TULP4

Summary

TULP4 (TUB like protein 4, HGNC:15530) is a protein-coding gene on chromosome 6q25.3, encoding Tubby-related protein 4 (Q9NRJ4). May be a substrate-recognition component of a SCF-like ECS (Elongin-Cullin-SOCS-box protein) E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.

Predicted to be involved in protein ubiquitination. Located in cytoplasm.

Source: NCBI Gene 56995 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 330 total
• MANE Select transcript: NM_020245

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15530
Approved symbol	TULP4
Name	TUB like protein 4
Location	6q25.3
Locus type	gene with protein product
Status	Approved
Aliases	TUSP, KIAA1397
Ensembl gene	ENSG00000130338
Ensembl biotype	protein_coding
OMIM	619442
Entrez	56995

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 3 protein_coding_CDS_not_defined, 2 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000367094, ENST00000367097, ENST00000432358, ENST00000613390, ENST00000613994, ENST00000616856, ENST00000620026

RefSeq mRNA: 2 — MANE Select: NM_020245 NM_001007466, NM_020245

CCDS: CCDS34561, CCDS34562

Canonical transcript exons

ENST00000367097 — 14 exons

Exon	Start	End
ENSE00000765520	158493573	158493717
ENSE00000765522	158489588	158489732
ENSE00000765523	158481055	158481289
ENSE00000894205	158498669	158498812
ENSE00000894207	158494753	158494846
ENSE00000894209	158479751	158479975
ENSE00000894211	158461563	158461729
ENSE00000894213	158452134	158452268
ENSE00000894215	158448996	158449176
ENSE00000894217	158429736	158429897
ENSE00000894219	158413065	158413193
ENSE00001411602	158501678	158504178
ENSE00001865172	158506578	158511828
ENSE00003714570	158312465	158314268

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 98.02.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.2730 / max 181.6420, expressed in 1739 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
70831	5.5877	1520
70830	5.2752	1599
70829	1.1719	693
70832	0.1550	60
70833	0.0832	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
medial globus pallidus	UBERON:0002477	98.02	gold quality
globus pallidus	UBERON:0001875	97.79	gold quality
corpus callosum	UBERON:0002336	97.50	gold quality
cerebellar vermis	UBERON:0004720	97.29	gold quality
inferior vagus X ganglion	UBERON:0005363	97.12	gold quality
buccal mucosa cell	CL:0002336	96.91	gold quality
lateral globus pallidus	UBERON:0002476	96.86	gold quality
superior vestibular nucleus	UBERON:0007227	96.52	gold quality
calcaneal tendon	UBERON:0003701	96.49	gold quality
ventral tegmental area	UBERON:0002691	96.42	gold quality
medulla oblongata	UBERON:0001896	96.10	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.03	gold quality
colonic epithelium	UBERON:0000397	95.71	gold quality
pigmented layer of retina	UBERON:0001782	95.68	gold quality
substantia nigra pars compacta	UBERON:0001965	95.66	gold quality
subthalamic nucleus	UBERON:0001906	95.58	gold quality
nipple	UBERON:0002030	94.76	gold quality
inferior olivary complex	UBERON:0002127	94.57	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	94.54	gold quality
saphenous vein	UBERON:0007318	94.54	gold quality
tendon	UBERON:0000043	94.37	gold quality
caput epididymis	UBERON:0004358	94.21	gold quality
corpus epididymis	UBERON:0004359	94.19	gold quality
mammary duct	UBERON:0001765	93.76	gold quality
Brodmann (1909) area 46	UBERON:0006483	93.76	gold quality
parietal lobe	UBERON:0001872	93.67	gold quality
sperm	CL:0000019	93.52	gold quality
dorsal plus ventral thalamus	UBERON:0001897	93.44	gold quality
postcentral gyrus	UBERON:0002581	93.21	gold quality
superior surface of tongue	UBERON:0007371	92.96	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-93593	no	10.55
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

212 targeting TULP4, 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-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
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-4262	100.00	73.26	3931
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-12121	99.99	66.64	255
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817

Literature-anchored findings (GeneRIF, showing 2)

• In Philippines families, overtransmission of alleles to persons born with CL+/-P. Results : We found statistical evidence of association between a marker of TULP4 (rs651333) with CL+/-P (P = .00007). Conclusions : Our results further support the linkage results for the chromosome 6q region and reveal a novel candidate gene for CL+/-P. (PMID:24066709)
• Effects of Tulp4 deficiency on murine embryonic development and adult phenotype. (PMID:38115643)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	tulp4a	ENSDARG00000045911
danio_rerio	tulp4b	ENSDARG00000063056
mus_musculus	Tulp4	ENSMUSG00000034377
rattus_norvegicus	Tulp4	ENSRNOG00000018012
drosophila_melanogaster	Tusp	FBGN0039530
caenorhabditis_elegans	tub-2	WBGENE00022139

Paralogs (5): TULP3 (ENSG00000078246), TULP2 (ENSG00000104804), TULP1 (ENSG00000112041), WDR35 (ENSG00000118965), TUB (ENSG00000166402)

Protein

Protein identifiers

Tubby-related protein 4 — Q9NRJ4 (reviewed: Q9NRJ4)

Alternative names: Tubby superfamily protein, Tubby-like protein 4

All UniProt accessions (2): Q9NRJ4, A0A087WYH3

UniProt curated annotations — full annotation on UniProt →

Function. May be a substrate-recognition component of a SCF-like ECS (Elongin-Cullin-SOCS-box protein) E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed mainly in the brain, skeletal muscle, testis and kidney.

Domain organisation. The SOCS box domain mediates the interaction with the Elongin BC complex, an adapter module in different E3 ubiquitin ligase complexes.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the TUB family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NRJ4-1	1	yes
Q9NRJ4-2	2

RefSeq proteins (2): NP_001007467, NP_064630* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000007	Tubby_C	Domain
IPR001496	SOCS_box	Domain
IPR001680	WD40_rpt	Repeat
IPR008983	Tumour_necrosis_fac-like_dom	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR025659	Tubby-like_C	Homologous_superfamily
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR056159	Beta-prop_IFT121_TULP_N	Domain

Pfam: PF01167, PF07525, PF24797

UniProt features (32 total): repeat 7, region of interest 6, sequence variant 6, modified residue 5, compositionally biased region 3, splice variant 2, chain 1, sequence conflict 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NRJ4-F1	53.93	0.21

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 (5): 577, 945, 950, 1343, 1374

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8951664	Neddylation

MSigDB gene sets: 202 (showing top): RACCACAR_AML_Q6, HNF1_Q6, CACCAGC_MIR138, HEIDENBLAD_AMPLICON_8Q24_DN, YORDY_RECIPROCAL_REGULATION_BY_ETS1_AND_SP100_DN, chr6q25, AML_Q6, WTGAAAT_UNKNOWN, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, BYSTRYKH_HEMATOPOIESIS_STEM_CELL_AND_BRAIN_QTL_TRANS, COATES_MACROPHAGE_M1_VS_M2_DN, CAIRO_HEPATOBLASTOMA_UP, TGTTTAC_MIR30A5P_MIR30C_MIR30D_MIR30B_MIR30E5P, MARKEY_RB1_ACUTE_LOF_UP, BURTON_ADIPOGENESIS_11

GO Biological Process (1): protein ubiquitination (GO:0016567)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (2): cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
protein modification by small protein conjugation	1
binding	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

658 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TULP4	MISP	Q8IVT2	720
TULP4	SERAC1	Q96JX3	593
TULP4	F8W876	F8W876	578
TULP4	GTF2H5	Q6ZYL4	534
TULP4	TMEM242	Q9NWH2	526
TULP4	TMEM181	Q9P2C4	481
TULP4	RIMS2	Q9UQ26	470
TULP4	ATPSCKMT	Q6P4H8	468
TULP4	GREB1L	Q9C091	464
TULP4	PCNP	Q8WW12	461
TULP4	IGDCC4	Q8TDY8	456
TULP4	SCAF8	Q9UPN6	450
TULP4	CUL5	Q93034	445
TULP4	KLHL2	O95198	440
TULP4	KCNE4	Q8WWG9	425

IntAct

20 interactions, top by confidence:

A	B	Type	Score
CUL5	SOCS2	psi-mi:“MI:0914”(association)	0.880
CUL5	SOCS7	psi-mi:“MI:0914”(association)	0.640
RNF7	SOCS7	psi-mi:“MI:0914”(association)	0.530
NEDD4	TULP4	psi-mi:“MI:0407”(direct interaction)	0.440
ABL1	TULP4	psi-mi:“MI:0915”(physical association)	0.400
SRC	TULP4	psi-mi:“MI:0915”(physical association)	0.400
TULP4	FYN	psi-mi:“MI:0915”(physical association)	0.400
TULP4	PIK3R1	psi-mi:“MI:0915”(physical association)	0.400
CUL5	DDX3X	psi-mi:“MI:0914”(association)	0.350
MAGI1	CIT	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
WWP2	CCDC85C	psi-mi:“MI:0914”(association)	0.350
FAM168A	CCDC85C	psi-mi:“MI:0914”(association)	0.350
RNF7	SOCS2	psi-mi:“MI:0914”(association)	0.350
TULP4	CASK	psi-mi:“MI:0914”(association)	0.350

BioGRID (40): TULP4 (Affinity Capture-MS), TULP4 (Affinity Capture-RNA), TULP4 (Affinity Capture-RNA), TULP4 (Affinity Capture-MS), TULP4 (Affinity Capture-RNA), TULP4 (Affinity Capture-MS), TULP4 (Affinity Capture-MS), TULP4 (Affinity Capture-MS), TULP4 (Affinity Capture-MS), TULP4 (Affinity Capture-MS), TULP4 (Affinity Capture-MS), TSEN15 (Affinity Capture-MS), BAG3 (Affinity Capture-MS), STXBP4 (Affinity Capture-MS), CASK (Affinity Capture-MS)

ESM2 similar proteins: A1ZA47, B6RSP1, O14964, O17583, O35625, O42400, O54916, O60885, O74252, O75553, P0C090, P15330, P16554, P49757, P57094, P97318, P98078, Q0V8S0, Q21502, Q24212, Q24478, Q2LC84, Q5F464, Q5TYQ8, Q5XI07, Q62415, Q641G3, Q69ZW3, Q6DFF2, Q6NUC6, Q75BK1, Q8BG30, Q8CJH2, Q8IPJ3, Q8NDI1, Q96D71, Q96KQ4, Q9BGX5, Q9H3P2, Q9HBD1

Diamond homologs: A0A644F0T7, Q9JIL5, Q9NRJ4, A8WN62, B0WI30, B0XFQ9, B3MDU3, B3NJY0, B4H4X0, B4I7J9, B4J6R7, B4KNA9, B4LMR9, B4MKC7, B4P9H8, B4QFM2, O00294, O00295, O75386, O88413, O88808, P46686, P50586, P50607, Q09306, Q0WPY0, Q10LG8, Q16IR1, Q16KI5, Q28X18, Q2QXB2, Q53PP5, Q5QM27, Q688Y7, Q68Y48, Q69U54, Q6NPQ1, Q6Z2G9, Q75HX5, Q7PZK5

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 18 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.

GO biological processes:

GO term	Partners	Fold	FDR
protein ubiquitination	7	16.1×	5e-05
proteasome-mediated ubiquitin-dependent protein catabolic process	5	14.5×	7e-04
intracellular signal transduction	6	12.7×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	281
Likely benign	20
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

3600 predictions. Top by Δscore:

Variant	Effect	Δscore
6:158429733:AAGGT:A	acceptor_gain	1.0000
6:158429735:GG:G	acceptor_loss	1.0000
6:158429735:GGTGA:G	acceptor_gain	1.0000
6:158429895:CAGG:C	donor_loss	1.0000
6:158429896:AG:A	donor_loss	1.0000
6:158452132:A:AG	acceptor_gain	1.0000
6:158452132:AGAT:A	acceptor_gain	1.0000
6:158452133:G:GT	acceptor_gain	1.0000
6:158452133:GAT:G	acceptor_gain	1.0000
6:158452133:GATG:G	acceptor_gain	1.0000
6:158452265:AAAG:A	donor_loss	1.0000
6:158452267:AGG:A	donor_loss	1.0000
6:158452268:GGTAC:G	donor_loss	1.0000
6:158452269:GTAC:G	donor_loss	1.0000
6:158452270:T:G	donor_loss	1.0000
6:158461558:TTCA:T	acceptor_loss	1.0000
6:158461559:TCA:T	acceptor_loss	1.0000
6:158461560:CA:C	acceptor_loss	1.0000
6:158461561:A:AG	acceptor_gain	1.0000
6:158461561:AGAG:A	acceptor_gain	1.0000
6:158461562:G:GA	acceptor_gain	1.0000
6:158461562:GA:G	acceptor_gain	1.0000
6:158461562:GAGG:G	acceptor_gain	1.0000
6:158461562:GAGGT:G	acceptor_gain	1.0000
6:158461728:AGG:A	donor_loss	1.0000
6:158461729:GGTA:G	donor_loss	1.0000
6:158461730:G:C	donor_loss	1.0000
6:158479750:GC:G	acceptor_gain	1.0000
6:158479904:G:GT	donor_gain	1.0000
6:158479972:CAAG:C	donor_loss	1.0000

AlphaMissense

10049 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:158314080:T:A	W22R	1.000
6:158314080:T:C	W22R	1.000
6:158314153:T:C	L46P	1.000
6:158314249:T:C	L78P	1.000
6:158413080:T:A	W90R	1.000
6:158413080:T:C	W90R	1.000
6:158413082:G:C	W90C	1.000
6:158413082:G:T	W90C	1.000
6:158413102:T:C	L97P	1.000
6:158413105:C:A	A98D	1.000
6:158413129:T:A	I106K	1.000
6:158413137:T:A	W109R	1.000
6:158413137:T:C	W109R	1.000
6:158413158:T:A	W116R	1.000
6:158413158:T:C	W116R	1.000
6:158413160:G:C	W116C	1.000
6:158413160:G:T	W116C	1.000
6:158413171:T:A	L120Q	1.000
6:158413171:T:C	L120P	1.000
6:158429746:T:C	F131S	1.000
6:158429751:T:A	W133R	1.000
6:158429751:T:C	W133R	1.000
6:158429752:G:C	W133S	1.000
6:158429753:G:C	W133C	1.000
6:158429753:G:T	W133C	1.000
6:158429763:G:A	G137R	1.000
6:158429763:G:C	G137R	1.000
6:158429764:G:A	G137E	1.000
6:158429764:G:T	G137V	1.000
6:158429776:T:C	L141P	1.000

dbSNP variants (sampled 300 via entrez): RS1000001719 (6:158292667 C>T), RS1000002267 (6:158230668 T>C), RS1000004803 (6:158461424 A>G), RS1000040495 (6:158329922 A>G), RS1000041505 (6:158396225 C>T), RS1000047133 (6:158319152 C>T), RS1000052794 (6:158464721 GA>G,GAA), RS1000053269 (6:158381949 T>C), RS1000069453 (6:158253072 A>G), RS1000085534 (6:158333859 C>A), RS1000087026 (6:158437003 A>G), RS1000096463 (6:158230808 T>C), RS1000100374 (6:158475263 C>T), RS1000106776 (6:158415349 C>T), RS1000107623 (6:158332452 G>C)

Disease associations

OMIM: gene MIM:619442 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST000817_105	Height	2.000000e-09
GCST002647_63	Height	2.000000e-15
GCST003127_10	Lipoprotein (a) levels	4.000000e-10
GCST006979_717	Heel bone mineral density	1.000000e-13
GCST008163_104	Height	7.000000e-06
GCST008163_248	Height	8.000000e-07
GCST012232_12	Lipoprotein (a) levels	5.000000e-12
GCST90000025_138	Appendicular lean mass	6.000000e-23
GCST90002400_597	Plateletcrit	5.000000e-11
GCST90002407_533	White blood cell count	1.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0006925	lipoprotein A measurement
EFO:0009270	heel bone mineral density
EFO:0004980	appendicular lean mass
EFO:0007985	platelet crit

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	5
bisphenol A	decreases methylation, affects cotreatment, decreases expression	2
Tretinoin	decreases expression, increases expression	2
Cadmium Chloride	increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
geraniol	increases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
aflatoxin B2	increases methylation	1
epigallocatechin gallate	decreases expression, increases expression, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
Vorinostat	decreases expression	1
Leflunomide	increases expression	1
Panobinostat	increases expression	1
Acetaminophen	increases expression	1
Camptothecin	decreases expression	1
Cisplatin	decreases expression	1
Coumestrol	affects cotreatment, decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Mercuric Chloride	decreases expression	1
Urethane	increases expression	1
Valproic Acid	increases methylation	1
Vincristine	increases expression	1

Clinical trials (associated diseases)

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