NRIP1

Summary

NRIP1 (nuclear receptor interacting protein 1, HGNC:8001) is a protein-coding gene on chromosome 21q11.2-q21.1, encoding Nuclear receptor-interacting protein 1 (P48552). Modulates transcriptional activation by steroid receptors such as NR3C1, NR3C2 and ESR1.

Nuclear receptor interacting protein 1 (NRIP1) is a nuclear protein that specifically interacts with the hormone-dependent activation domain AF2 of nuclear receptors. Also known as RIP140, this protein modulates transcriptional activity of the estrogen receptor.

Source: NCBI Gene 8204 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital anomalies of kidney and urinary tract 3 (Limited, GenCC)
• GWAS associations: 41
• Clinical variants (ClinVar): 359 total — 1 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 12
• MANE Select transcript: NM_003489

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8001
Approved symbol	NRIP1
Name	nuclear receptor interacting protein 1
Location	21q11.2-q21.1
Locus type	gene with protein product
Status	Approved
Aliases	RIP140
Ensembl gene	ENSG00000180530
Ensembl biotype	protein_coding
OMIM	602490
Entrez	8204

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000318948, ENST00000400199, ENST00000400202, ENST00000411932, ENST00000637630, ENST00000637963, ENST00000638122

RefSeq mRNA: 1 — MANE Select: NM_003489 NM_003489

CCDS: CCDS13568

Canonical transcript exons

ENST00000318948 — 4 exons

Exon	Start	End
ENSE00001541960	15043495	15043574
ENSE00001541969	15014344	15014466
ENSE00001541970	15064745	15065000
ENSE00003773881	14961235	14968526

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 98.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.3148 / max 2213.8395, expressed in 1787 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
189813	34.1061	1778
189816	2.5596	875
189814	1.6983	1029
189812	0.6933	360
189815	0.1353	58
189807	0.0681	12
189808	0.0541	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	98.94	gold quality
caput epididymis	UBERON:0004358	98.87	gold quality
jejunal mucosa	UBERON:0000399	98.54	gold quality
jejunum	UBERON:0002115	97.78	gold quality
pigmented layer of retina	UBERON:0001782	97.55	gold quality
cauda epididymis	UBERON:0004360	97.41	gold quality
mammary duct	UBERON:0001765	97.22	gold quality
trabecular bone tissue	UBERON:0002483	96.94	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.89	gold quality
epithelium of mammary gland	UBERON:0003244	96.60	gold quality
biceps brachii	UBERON:0001507	96.53	gold quality
superficial temporal artery	UBERON:0001614	96.27	gold quality
penis	UBERON:0000989	96.12	gold quality
mammalian vulva	UBERON:0000997	95.91	gold quality
mucosa of paranasal sinus	UBERON:0005030	95.78	gold quality
adrenal tissue	UBERON:0018303	95.42	gold quality
lower lobe of lung	UBERON:0008949	95.26	gold quality
tibialis anterior	UBERON:0001385	95.21	gold quality
urethra	UBERON:0000057	95.20	gold quality
deltoid	UBERON:0001476	95.14	gold quality
renal medulla	UBERON:0000362	95.07	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.95	gold quality
vastus lateralis	UBERON:0001379	94.94	gold quality
quadriceps femoris	UBERON:0001377	94.90	gold quality
tongue squamous epithelium	UBERON:0006919	94.87	gold quality
colonic mucosa	UBERON:0000317	94.64	gold quality
superior surface of tongue	UBERON:0007371	94.60	gold quality
pericardium	UBERON:0002407	94.51	gold quality
body of tongue	UBERON:0011876	94.47	gold quality
cerebellar vermis	UBERON:0004720	94.43	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	659.72
E-HCAD-6	yes	35.76
E-CURD-112	yes	5.52
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
PPARA	Repression
PPARD	Repression
SLC7A1	Activation

Upstream regulators (CollecTRI, top): AHR, AR, E2F1, ESR1, ESR2, ESRRA, ESRRB, ESRRG, NCOA1, NCOA3, NCOR1, NCOR2, NR0B1, NR5A1, NRF1, POU1F1, RARA, SP1, TFDP1, ZBTB7A

miRNA regulators (miRDB)

255 targeting NRIP1, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-8485	100.00	77.57	4731
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548P	99.98	72.25	3784
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955

Literature-anchored findings (GeneRIF, showing 40)

• RIP140 has a role in binding to nuclear receptors, as well as additional functions mediated by the formation and intranuclear relocalization of a repressive protein complex (PMID:12773562)
• there are four autonomous repression domains in the corepressor receptor interacting protein 140 (PMID:14736873)
• RIP140 has a regulatory role in mediating anti-estrogenic effects of RA in estrogen-dependent breast cancer cells (PMID:15632153)
• RIP140 differentially regulates ERR activity depending on the target sequence on the promoters. (PMID:16439465)
• Receptor-interacting protein 140 is a repressor of the androgen receptor activity. (PMID:16527872)
• RIP140 discriminates among different classes of retinoic acid target genes. RIP140 limits RA signaling & tumor-cell differentiation. RIP140 silencing sensitizes embryonal carcinoma cells to low doses of RA. (PMID:17880687)
• the transcription repressor function of RIP140 is modulated by SUMOylation (PMID:18211901)
• Receptor-interacting protein 140 (RIP140) is a corepressor for nuclear receptors with an important role in the inhibition of energy expenditure. (PMID:19367438)
• The results presented here suggested the cooperative transcriptional regulation of estrogen signaling by FHL1 and RIP140. (PMID:19401155)
• RIP140 may have a role in retinoic acid mediation of long-paced oscillations in retinoid receptor activity (PMID:19862326)
• The RIP140 gene does not play a pivotal role in the process of ovulation, insulin resistance, or fat accumulation in women with PCOS. (PMID:19887821)
• RIP140 transgenic mice, expressing increased levels of RIP140 mRNA/protein in the heart, exhibit rapid and progressive postnatal cardiomyopathy leading to premature death predominantly owing to compromised energy production. (PMID:20083575)
• Down-regulation of PROS1 gene expression by 17beta-estradiol via estrogen receptor alpha (ERalpha)-Sp1 interaction recruiting receptor-interacting protein 140 and the corepressor-HDAC3 complex. (PMID:20200160)
• This study shows that RIP140 is a regulator of the E2F pathway, which discriminates luminal- and basal-like tumors, emphasizing the importance of these regulations for a clinical cancer phenotype. (PMID:20410059)
• We demonstrate that NRIP is a novel binding protein for human papillomavirus 16 (HPV-16) E2 protein and directly interacts with the TAD of HPV-16 E2. (PMID:21543494)
• Decreased RIP140 protein content not required for exercise and AMPK-dependent increases in skeletal muscle mitochondrial content. (PMID:21700896)
• Highlight the importance of cross-regulation between AhR and ERalpha and a novel mechanism by which AhR controls, through modulating the recruitment of RIP140 to ERalpha-binding sites, the kinetics and magnitude of ERalpha-mediated gene stimulation. (PMID:22071320)
• The fusion of NRIP1 with UHRF1 involved in the unbalanced translocation between chromosomes 19 and 21 in a patient with an ALL-positive for a t(9;22) translocation. (PMID:22285022)
• this work identifies the RIP140 gene as a new transcriptional target of E2F1 which may explain some of the effect of E2F1 in both cancer and metabolic diseases. (PMID:22629304)
• Increased RIP140 level may be closely associated with inflammation and disorder of lipid and glucose metabolism in diabetic patients. (PMID:22956256)
• genetic association studies in population of women in Spain: Data suggest an association between an SNP in NRIP1 (rs2229741) and age at menopause; thus, duration of fertility in women may have genetic determinants involved in estrogen metabolism. (PMID:23173577)
• RIP140, a Janus metabolic switch involved in defense functions. (PMID:23241901)
• Estrogen receptors alpha and beta and their key coregulators, SRC3 and RIP140, generate overlapping as well as unique chromatin-binding and transcription-regulating modules. (PMID:23774759)
• these data demonstrate the inhibitory effects of ERbeta on estrogen signaling in ovarian cancer cells and the key role that RIP140 plays in this phenomenon. (PMID:23885094)
• RIP140 stimulated APC transcription and inhibited beta-catenin activation and target gene expression. (PMID:24667635)
• NRIP1 contributes to the mitochondrial dysfunction observed in DS. Furthermore, they suggest that the NRIP1-PGC-1alpha axe might represent a potential therapeutic target for restoring altered mitochondrial function in DS. (PMID:24698981)
• Data suggest that vitamin D receptor target genes (NRIP1; DUSP10, dual specificity phosphatase 10; THBD, thrombomodulin; TRAK1, trafficking protein kinesin binding 1) can be used as markers for individual’s response to vitamin D3 supplements. (PMID:24975273)
• data suggest that RIP140 plays an important role in ERalpha-mediated transcriptional regulation in breast cancer and response to tamoxifen treatment (PMID:25145671)
• In breast cancer cells, GSTP1 inhibits the expression of RIP140, a negative regulator of estrogen receptor alpha transcription, at both mRNA and protein levels. (PMID:25218501)
• Downregulation of RIP140 promoted the tumorigenicity of HCC cells in vitro. (PMID:25391428)
• RIP140 negatively regulated the macrophage expression of ATP-binding cassette transporters A1 and G1. (PMID:25616132)
• The associations of rs2616984 in CSMD1 gene, putative associations of rs3131296 in NOTCH4 gene, and associations of rs2229741 of NRIP1 gene with Alzheimer’s disease have been found in a Russian population. (PMID:25845235)
• RIP140 gene has been shown to be involved in the regulation of energy expenditure, in mammary gland development and intestinal homeostasis as well as in behavior and cognition (PMID:26116758)
• NOP14 suppresses breast cancer progression by inhibiting NRIP1/Wnt/beta-catenin pathway. (PMID:26213846)
• Data indicate that nuclear receptor interacting protein 1 (NRIP1) is elevated in tumors compared to cancer adjacent normal tissue. (PMID:26492163)
• results indicated that there was a significant association between migraine and gene-gene interaction among the CYP19A1, FSHR, ESR1 and NRIP1. (PMID:27019440)
• Data suggests that NRIP1 is overexpressed both in skin and PBMCs of psoriasis patients and may be involved in the abnormal proliferation and apoptosis of keratinocytes. (PMID:27708240)
• Study found low expression level of RIP140 in tumor-associated macrophages (TAM) of hepatocellular carcinoma (HCC) tissues and demonstrated that RIP140 expression in plays a role in the growth of hepatoma cells. (PMID:28393222)
• Taken together, these results provide new insights into the mechanism of action of LCoR and RIP140 and highlight their strong interplay for the control of gene expression and cell proliferation in breast cancer cells. (PMID:28414308)
• In skeletal muscle, imposed rest increased NRIP1 expression by 80%, and strength training increased expression by 25% compared to baseline. Following rest, NRIP1 expression became sensitive to insulin stimulation. After re-training, NRIP1 expression decreased. Interactome analysis showed significant proximity of NRIP1 interacting partners to the obesity network/module. (PMID:28656645)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	nrip1b	ENSDARG00000068894
danio_rerio	nrip1a	ENSDARG00000068965
mus_musculus	Nrip1	ENSMUSG00000048490
rattus_norvegicus	Nrip1	ENSRNOG00000001585

Protein

Protein identifiers

Nuclear receptor-interacting protein 1 — P48552 (reviewed: P48552)

Alternative names: Nuclear factor RIP140, Receptor-interacting protein 140

All UniProt accessions (3): A0A1B0GUG9, C9J130, P48552

UniProt curated annotations — full annotation on UniProt →

Function. Modulates transcriptional activation by steroid receptors such as NR3C1, NR3C2 and ESR1. Also modulates transcriptional repression by nuclear hormone receptors. Positive regulator of the circadian clock gene expression: stimulates transcription of BMAL1, CLOCK and CRY1 by acting as a coactivator for RORA and RORC. Involved in the regulation of ovarian function. Plays a role in renal development.

Subunit / interactions. Interacts with RARA and RXRB homodimers and RARA/RXRB heterodimers in the presence of ligand. Interacts with HDAC1 and HDAC3 via its N-terminal domain. Interacts with NR2C1 (sumoylated form and via the ligand-binding domain); the interaction results in promoting the repressor activity of NR2C1. Interacts with CTBP1, CTBP2, ESR1, HDAC1, HDAC2, HDAC5, HDAC6, NR2C2, NR3C1, NR3C2, YWHAH, JUN and FOS. Found in a complex with both NR3C1 and YWHAH. Interacts with ZNF366. Interacts with RORA.

Subcellular location. Nucleus.

Post-translational modifications. Acetylation regulates its nuclear translocation and corepressive activity. Acetylation abolishes interaction with CTBP1. Phosphorylation enhances interaction with YWHAH.

Disease relevance. Congenital anomalies of kidney and urinary tract 3 (CAKUT3) [MIM:618270] A disorder encompassing a broad spectrum of renal and urinary tract malformations that include renal agenesis, kidney hypodysplasia, multicystic kidney dysplasia, duplex collecting system, posterior urethral valves and ureter abnormalities. Congenital anomalies of kidney and urinary tract are the commonest cause of chronic kidney disease in children. CAKUT3 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Contains 9 Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs, which have different affinities for nuclear receptors. The C-terminal LTKTNPILYYMLQK motif is required for ligand-dependent interaction with RAAR and RXRB homodimers and heterodimers, for the corepressor activity, and for the formation of an HDAC3 complex with RARA/RXRB. Contains at least four autonomous repression domains (RD1-4). RD1 functions via a histone deacetylase (HDAC)-independent mechanism, whereas RD2, RD3 and RD4 can function by HDAC-dependent or independent mechanisms, depending on cell type. RD2 is dependent on CTBP binding.

Induction. Expressed in a circadian manner in the liver (at protein level).

RefSeq proteins (1): NP_003480* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026649	NRIP1	Family
IPR031405	NRIP1_RD1	Domain
IPR031406	NRIP1_RD2	Domain
IPR031407	NRIP1_RD3	Family
IPR031408	NRIP1_RD4	Domain

Pfam: PF15687, PF15688, PF15689, PF15690

UniProt features (94 total): modified residue 21, region of interest 14, short sequence motif 14, cross-link 14, mutagenesis site 10, sequence variant 8, compositionally biased region 6, sequence conflict 4, helix 2, chain 1

Structure

Experimental structures (PDB)

17 structures.

PDB	Method	Resolution (Å)
9KNG	X-RAY DIFFRACTION	1.5
9KND	X-RAY DIFFRACTION	1.52
9KNF	X-RAY DIFFRACTION	1.62
5NTW	X-RAY DIFFRACTION	1.64
6G07	X-RAY DIFFRACTION	1.66
6FZU	X-RAY DIFFRACTION	1.8
9KNE	X-RAY DIFFRACTION	1.8
5NU1	X-RAY DIFFRACTION	1.85
4S15	X-RAY DIFFRACTION	1.9
5NTN	X-RAY DIFFRACTION	1.9
6G05	X-RAY DIFFRACTION	1.9
9KNC	X-RAY DIFFRACTION	1.9
2GPO	X-RAY DIFFRACTION	1.95
5NTI	X-RAY DIFFRACTION	2.4
2GPP	X-RAY DIFFRACTION	2.6
9CWN	X-RAY DIFFRACTION	2.7
4S14	X-RAY DIFFRACTION	3.54

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48552-F1	46.10	0.01

Functional residue map

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

Post-translational modifications (35): 104, 111, 158, 207, 218, 286, 310, 356, 378, 446, 481, 487, 518, 528, 542, 564, 606, 671, 807, 931 …

Mutagenesis-validated functional residues (10):

Position	Phenotype
440–443	abolishes interaction with ctbp1.
440–442	abolishes interaction with ctbp1 and attenuates nuclear hormone receptor-dependent transcription repression.
442–443	reduces, but does not completely abolish, interaction with ctbp. reduces transcriptional repression.
442–443	disrupts interaction with ctbp1, and ctbp2 to a lesser extent. disrupts transcriptional repression; when associated with
446	disrupts interaction with ctbp1. decreases lysine acetylation. disrupts nuclear hormone receptor-dependent transcription
446	does not disrupt nuclear hormone receptor-dependent transcription repression.
567–568	disrupts transcriptional repression.
567–568	disrupts interaction with ctbp1 and ctbp2. disrupts transcriptional repression; when associated with 442-as-443.
599–603	does not further disrupt transcriptional repression; when associated with 442-aa-443 and 567-aa-568.
948–949	abolishes ctbp binding but retains transcriptional repressor activity.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-3899300	SUMOylation of transcription cofactors
R-HSA-9018519	Estrogen-dependent gene expression
R-HSA-9029558	NR1H2 & NR1H3 regulate gene expression linked to lipogenesis
R-HSA-9632974	NR1H2 & NR1H3 regulate gene expression linked to gluconeogenesis
R-HSA-9707616	Heme signaling
R-HSA-9931509	Expression of BMAL (ARNTL), CLOCK, and NPAS2
R-HSA-9933387	RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression

MSigDB gene sets: 454 (showing top): GOBP_CIRCADIAN_RHYTHM, WANG_CLIM2_TARGETS_UP, GOBP_RESPONSE_TO_ESTRADIOL, GOBP_CELLULAR_RESPONSE_TO_LIPID, BECKER_TAMOXIFEN_RESISTANCE_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, HASLINGER_B_CLL_WITH_MUTATED_VH_GENES, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, MCBRYAN_TERMINAL_END_BUD_DN, GOBP_CIRCADIAN_REGULATION_OF_GENE_EXPRESSION, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, STOSSI_RESPONSE_TO_ESTRADIOL, ATGTTAA_MIR302C, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_ERYTHROCYTE_UP, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1

GO Biological Process (10): negative regulation of transcription by RNA polymerase II (GO:0000122), ovarian follicle rupture (GO:0001543), circadian rhythm (GO:0007623), lipid storage (GO:0019915), circadian regulation of gene expression (GO:0032922), positive regulation of transcription by RNA polymerase II (GO:0045944), cellular response to estradiol stimulus (GO:0071392), regulation of transcription by RNA polymerase II (GO:0006357), ovulation (GO:0030728), rhythmic process (GO:0048511)

GO Molecular Function (12): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), transcription coactivator activity (GO:0003713), transcription corepressor activity (GO:0003714), signaling receptor binding (GO:0005102), nuclear receptor binding (GO:0016922), nuclear estrogen receptor binding (GO:0030331), nuclear glucocorticoid receptor binding (GO:0035259), histone deacetylase binding (GO:0042826), nuclear retinoid X receptor binding (GO:0046965), transcription coregulator activity (GO:0003712), protein binding (GO:0005515), nuclear retinoic acid receptor binding (GO:0042974)

GO Cellular Component (8): histone deacetylase complex (GO:0000118), chromatin (GO:0000785), fibrillar center (GO:0001650), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytosol (GO:0005829), nuclear speck (GO:0016607)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
NR1H2 and NR1H3-mediated signaling	2
Circadian clock	2
SUMO E3 ligases SUMOylate target proteins	1
ESR-mediated signaling	1
Cellular responses to stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
transcription by RNA polymerase II	3
nuclear receptor binding	3
regulation of transcription by RNA polymerase II	2
negative regulation of DNA-templated transcription	2
positive regulation of DNA-templated transcription	2
transcription coregulator activity	2
nuclear lumen	2
ovulation from ovarian follicle	1
ovulation cycle process	1
rhythmic process	1
nutrient storage	1
circadian rhythm	1
regulation of gene expression	1
response to estradiol	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
regulation of DNA-templated transcription	1
female gamete generation	1
multicellular organismal reproductive process	1
biological_process	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
cis-regulatory region sequence-specific DNA binding	1
protein binding	1
RNA polymerase II-specific DNA-binding transcription factor binding	1
enzyme binding	1
nuclear retinoic acid receptor binding	1
transcription regulator activity	1
binding	1
nucleoplasm	1
nuclear protein-containing complex	1
catalytic complex	1
chromosome	1
nucleolus	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
cytoplasm	1
nuclear ribonucleoprotein granule	1

Protein interactions and networks

STRING

1284 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NRIP1	ESR1	P03372	988
NRIP1	NR2C1	P13056	906
NRIP1	PPARGC1A	Q9UBK2	905
NRIP1	CTBP1	Q13363	862
NRIP1	LCOR	Q96JN0	832
NRIP1	NCOR1	O75376	813
NRIP1	SLC7A1	P30825	792
NRIP1	CTBP2	P56545	752
NRIP1	ESRRA	P11474	745
NRIP1	HDAC1	Q13547	744
NRIP1	NCOA1	Q15788	742
NRIP1	NCOA3	Q9Y6Q9	736
NRIP1	UCP1	P25874	728
NRIP1	NCOA2	Q15596	727
NRIP1	DCAF6	Q58WW2	724

IntAct

156 interactions, top by confidence:

A	B	Type	Score
ESR1	PGR	psi-mi:“MI:0915”(physical association)	0.770
CEP70	NRIP1	psi-mi:“MI:0915”(physical association)	0.710
NRIP1	CEP70	psi-mi:“MI:0915”(physical association)	0.710
CTBP1	NRIP1	psi-mi:“MI:0915”(physical association)	0.680
NRIP1	CTBP1	psi-mi:“MI:0407”(direct interaction)	0.680
NRIP1	RARA	psi-mi:“MI:0915”(physical association)	0.670
RARA	NRIP1	psi-mi:“MI:0915”(physical association)	0.670
ESR1	TRIM24	psi-mi:“MI:0914”(association)	0.640
FHL1	NRIP1	psi-mi:“MI:0915”(physical association)	0.630
NRIP1	FHL1	psi-mi:“MI:0407”(direct interaction)	0.630
NRIP1	FHL1	psi-mi:“MI:0915”(physical association)	0.630
NRIP1	LDOC1	psi-mi:“MI:0915”(physical association)	0.620
NRIP1	PRMT1	psi-mi:“MI:0213”(methylation reaction)	0.600
PRMT1	NRIP1	psi-mi:“MI:0915”(physical association)	0.600
NRIP1	PRMT1	psi-mi:“MI:0915”(physical association)	0.600
NRIP1	ARPC3	psi-mi:“MI:0915”(physical association)	0.560
NRIP1	RARA	psi-mi:“MI:0915”(physical association)	0.560
RARA	NRIP1	psi-mi:“MI:0915”(physical association)	0.560
ARPC3	NRIP1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (241): NRIP1 (Affinity Capture-Western), NRIP1 (Two-hybrid), ARPC3 (Two-hybrid), NRIP1 (Protein-peptide), BRCA1 (Two-hybrid), NRIP1 (Protein-peptide), NRIP1 (Affinity Capture-MS), LDOC1 (Two-hybrid), TEX11 (Two-hybrid), CEP70 (Two-hybrid), NRIP1 (Two-hybrid), NRIP1 (Two-hybrid), CCDC85B (Two-hybrid), NRIP1 (Reconstituted Complex), NRIP1 (Reconstituted Complex)

ESM2 similar proteins: A0A1L8GSA2, A0A1L8H0H2, A0JP82, A0MS83, A2AWL7, A2RRX6, A2X0Q0, A6NCI8, A9ZPC9, F8VPJ6, K9JHZ4, O13186, O46567, O60284, O75362, P15822, P35547, P37275, P48552, P52551, P79269, Q03172, Q14207, Q28DZ0, Q2KHR2, Q3V0A6, Q3Y4E1, Q4JK59, Q4V7J0, Q5DTW7, Q5R782, Q5W1J6, Q5ZJK5, Q61624, Q62806, Q6N021, Q6YXZ4, Q7SZL5, Q80TY4, Q8BMA5

Diamond homologs: P48552, Q8CBD1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
RXRB	up-regulates	NRIP1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 123 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SUMOylation of intracellular receptors	9	34.0×	8e-10
Nuclear Receptor transcription pathway	11	24.8×	2e-10

GO biological processes:

GO term	Partners	Fold	FDR
retinoic acid receptor signaling pathway	5	27.7×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	244
Likely benign	70
Benign	26

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
548653	NM_003489.4(NRIP1):c.279del (p.Asp92_Trp93insTer)	Pathogenic
4533294	NM_003489.4(NRIP1):c.2791A>T (p.Lys931Ter)	Likely pathogenic
4812934	NM_003489.4(NRIP1):c.3203T>C (p.Leu1068Pro)	Likely pathogenic

SpliceAI

1414 predictions. Top by Δscore:

Variant	Effect	Δscore
21:14968527:C:CC	acceptor_gain	0.9900
21:15014468:T:C	acceptor_gain	0.9900
21:15064738:CACT:C	donor_loss	0.9900
21:15064739:ACTC:A	donor_loss	0.9900
21:15064740:CTCA:C	donor_loss	0.9900
21:15064741:TCAC:T	donor_loss	0.9900
21:15064742:C:CG	donor_loss	0.9900
21:15064743:A:AC	donor_gain	0.9900
21:15064743:A:AT	donor_loss	0.9900
21:15064743:AC:A	donor_gain	0.9900
21:15064743:ACC:A	donor_gain	0.9900
21:15064744:C:CC	donor_gain	0.9900
21:15064744:CC:C	donor_gain	0.9900
21:15064744:CCC:C	donor_gain	0.9900
21:14968525:TTCTA:T	acceptor_loss	0.9800
21:14968526:TC:T	acceptor_loss	0.9800
21:14968527:CTAA:C	acceptor_loss	0.9800
21:14968528:T:G	acceptor_loss	0.9800
21:15014343:CCGT:C	donor_gain	0.9800
21:15014468:T:TC	acceptor_gain	0.9800
21:15064679:C:CA	donor_gain	0.9800
21:14968525:TT:T	acceptor_gain	0.9700
21:15005400:T:TA	donor_gain	0.9700
21:14968523:TGTT:T	acceptor_gain	0.9600
21:15014467:C:CC	acceptor_gain	0.9600
21:14968522:GTGTT:G	acceptor_gain	0.9500
21:15013627:T:TG	acceptor_gain	0.9500
21:15064736:GTCAC:G	donor_loss	0.9500
21:15064737:TCACT:T	donor_loss	0.9500
21:14968524:GTT:G	acceptor_gain	0.9400

AlphaMissense

7693 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:14965377:A:G	L939P	1.000
21:14967396:A:G	L266S	1.000
21:14967465:A:T	V243D	1.000
21:14967474:A:G	L240S	1.000
21:14967783:A:G	L137P	1.000
21:14964978:A:G	L1072P	0.999
21:14964990:A:G	L1068P	0.999
21:14964993:A:C	I1067R	0.999
21:14964993:A:T	I1067K	0.999
21:14964998:G:C	N1065K	0.999
21:14964998:G:T	N1065K	0.999
21:14965374:A:G	L940P	0.999
21:14965383:T:A	K937I	0.999
21:14966301:A:G	L631S	0.999
21:14966304:A:G	L630P	0.999
21:14967384:A:G	L270P	0.999
21:14967387:A:G	L269P	0.999
21:14967762:A:G	L144P	0.999
21:14967773:G:C	F140L	0.999
21:14967773:G:T	F140L	0.999
21:14967774:A:G	F140S	0.999
21:14967775:A:G	F140L	0.999
21:14964993:A:G	I1067T	0.998
21:14964996:G:T	P1066Q	0.998
21:14965371:A:G	L941P	0.998
21:14965374:A:T	L940H	0.998
21:14965382:T:A	K937N	0.998
21:14965382:T:G	K937N	0.998
21:14965386:A:G	L936P	0.998
21:14965616:C:A	R859S	0.998

dbSNP variants (sampled 300 via entrez): RS1000009610 (21:15038384 G>A), RS1000023839 (21:14977430 A>G,T), RS1000074327 (21:15038703 T>A,G), RS1000078387 (21:15020913 G>C,T), RS1000089297 (21:14983019 C>A,T), RS1000092252 (21:15022320 T>C), RS1000119941 (21:14977154 C>T), RS1000160922 (21:15067728 G>A,T), RS1000188084 (21:15022031 C>T), RS1000199469 (21:15004636 T>C), RS1000212946 (21:15067445 G>A), RS1000256742 (21:15050864 A>G), RS1000259850 (21:14985935 A>G,T), RS1000284896 (21:15003130 G>A), RS1000338674 (21:14988537 T>C)

Disease associations

OMIM: gene MIM:602490 | disease phenotypes: MIM:618270, MIM:610805

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital anomalies of kidney and urinary tract 3	Limited	Autosomal dominant

Mondo (3): congenital anomalies of kidney and urinary tract 3 (MONDO:0032646), long QT syndrome (MONDO:0002442), congenital anomaly of kidney and urinary tract (MONDO:0019719)

Orphanet (1): Renal or urinary tract malformation (Orphanet:93545)

HPO phenotypes

12 total (12 of 12 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000006	Autosomal dominant inheritance
HP:0000076	Vesicoureteral reflux
HP:0000086	Ectopic kidney
HP:0000089	Renal hypoplasia
HP:0000126	Hydronephrosis
HP:0003577	Congenital onset
HP:0003584	Late onset
HP:0003621	Juvenile onset
HP:0003829	Typified by incomplete penetrance
HP:0011463	Childhood onset
HP:0030674	Antenatal onset

GWAS associations

41 associations (top):

Study	Trait	p-value
GCST000477_34	Cognitive performance	6.000000e-07
GCST001937_44	Breast cancer	7.000000e-16
GCST003121_14	Alcohol dependence	6.000000e-06
GCST004616_172	Platelet distribution width	8.000000e-12
GCST004988_189	Breast cancer	2.000000e-20
GCST005146_55	Birth weight	2.000000e-08
GCST006291_42	Spherical equivalent or myopia (age of diagnosis)	5.000000e-12
GCST006291_80	Spherical equivalent or myopia (age of diagnosis)	9.000000e-10
GCST006427_42	Depression in smokers	9.000000e-06
GCST007096_185	Pulse pressure	7.000000e-07
GCST007099_240	Systolic blood pressure	6.000000e-09
GCST007344_46	Estimated glomerular filtration rate	4.000000e-09
GCST007876_131	Estimated glomerular filtration rate	1.000000e-09
GCST007928_22	Medication use (diuretics)	4.000000e-09
GCST007930_180	Medication use (agents acting on the renin-angiotensin system)	1.000000e-08
GCST008058_52	Estimated glomerular filtration rate	1.000000e-29
GCST008059_143	Estimated glomerular filtration rate	2.000000e-27
GCST008062_85	Blood urea nitrogen levels	8.000000e-12
GCST008064_25	Chronic kidney disease	1.000000e-08
GCST008362_128	Birth weight	7.000000e-11
GCST008485_6	Crohn’s disease	2.000000e-07
GCST008745_30	Estimated glomerular filtration rate in non-diabetics	3.000000e-11
GCST008747_160	Estimated glomerular filtration rate	7.000000e-17
GCST008747_33	Estimated glomerular filtration rate	1.000000e-13
GCST008832_18	Gastroesophageal reflux disease	2.000000e-08
GCST009066_31	Mosaic loss of chromosome Y (Y chromosome dosage)	1.000000e-08
GCST010002_72	Refractive error	1.000000e-29
GCST010242_76	HDL cholesterol levels	5.000000e-09
GCST90002381_256	Eosinophil count	1.000000e-15
GCST90002382_534	Eosinophil percentage of white cells	4.000000e-17

EFO canonical traits (20, from GWAS)

EFO ID	Trait name
EFO:0003926	neuropsychological test
EFO:0007984	platelet component distribution width
EFO:0004344	birth weight
EFO:0004847	age at onset
EFO:0005763	pulse pressure measurement
EFO:0006335	systolic blood pressure
EFO:0009928	Diuretic use measurement
EFO:0009931	Agents acting on the renin-angiotensin system use measurement
EFO:0007783	mosaic loss of chromosome Y measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0004587	lymphocyte count
EFO:0005091	monocyte count
EFO:0007989	monocyte percentage of leukocytes
EFO:0007985	platelet crit
EFO:0004309	platelet count
EFO:0004305	erythrocyte count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
C566906	Cakut (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	increases expression, decreases reaction, affects reaction, affects expression, affects cotreatment (+4 more)	14
Valproic Acid	decreases methylation, affects cotreatment, increases expression, affects expression	7
Genistein	affects binding, increases reaction, increases expression	5
bisphenol A	affects reaction, affects folding, increases expression, affects binding	4
trichostatin A	affects cotreatment, increases expression, affects expression	4
sodium arsenite	decreases expression	3
Tetrachlorodibenzodioxin	affects binding, increases reaction, increases expression, decreases expression, affects expression	3
Tretinoin	increases expression	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	3
Particulate Matter	decreases expression, increases abundance, increases expression	3
arsenite	increases expression, affects binding, decreases reaction	2
bisphenol AF	affects binding, affects folding, affects reaction, decreases reaction	2
Fulvestrant	increases expression, decreases expression, affects cotreatment, increases methylation, decreases reaction	2
Panobinostat	affects cotreatment, increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Diethylstilbestrol	affects binding, increases reaction, increases expression	2
Etoposide	decreases expression, affects response to substance	2
Fluorouracil	affects cotreatment, increases expression, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	affects cotreatment, increases methylation	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
daidzein	increases expression	1
oxybenzone	increases expression	1
triphenyl phosphate	affects expression	1
1,12-benzoperylene	increases expression	1
sodium arsenate	decreases expression	1
afimoxifene	decreases reaction, 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_1661	ZR-75-30	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT04115345	PHASE1	COMPLETED	A Study of a Renal Autologous Cell Therapy (REACT) in Patients With Chronic Kidney Disease (CKD) From Congenital Anomalies of the Kidney and Urinary Tract (CAKUT).
NCT05694169	PHASE1	TERMINATED	A Study of Participants With Chronic Kidney Disease Previously Treated With REACT
NCT05906732	PHASE1/PHASE2	TERMINATED	Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).
NCT00005176	Not specified	COMPLETED	Long QT Syndrome-Population Genetics and Cardiac Studies
NCT00005250	Not specified	COMPLETED	Linkage Study of Long QT Syndrome In An Amish Kindred
NCT00005367	Not specified	COMPLETED	Epidemiology of Long QTand Asian Sudden Death in Sleep
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00335036	Not specified	TERMINATED	Pediatric Lead Extractability and Survival Evaluation (PLEASE)
NCT00399412	Not specified	COMPLETED	ECG Signal Collection From Long QT Syndrome, Wide QRS Complexes, Heart Failure, and Cardiac Resynchronization Patients
NCT00488254	Not specified	COMPLETED	The Long QT Syndrome in Pregnancy
NCT00588965	Not specified	COMPLETED	Effect of Beta-blocker Therapy on QTc Response in Exercise and Recovery in Normal Subjects
NCT01705925	Not specified	COMPLETED	Multicenter Evaluation of Children and Young Adults With Genotype Positive Long QT Syndrome
NCT01903564	Not specified	COMPLETED	Fetal and Neonatal Magnetophysiology
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT02425189	Not specified	COMPLETED	The Canadian National Long QT Syndrome Registry
NCT02439645	Not specified	TERMINATED	A Registry to Determine the Clinical and Genetic Risk Factors for Torsade De Pointes
NCT02439658	Not specified	UNKNOWN	Genetics of QT Prolongation With Antiarrhythmics
NCT02549664	Not specified	COMPLETED	Exercise in Genetic Cardiovascular Conditions
NCT02581241	Not specified	COMPLETED	Abnormal QT-Response to the Sudden Tachycardia Provoked by Standing in Individuals With Drug-induced Long QT Syndrome
NCT02680080	Not specified	COMPLETED	Effect of Grapefruit on QT Interval in Healthy Volunteers and Patients With Congenital Long QT Syndrome
NCT02775513	Not specified	UNKNOWN	Metabolism of Patients With Genetically Caused Cardiac Arrhythmia
NCT02814981	Not specified	UNKNOWN	Hydroxyzine and Risk of Prolongation of QT Interval
NCT02876380	Not specified	COMPLETED	Prospective Identification of Long QT Syndrome in Fetal Life
NCT03182777	Not specified	COMPLETED	Safety of Local Dental Anesthesia in Patients With Cardiac Channelopathies
NCT03544918	Not specified	COMPLETED	Prevalence of Congenital Long QT Syndrome and Acquired QT Prolongation in a Hospital Cohort