NICOL1

Summary

NICOL1 (NELL2 interacting cell ontogeny regulator 1, HGNC:34437) is a protein-coding gene on chromosome 4p16.3, encoding NELL2-interacting cell ontogeny regulator 1 (Q5BLP8). mRNA-binding protein which interacts with a range of target mRNAs including SERPINE1, ACTA2, CCN2 and COL4A1 and may promote extracellular matrix production.

Predicted to enable mRNA 3’-UTR binding activity. Predicted to be involved in 3’-UTR-mediated mRNA stabilization and spermatogenesis. Predicted to be located in perinuclear region of cytoplasm. Predicted to be active in extracellular space.

Source: NCBI Gene 401115 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 5 total
• MANE Select transcript: NM_001168243

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:34437
Approved symbol	NICOL1
Name	NELL2 interacting cell ontogeny regulator 1
Location	4p16.3
Locus type	gene with protein product
Status	Approved
Aliases	NICOL
Ensembl gene	ENSG00000243449
Ensembl biotype	protein_coding
OMIM	614690
Entrez	401115

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000409248, ENST00000409860, ENST00000898696, ENST00000962324

RefSeq mRNA: 2 — MANE Select: NM_001168243 NM_001141936, NM_001168243

CCDS: CCDS47000

Canonical transcript exons

ENST00000409248 — 4 exons

Exon	Start	End
ENSE00001578089	2043861	2043964
ENSE00001581117	2041995	2042068
ENSE00002208341	2042736	2042824
ENSE00003689351	2042327	2042484

Expression profiles

Bgee: expression breadth ubiquitous, 239 present calls, max score 96.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 50.5771 / max 586.3071, expressed in 1817 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
46588	49.6076	1817
46590	0.6701	253
46589	0.2995	150

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	96.57	gold quality
spinal cord	UBERON:0002240	96.39	gold quality
inferior vagus X ganglion	UBERON:0005363	96.38	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.21	gold quality
endothelial cell	CL:0000115	95.74	gold quality
substantia nigra pars compacta	UBERON:0001965	95.68	gold quality
subthalamic nucleus	UBERON:0001906	95.45	gold quality
midbrain	UBERON:0001891	95.11	gold quality
substantia nigra	UBERON:0002038	95.11	gold quality
hypothalamus	UBERON:0001898	95.06	gold quality
medulla oblongata	UBERON:0001896	95.04	gold quality
dorsal plus ventral thalamus	UBERON:0001897	95.04	gold quality
superior vestibular nucleus	UBERON:0007227	94.75	gold quality
mucosa of transverse colon	UBERON:0004991	94.68	gold quality
lateral nuclear group of thalamus	UBERON:0002736	94.59	gold quality
lateral globus pallidus	UBERON:0002476	94.56	gold quality
ventral tegmental area	UBERON:0002691	94.41	gold quality
cortical plate	UBERON:0005343	94.36	gold quality
amygdala	UBERON:0001876	94.03	gold quality
ileal mucosa	UBERON:0000331	93.99	gold quality
adenohypophysis	UBERON:0002196	93.96	gold quality
pons	UBERON:0000988	93.94	gold quality
pituitary gland	UBERON:0000007	93.85	gold quality
putamen	UBERON:0001874	93.85	gold quality
Ammon’s horn	UBERON:0001954	93.63	gold quality
primary visual cortex	UBERON:0002436	93.47	gold quality
occipital lobe	UBERON:0002021	93.14	gold quality
temporal lobe	UBERON:0001871	93.06	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.91	gold quality
nucleus accumbens	UBERON:0001882	92.73	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 15.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	1047.88
E-MTAB-8381	yes	461.38
E-MTAB-8205	yes	335.65
E-GEOD-134144	yes	44.38
E-MTAB-7037	yes	44.02
E-GEOD-125970	yes	26.80
E-MTAB-8410	yes	26.03
E-MTAB-10042	yes	11.12
E-CURD-112	yes	10.71
E-MTAB-9388	yes	10.37
E-ANND-3	yes	9.85
E-GEOD-84465	yes	9.69
E-MTAB-9801	yes	9.17
E-MTAB-7316	yes	7.61
E-HCAD-10	yes	6.86

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 2)

• C4Orf48 probably encodes a novel neuropeptide, which, if hemizygously deleted, may be involved in the observed intellectual and fine motor disabilities and thus in the overall neurological aspects of Wolf-Hirschhorn syndrome. (PMID:21287218)
• The secreted micropeptide C4orf48 enhances renal fibrosis via an RNA-binding mechanism. (PMID:38625739)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	nicol1	ENSDARG00000089877
mus_musculus	Nicol1	ENSMUSG00000070858
rattus_norvegicus	Nicol1	ENSRNOG00000074184

Protein

Protein identifiers

NELL2-interacting cell ontogeny regulator 1 — Q5BLP8 (reviewed: Q5BLP8)

Alternative names: NELL2-interacting cofactor for lumicrine signaling

All UniProt accessions (1): Q5BLP8

UniProt curated annotations — full annotation on UniProt →

Function. mRNA-binding protein which interacts with a range of target mRNAs including SERPINE1, ACTA2, CCN2 and COL4A1 and may promote extracellular matrix production. Binds to the 3’-UTR of SERPINE1 mRNA and stabilizes the mRNA, possibly by competing for binding with SERBP1 and preventing SERBP1-mediated mRNA degradation. Also binds to the 3’-UTR of ACTA2. Testis-derived lumicrine factor that triggers epididymal differentiation and sperm maturation.

Subunit / interactions. Interacts with NELL2; triggers epididymal differentiation. Interacts with cell surface receptor TFRC; the interaction mediates uptake of NICOL1 into fibroblasts.

Subcellular location. Secreted. Cytoplasm. Perinuclear region.

Tissue specificity. Detected in the brain (at protein level). Also expressed at low levels in the kidney, primarily in tubular epithelial cells.

Miscellaneous. Up-regulated in the kidneys and serum of patients with diabetic nephropathy and enhances renal fibrosis so may have promise as a biomarker of renal fibrosis and as a therapeutic agent for chronic kidney disease.

Similarity. Belongs to the NICOL family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q5BLP8-1	1	yes
Q5BLP8-2	2
Q5BLP8-3	3

RefSeq proteins (2): NP_001135408, NP_001161715* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR028147	NICOL	Family

Pfam: PF15161

UniProt features (5 total): splice variant 2, signal peptide 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9OZC	ELECTRON MICROSCOPY	4
9OZ8	ELECTRON MICROSCOPY	4.1
9OZH	ELECTRON MICROSCOPY	4.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5BLP8-F1	77.58	0.28

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 105 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_3_UTR_MEDIATED_MRNA_STABILIZATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_MALE_GAMETE_GENERATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_REGULATION_OF_CATABOLIC_PROCESS, KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN, chr4p16, LIAO_METASTASIS, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOMF_SIGNALING_RECEPTOR_BINDING, GOBP_NEGATIVE_REGULATION_OF_CATABOLIC_PROCESS, NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_UP

GO Biological Process (2): spermatogenesis (GO:0007283), 3’-UTR-mediated mRNA stabilization (GO:0070935)

GO Molecular Function (3): mRNA 3’-UTR binding (GO:0003730), transferrin receptor binding (GO:1990459), RNA binding (GO:0003723)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), perinuclear region of cytoplasm (GO:0048471), extracellular region (GO:0005576), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
developmental process involved in reproduction	1
male gamete generation	1
mRNA stabilization	1
mRNA binding	1
signaling receptor binding	1
nucleic acid binding	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

264 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NICOL1	H0YIS7	H0YIS7	448
NICOL1	NPIPB15	A6NHN6	418
NICOL1	CIMIP2A	Q6J272	394
NICOL1	DRGX	A6NNA5	362
NICOL1	POLN	Q7Z5Q5	359
NICOL1	LRRC75A	Q8NAA5	359
NICOL1	MANEAL	Q5VSG8	351
NICOL1	ASPNAT	Q8N9F0	348
NICOL1	C1QTNF2	Q9BXJ5	335
NICOL1	KCNT2	Q6UVM3	333
NICOL1	ZNF721	Q8TF20	326
NICOL1	KLHL35	Q6PF15	324
NICOL1	STON1	Q9Y6Q2	321
NICOL1	KLHDC8B	Q8IXV7	318
NICOL1	SLC25A48	Q6ZT89	316

IntAct

4 interactions, top by confidence:

A	B	Type	Score
TGFB1	NMT2	psi-mi:“MI:0914”(association)	0.530
NELL1	MATN2	psi-mi:“MI:0914”(association)	0.350
NELL2	MATN2	psi-mi:“MI:0914”(association)	0.350

ESM2 similar proteins: A0A140LIA7, A0A1B0GTL2, A2VDX9, A3FFS8, A6NCS6, A8MVW0, K9M1U5, O43541, P01588, P03971, P03972, P07321, P07865, P0C7N4, P0DPE3, P13725, P27106, P29676, P33707, P33708, P33709, P48617, P49000, P49157, P53346, P79295, Q02011, Q0Z956, Q16619, Q1HCM0, Q28513, Q29RM6, Q5BLP8, Q5S1V9, Q60753, Q63086, Q65Z15, Q6H8S9, Q6H8T0, Q6H8T1

Diamond homologs: A0JNN8, B5X8I6, E1BRC3, Q3UR78, Q5BLP8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	3
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

347 predictions. Top by Δscore:

Variant	Effect	Δscore
4:2042480:GCAGA:G	donor_gain	1.0000
4:2042483:GA:G	donor_gain	1.0000
4:2042485:G:GG	donor_gain	1.0000
4:2042821:GCGG:G	donor_gain	1.0000
4:2042823:GG:G	donor_gain	1.0000
4:2042824:GG:G	donor_gain	1.0000
4:2042825:G:GG	donor_gain	1.0000
4:2042464:G:GT	donor_gain	0.9900
4:2042483:GAGTA:G	donor_loss	0.9900
4:2042484:AG:A	donor_loss	0.9900
4:2042485:G:GA	donor_loss	0.9900
4:2042486:T:G	donor_loss	0.9900
4:2042731:CGCA:C	acceptor_loss	0.9900
4:2042732:GCA:G	acceptor_loss	0.9900
4:2042733:CAGG:C	acceptor_loss	0.9900
4:2042734:A:AG	acceptor_gain	0.9900
4:2042735:G:GG	acceptor_gain	0.9900
4:2042735:GGCC:G	acceptor_gain	0.9900
4:2042825:G:T	donor_loss	0.9900
4:2042826:T:A	donor_loss	0.9900
4:2043859:A:AG	acceptor_gain	0.9900
4:2043859:AGAC:A	acceptor_gain	0.9900
4:2043860:G:GG	acceptor_gain	0.9900
4:2043860:GAC:G	acceptor_gain	0.9900
4:2043860:GACG:G	acceptor_gain	0.9900
4:2042158:G:GT	donor_gain	0.9800
4:2042173:G:GT	donor_gain	0.9800
4:2042734:AG:A	acceptor_gain	0.9800
4:2042735:GG:G	acceptor_gain	0.9800
4:2042735:GGC:G	acceptor_gain	0.9800

AlphaMissense

786 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:2042768:T:C	F56L	0.999
4:2042770:C:A	F56L	0.999
4:2042770:C:G	F56L	0.999
4:2042769:T:G	F56C	0.997
4:2042773:G:A	M57I	0.996
4:2042773:G:C	M57I	0.996
4:2042773:G:T	M57I	0.996
4:2042762:T:C	F54L	0.995
4:2042764:C:A	F54L	0.995
4:2042764:C:G	F54L	0.995
4:2042769:T:C	F56S	0.995
4:2042763:T:G	F54C	0.994
4:2042754:G:A	C51Y	0.988
4:2042754:G:T	C51F	0.987
4:2042793:T:C	L64P	0.987
4:2042762:T:A	F54I	0.986
4:2042805:C:A	A68D	0.982
4:2042753:T:C	C51R	0.981
4:2042763:T:C	F54S	0.981
4:2042772:T:C	M57T	0.981
4:2042793:T:A	L64Q	0.981
4:2042751:A:T	D50V	0.980
4:2042753:T:A	C51S	0.980
4:2042754:G:C	C51S	0.980
4:2042755:C:G	C51W	0.980
4:2042772:T:A	M57K	0.979
4:2042768:T:A	F56I	0.978
4:2042778:G:C	R59P	0.975
4:2042745:G:A	C48Y	0.974
4:2042784:T:C	L61P	0.973

dbSNP variants (sampled 300 via entrez): RS1000076026 (4:2041773 C>A), RS1000420320 (4:2036193 G>A), RS10006421 (4:2039561 G>A), RS1000834098 (4:2035620 A>G), RS1000978811 (4:2041624 C>T), RS1000998479 (4:2041332 T>A), RS1001285993 (4:2035551 G>A,T), RS1001469797 (4:2040384 TTGTCCGTGGGCGCGAC>T), RS1001581560 (4:2036051 C>T), RS1001590828 (4:2044066 C>A,T), RS10016224 (4:2034579 C>A,G), RS1001655626 (4:2039161 C>A,T), RS1001665577 (4:2038935 C>T), RS1001861405 (4:2036839 G>A), RS1001870250 (4:2042576 C>A,T)

Disease associations

OMIM: gene MIM:614690 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation, affects expression	4
aristolochic acid I	increases expression	1
bisphenol A	affects cotreatment, decreases expression	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
chloropicrin	decreases expression	1
bisphenol B	decreases expression	1
Temozolomide	increases expression	1
Zoledronic Acid	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Estradiol	decreases expression	1
Glucose	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Quercetin	increases expression	1
Tobacco Smoke Pollution	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Cyclosporine	decreases expression	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

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