O73753, O73754, O73755, O88273, P09858, P12034, P15656, P20827, P21214, P27090, P30371, P39905, P41271, P48540, P48807, P49767, P50291, P61811, P61812, P97401, P97553, P97953, Q06880, Q06AS9, Q07257, Q07731, Q20FD0, Q38L25, Q61477, Q6DF53, Q6NW40, Q6NZ13, Q7TQ33

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

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	0
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2097 predictions. Top by Δscore:

Variant	Effect	Δscore
1:19597105:GATAG:G	donor_gain	1.0000
1:19597106:A:G	donor_gain	1.0000
1:19597106:ATAGG:A	donor_loss	1.0000
1:19597108:AGGT:A	donor_loss	1.0000
1:19597109:GGTAA:G	donor_loss	1.0000
1:19597110:GTAAG:G	donor_loss	1.0000
1:19597111:T:A	donor_loss	1.0000
1:19622148:G:GG	donor_gain	1.0000
1:19626474:GGA:G	donor_gain	1.0000
1:19626475:GAG:G	donor_gain	1.0000
1:19626477:G:GG	donor_gain	1.0000
1:19655006:TTCTA:T	acceptor_loss	1.0000
1:19655007:TCTA:T	acceptor_loss	1.0000
1:19655008:CTA:C	acceptor_loss	1.0000
1:19655008:CTAG:C	acceptor_loss	1.0000
1:19655009:TA:T	acceptor_loss	1.0000
1:19655009:TAG:T	acceptor_loss	1.0000
1:19655010:A:AC	acceptor_loss	1.0000
1:19655010:AG:A	acceptor_gain	1.0000
1:19655011:G:GA	acceptor_loss	1.0000
1:19655011:G:GC	acceptor_loss	1.0000
1:19655011:GG:G	acceptor_gain	1.0000
1:19655197:ACAG:A	donor_loss	1.0000
1:19655199:AGGT:A	donor_loss	1.0000
1:19655201:GTG:G	donor_loss	1.0000
1:19655432:GATT:G	donor_gain	1.0000
1:19655436:G:GG	donor_gain	1.0000
1:19656862:GCA:G	acceptor_loss	1.0000
1:19656864:A:AC	acceptor_loss	1.0000
1:19656864:AGGT:A	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000022457 (1:19642359 G>A), RS1000916357 (1:19644502 G>T), RS1001080705 (1:19655262 C>G,T), RS1001138830 (1:19654441 G>A,T), RS1001521087 (1:19655223 G>A), RS1001636473 (1:19645317 G>A,T), RS1001970300 (1:19654924 A>G), RS1001979794 (1:19649932 A>C), RS1002035129 (1:19649699 T>C), RS1002259349 (1:19649657 C>T), RS1002274747 (1:19645345 CG>C), RS1002409469 (1:19644985 C>A), RS1002515374 (1:19641741 T>C), RS1002537020 (1:19656662 G>A,T), RS1002648724 (1:19650924 T>C)

Disease associations

OMIM: gene MIM:600613 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST002458_2	Serum thyroid-stimulating hormone levels	3.000000e-07
GCST006460_1	Bronchopulmonary dysplasia in preterm infants	7.000000e-07
GCST006585_2987	Blood protein levels	2.000000e-07
GCST010696_18	Cortical thickness (min-P)	1.000000e-10
GCST010697_49	Cortical surface area (min-P)	9.000000e-13
GCST010698_58	Subcortical volume (min-P)	9.000000e-10
GCST010699_28	Brain morphology (min-P)	3.000000e-09
GCST010700_3	Cortical thickness (MOSTest)	2.000000e-20
GCST010701_23	Cortical surface area (MOSTest)	2.000000e-44
GCST010702_68	Subcortical volume (MOSTest)	2.000000e-11
GCST010703_80	Brain morphology (MOSTest)	3.000000e-16
GCST90002388_284	Lymphocyte count	4.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0004587	lymphocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases expression, increases methylation	5
sodium arsenite	increases expression	2
Temozolomide	affects response to substance, increases expression	2
Vehicle Emissions	decreases reaction, increases expression, affects expression, increases abundance	2
Benzo(a)pyrene	increases methylation, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Particulate Matter	increases expression, affects expression, increases abundance, decreases reaction	2
methylmercuric chloride	increases expression	1
methyleugenol	increases expression	1
propylparaben	increases expression	1
lead acetate	increases expression	1
trichostatin A	decreases expression	1
methylparaben	increases expression	1
cobaltous chloride	decreases expression	1
cupric chloride	increases expression	1
beta-methylcholine	affects expression	1
octa-2,4,6-trienoic acid	increases expression	1
chromium hexavalent ion	increases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
acyline	decreases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	increases expression	1
14-deoxy-11,12-didehydroandrographolide	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases reaction, increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
LG 100815	increases expression	1
jinfukang	affects cotreatment, increases expression, decreases expression	1
apatinib	affects cotreatment, decreases expression	1
Rosiglitazone	increases 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_D8R1	Ubigene HCT 116 NBL1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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