LEPROT

Summary

LEPROT (leptin receptor overlapping transcript, HGNC:29477) is a protein-coding gene on chromosome 1p31.3, encoding Leptin receptor gene-related protein (O15243). Negatively regulates leptin receptor (LEPR) cell surface expression, and thus decreases response to leptin.

LEPROT is associated with the Golgi complex and endosomes and has a role in cell surface expression of growth hormone receptor (GHR; MIM 600946) and leptin receptor (OBR, or LEPR; MIM 601007), thereby altering receptor-mediated cell signaling (Couturier et al., 2007 [PubMed 18042720]; Touvier et al., 2009 [PubMed 19907080]).

Source: NCBI Gene 54741 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 1 total
• MANE Select transcript: NM_017526

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29477
Approved symbol	LEPROT
Name	leptin receptor overlapping transcript
Location	1p31.3
Locus type	gene with protein product
Status	Approved
Aliases	OBRGRP, OB-RGRP, VPS55, FLJ90360
Ensembl gene	ENSG00000213625
Ensembl biotype	protein_coding
OMIM	613461
Entrez	54741

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000371065, ENST00000475108, ENST00000484243, ENST00000488747, ENST00000497874, ENST00000613538

RefSeq mRNA: 3 — MANE Select: NM_017526 NM_001198681, NM_001198683, NM_017526

CCDS: CCDS630, CCDS72801

Canonical transcript exons

ENST00000371065 — 4 exons

Exon	Start	End
ENSE00000774050	65429862	65430048
ENSE00001902697	65431803	65436007
ENSE00003644138	65425303	65425378
ENSE00003850890	65420668	65420740

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 98.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.2493 / max 514.5823, expressed in 1818 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
3289	37.2493	1818
3284	1.2483	836
3286	0.7514	479
3285	0.6069	382

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
metanephric glomerulus	UBERON:0004736	98.64	gold quality
renal glomerulus	UBERON:0000074	98.63	gold quality
visceral pleura	UBERON:0002401	98.53	gold quality
stromal cell of endometrium	CL:0002255	98.46	gold quality
parietal pleura	UBERON:0002400	98.38	gold quality
pleura	UBERON:0000977	98.36	gold quality
renal medulla	UBERON:0000362	98.34	gold quality
calcaneal tendon	UBERON:0003701	98.26	gold quality
kidney epithelium	UBERON:0004819	98.16	gold quality
nipple	UBERON:0002030	98.06	gold quality
lower lobe of lung	UBERON:0008949	98.05	gold quality
cauda epididymis	UBERON:0004360	97.91	gold quality
secondary oocyte	CL:0000655	97.74	gold quality
germinal epithelium of ovary	UBERON:0001304	97.65	gold quality
tendon	UBERON:0000043	97.59	gold quality
caput epididymis	UBERON:0004358	97.56	gold quality
placenta	UBERON:0001987	97.50	gold quality
mammary duct	UBERON:0001765	97.48	gold quality
corpus epididymis	UBERON:0004359	97.41	gold quality
epithelium of mammary gland	UBERON:0003244	97.40	gold quality
urethra	UBERON:0000057	97.38	gold quality
skin of hip	UBERON:0001554	97.37	gold quality
trabecular bone tissue	UBERON:0002483	97.36	gold quality
synovial joint	UBERON:0002217	97.35	gold quality
upper leg skin	UBERON:0004262	97.35	gold quality
metanephros	UBERON:0000081	97.25	gold quality
decidua	UBERON:0002450	97.24	gold quality
nephron tubule	UBERON:0001231	97.22	gold quality
cardia of stomach	UBERON:0001162	97.17	gold quality
pericardium	UBERON:0002407	97.17	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-HCAD-6	yes	45.47
E-HCAD-4	yes	19.35
E-HCAD-10	yes	18.10
E-HCAD-13	yes	12.43
E-CURD-112	yes	10.18
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

218 targeting LEPROT, 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-3613-3P	100.00	76.36	7965
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
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-548C-3P	99.99	74.01	7587
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4803	99.98	71.99	3117
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-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882

Literature-anchored findings (GeneRIF, showing 2)

• Transgenic mice expressing either human LEPROT or human LEPROTL1 displayed growth retardation, reduced plasma IGF1 levels, and impaired hepatic sensitivity to GH, as measured by STAT5 phosphorylation and Socs2 mRNA expression. (PMID:19907080)
• Whole-body deletion of Endospanin 1 protects from obesity-associated deleterious metabolic alterations. (PMID:38716728)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000110105
mus_musculus	Leprot	ENSMUSG00000035212
rattus_norvegicus	Leprot	ENSRNOG00000050849
drosophila_melanogaster	CG30423	FBGN0050423
caenorhabditis_elegans		WBGENE00016244

Paralogs (1): LEPROTL1 (ENSG00000104660)

Protein

Protein identifiers

Leptin receptor gene-related protein — O15243 (reviewed: O15243)

Alternative names: Endospanin-1, Leptin receptor overlapping transcript protein, OB-R gene-related protein

All UniProt accessions (5): A0A087X0N2, A0A3B3ISI6, A0A3B3ISI8, A0A3B3ITV1, O15243

UniProt curated annotations — full annotation on UniProt →

Function. Negatively regulates leptin receptor (LEPR) cell surface expression, and thus decreases response to leptin. Negatively regulates growth hormone (GH) receptor cell surface expression in liver. May play a role in liver resistance to GH during periods of reduced nutrient availability.

Subunit / interactions. Interacts with LEPR. Interacts with RAB13.

Subcellular location. Golgi apparatus membrane. Endosome membrane.

Tissue specificity. Expressed at the highest levels in heart and placenta and at a lesser extent in lung, liver, skeletal muscle, kidney and pancreas.

Similarity. Belongs to the OB-RGRP/VPS55 family.

RefSeq proteins (2): NP_001185610, NP_059996* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007262	Vps55/LEPROT	Family

Pfam: PF04133

UniProt features (5 total): transmembrane region 4, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15243-F1	80.89	0.33

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 261 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_PROTEIN_TARGETING, GOBP_VACUOLAR_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_CELL_SURFACE_RECEPTOR_SIGNALING_PATHWAY_VIA_JAK_STAT, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, LI_WILMS_TUMOR_VS_FETAL_KIDNEY_1_UP, GOBP_REGULATION_OF_PROTEIN_LOCALIZATION_TO_CELL_SURFACE, GOBP_RESPONSE_TO_GROWTH_HORMONE, GATA6_01

GO Biological Process (5): late endosome to vacuole transport via multivesicular body sorting pathway (GO:0032511), negative regulation of receptor signaling pathway via JAK-STAT (GO:0046426), negative regulation of growth hormone receptor signaling pathway (GO:0060400), obsolete positive regulation of protein targeting to mitochondrion (GO:1903955), negative regulation of protein localization to cell surface (GO:2000009)

GO Molecular Function (2): signaling receptor binding (GO:0005102), protein binding (GO:0005515)

GO Cellular Component (5): Golgi membrane (GO:0000139), endosome (GO:0005768), Golgi apparatus (GO:0005794), endosome membrane (GO:0010008), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
bounding membrane of organelle	2
endomembrane system	2
endosome transport via multivesicular body sorting pathway	1
late endosome to vacuole transport	1
cell surface receptor signaling pathway via JAK-STAT	1
regulation of receptor signaling pathway via JAK-STAT	1
negative regulation of receptor signaling pathway via STAT	1
negative regulation of signal transduction	1
growth hormone receptor signaling pathway	1
regulation of growth hormone receptor signaling pathway	1
protein localization to cell surface	1
negative regulation of protein localization	1
regulation of protein localization to cell surface	1
protein binding	1
binding	1
Golgi apparatus	1
cytoplasmic vesicle	1
cytoplasm	1
intracellular membrane-bounded organelle	1
endosome	1
cytoplasmic vesicle membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

530 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LEPROT	LEPR	P48357	844
LEPROT	GHR	P10912	671
LEPROT	LEP	P41159	636
LEPROT	INS	P01308	475
LEPROT	JAK2	O60674	452
LEPROT	DNAJC6	O75061	420
LEPROT	CCDC9B	Q6ZUT6	401
LEPROT	MTRF1	O75570	394
LEPROT	FGF21	Q9NSA1	348
LEPROT	LEMD1	Q68G75	344
LEPROT	PDE1A	P54750	331
LEPROT	FBXL4	Q9UKA2	328
LEPROT	AK4	P27144	322
LEPROT	LUZP6	Q538Z0	310
LEPROT	ATP6V0A1	Q93050	299

IntAct

42 interactions, top by confidence:

A	B	Type	Score
LEPROT	RHCG	psi-mi:“MI:0915”(physical association)	0.560
TMEM50B	LEPROT	psi-mi:“MI:0915”(physical association)	0.560
LEPROT	TMEM50B	psi-mi:“MI:0915”(physical association)	0.560
	LEPROT	psi-mi:“MI:0915”(physical association)	0.560
LEPROT	YIPF1	psi-mi:“MI:0915”(physical association)	0.560
LEPROT	AQP6	psi-mi:“MI:0915”(physical association)	0.560
LEPROT	TMEM50A	psi-mi:“MI:0915”(physical association)	0.560
LEPROT	TMX2	psi-mi:“MI:0915”(physical association)	0.560
LEPROT	PLPPR1	psi-mi:“MI:0915”(physical association)	0.560
LEPROT	SLC7A1	psi-mi:“MI:0915”(physical association)	0.560
LEPROT	TMEM120A	psi-mi:“MI:0915”(physical association)	0.560
LEPROT	SYNGR1	psi-mi:“MI:0915”(physical association)	0.560
LEPROT	GJA5	psi-mi:“MI:0915”(physical association)	0.560
LEPR	LEPROT	psi-mi:“MI:0915”(physical association)	0.540
LEPR	LEPROT	psi-mi:“MI:0407”(direct interaction)	0.540
GPC1	GANAB	psi-mi:“MI:0915”(physical association)	0.400
MEP1B	LEPROT	psi-mi:“MI:0915”(physical association)	0.370
LEPROT	SMO	psi-mi:“MI:0915”(physical association)	0.370
YIPF1	LEPROT	psi-mi:“MI:0915”(physical association)	0.000
LEPROT	AQP6	psi-mi:“MI:0915”(physical association)	0.000
TMEM50A	LEPROT	psi-mi:“MI:0915”(physical association)	0.000
LEPROT	TMX2	psi-mi:“MI:0915”(physical association)	0.000
LEPROT	PLPPR1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (15): LEPROT (Synthetic Lethality), LEPROT (Two-hybrid), LEPROT (Two-hybrid), LEPROT (Two-hybrid), LEPROT (Two-hybrid), LEPROT (Two-hybrid), LEPROT (Two-hybrid), LEPROT (Two-hybrid), LEPROT (Two-hybrid), LEPROT (Two-hybrid), GJA5 (Two-hybrid), LEPROT (Two-hybrid), LEPROT (Affinity Capture-MS), LEPROT (Affinity Capture-RNA), LEPROT (Affinity Capture-RNA)

ESM2 similar proteins: A2VDC7, A4FUZ5, A9CAZ8, B9TRX0, O15243, O89013, O95807, P04116, P23289, P23294, P36963, P36965, P47789, P47790, P56557, P60201, P60202, P60203, Q0P442, Q0P467, Q13491, Q13530, Q1E1E0, Q3SYT0, Q3SZL9, Q3T110, Q3ZC23, Q4R6L9, Q561T9, Q566G2, Q5PSV5, Q5R4C3, Q5R533, Q5R603, Q5R6E6, Q5ZJD9, Q712P7, Q7TNK0, Q7Z0Q2, Q803X0

Diamond homologs: B3Y064, B9TRX0, O15243, O89013, O95214, P47111, Q18319, Q32PD8, Q3SYT0, Q561T9, Q5PSV5, Q5RDE9, Q5ZJD9, Q6PDU4, Q9CQ74, Q9JLS8, Q54VP1, Q9AST6, Q9UUH1

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	1
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

629 predictions. Top by Δscore:

Variant	Effect	Δscore
1:65425301:A:AG	acceptor_gain	1.0000
1:65425302:G:GG	acceptor_gain	1.0000
1:65425377:GG:G	donor_gain	1.0000
1:65425378:GG:G	donor_gain	1.0000
1:65425379:G:GG	donor_gain	1.0000
1:65429835:T:A	acceptor_gain	1.0000
1:65429835:T:TA	acceptor_gain	1.0000
1:65429836:G:A	acceptor_gain	1.0000
1:65429846:T:A	acceptor_gain	1.0000
1:65429847:G:A	acceptor_gain	1.0000
1:65420736:TAAAG:T	donor_loss	0.9900
1:65420738:AAGGT:A	donor_loss	0.9900
1:65420739:AGG:A	donor_loss	0.9900
1:65420740:GGTAC:G	donor_loss	0.9900
1:65420741:G:GA	donor_loss	0.9900
1:65425297:TCACA:T	acceptor_loss	0.9900
1:65425298:CACA:C	acceptor_loss	0.9900
1:65425299:ACAG:A	acceptor_loss	0.9900
1:65425300:C:G	acceptor_gain	0.9900
1:65425300:CAGC:C	acceptor_loss	0.9900
1:65425301:AGCTC:A	acceptor_loss	0.9900
1:65425302:G:T	acceptor_loss	0.9900
1:65425302:GCT:G	acceptor_gain	0.9900
1:65425375:ATGG:A	donor_loss	0.9900
1:65425376:TGGG:T	donor_loss	0.9900
1:65425377:GGGTA:G	donor_loss	0.9900
1:65425378:GGT:G	donor_loss	0.9900
1:65425379:G:GC	donor_loss	0.9900
1:65425380:T:A	donor_loss	0.9900
1:65425381:AAG:A	donor_loss	0.9900

AlphaMissense

844 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:65430002:T:A	V78D	0.984
1:65431837:G:A	G105D	0.983
1:65425335:G:A	G17R	0.978
1:65425335:G:C	G17R	0.978
1:65425336:G:A	G17E	0.978
1:65429983:T:C	F72L	0.978
1:65429985:C:A	F72L	0.978
1:65429985:C:G	F72L	0.978
1:65425323:A:C	S13R	0.977
1:65425325:T:A	S13R	0.977
1:65425325:T:G	S13R	0.977
1:65430017:G:A	G83E	0.977
1:65430005:T:A	V79D	0.976
1:65430011:C:A	A81D	0.974
1:65431836:G:C	G105R	0.974
1:65430010:G:C	A81P	0.970
1:65431914:T:A	W131R	0.970
1:65431914:T:C	W131R	0.970
1:65425327:G:A	G14E	0.968
1:65429995:G:A	G76R	0.968
1:65429995:G:C	G76R	0.968
1:65431841:T:A	N106K	0.968
1:65431841:T:G	N106K	0.968
1:65431881:T:C	F120L	0.968
1:65431883:T:A	F120L	0.968
1:65431883:T:G	F120L	0.968
1:65425339:T:C	L18P	0.966
1:65425326:G:A	G14R	0.965
1:65425326:G:C	G14R	0.965
1:65429996:G:A	G76E	0.965

dbSNP variants (sampled 300 via entrez): RS1000207814 (1:65435681 C>T), RS1000388537 (1:65429430 G>C), RS1000401626 (1:65435410 C>G,T), RS1000491367 (1:65435961 T>A), RS1000759696 (1:65429135 A>G,T), RS1000804405 (1:65425569 C>A), RS1000836931 (1:65425799 A>G), RS1001063250 (1:65419550 A>G), RS1001107615 (1:65430826 C>T), RS1001122252 (1:65424256 C>A), RS1001267112 (1:65418722 A>G), RS1001433809 (1:65419381 C>G), RS1001634398 (1:65435063 G>A), RS1001665616 (1:65435374 T>C,G), RS1001697219 (1:65418964 G>A,C)

Disease associations

OMIM: gene MIM:613461 | disease phenotypes: MIM:614963

GenCC curated gene-disease

Mondo (1): obesity due to leptin receptor gene deficiency (MONDO:0013992)

Orphanet (1): Obesity due to leptin receptor gene deficiency (Orphanet:179494)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009556_1	BMI at adiposity peak	8.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005937	longitudinal BMI measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1137101	LEPR, LEPROT	3	2.50	4	simvastatin;valproic acid;antipsychotics
rs1805094	LEPR, LEPROT	3	1.25	1	atorvastatin
rs1045895	LEPR, LEPROT		0.00	0

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	decreases expression, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cyclosporine	decreases expression	2
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
arsenite	increases methylation	1
butyraldehyde	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Bilirubin	decreases expression	1
Calcitriol	increases expression, affects cotreatment	1
Doxorubicin	decreases expression	1
Formaldehyde	increases expression	1
Phenobarbital	affects expression	1
Smoke	decreases expression, increases abundance	1
Testosterone	affects cotreatment, increases expression	1
Valproic Acid	increases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1
Vitamin K 3	affects expression	1
Particulate Matter	increases abundance, decreases expression	1

Clinical trials (associated diseases)

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