LEPR

Summary

LEPR (leptin receptor, HGNC:6554) is a protein-coding gene on chromosome 1p31.3, encoding Leptin receptor (P48357). Receptor for hormone LEP/leptin.

The protein encoded by this gene belongs to the gp130 family of cytokine receptors that are known to stimulate gene transcription via activation of cytosolic STAT proteins. This protein is a receptor for leptin (an adipocyte-specific hormone that regulates body weight), and is involved in the regulation of fat metabolism, as well as in a novel hematopoietic pathway that is required for normal lymphopoiesis. Mutations in this gene have been associated with obesity and pituitary dysfunction. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. It is noteworthy that this gene and LEPROT gene (GeneID:54741) share the same promoter and the first 2 exons, however, encode distinct proteins (PMID:9207021).

Source: NCBI Gene 3953 — RefSeq curated summary.

At a glance

• Gene–disease (curated): obesity due to leptin receptor gene deficiency (Strong, GenCC)
• GWAS associations: 77 (top 1% of genes corpus-wide)
• Clinical variants (ClinVar): 556 total — 19 pathogenic, 21 likely-pathogenic (top 6% of genes corpus-wide)
• Expression (HPA): Tissue enriched — highest in putamen, pons, thalamus
• GTEx eGene: eQTL in 32 tissues, sQTL in 9 (q < 0.05)
• Phenotypes (HPO): 32
• Drug target: yes — 2 curated mechanism-of-action drugs
• Approved drugs (ChEMBL mechanism of action): 1 — Metreleptin
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.59 (moderately constrained)
• MANE Select transcript: NM_002303
• Interaction hub: 1,914 STRING partners (top 8% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6554
Approved symbol	LEPR
Name	leptin receptor
Location	1p31.3
Locus type	gene with protein product
Status	Approved
Aliases	OBR, CD295, LEP-R, OB-R
Ensembl gene	ENSG00000116678
Ensembl biotype	protein_coding
OMIM	601007
Entrez	3953

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 14 protein_coding, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

MANE Select: ENST00000349533

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 6, TSL 3: 1, TSL 5: 1

ENST00000349533, ENST00000344610, ENST00000371058, ENST00000371059, ENST00000371060, ENST00000462765, ENST00000471762, ENST00000616738, ENST00000981042, ENST00000981043, ENST00000981044, ENST00000981045, ENST00000981046, ENST00001037957, ENST00001037958, ENST00001072944, ENST00001112052, ENST00001143282

RefSeq mRNA: 6 — MANE Select: NM_002303 NM_001003679, NM_001003680, NM_001198687, NM_001198688, NM_001198689, NM_002303

CCDS: CCDS30740, CCDS30741, CCDS55604, CCDS631

Canonical transcript exons

ENST00000349533 — 20 exons

Exon	Start	End
ENSE00000000357	65420668	65420740
ENSE00001295071	65610214	65610296
ENSE00001298588	65617964	65618146
ENSE00001302126	65619928	65620023
ENSE00001303665	65616008	65616224
ENSE00001306788	65622906	65622981
ENSE00001310674	65636191	65641559
ENSE00003459486	65565546	65565605
ENSE00003504765	65621353	65621458
ENSE00003528068	65608753	65608901
ENSE00003547600	65572326	65572449
ENSE00003559375	65425303	65425378
ENSE00003575758	65601392	65601682
ENSE00003576938	65570473	65570802
ENSE00003585777	65598660	65598804
ENSE00003652322	65596448	65596593
ENSE00003664750	65601843	65601960
ENSE00003671220	65592657	65592865
ENSE00003683686	65609947	65610106
ENSE00003690482	65605038	65605237

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 98.83.

FANTOM5 (CAGE): breadth broad, TPM avg 10.9238 / max 1122.3550, expressed in 725 samples.

Highest expression (Bgee): trabecular bone tissue, choroid plexus epithelium, trigeminal ganglion, pericardium, skin of hip.

Genetic regulation across tissues (GTEx eQTL / sQTL)

LEPR is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 32 tissues and its splicing (sQTL) in 9 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 41 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	eqtl	1.3e-16	-0.24	1:65524739:C:T
Whole Blood	eqtl	3.4e-14	-0.27	1:65431185:C:T
Adipose Subcutaneous	eqtl	5.2e-12	-0.22	1:65468671:T:C
Cells Cultured fibroblasts	sqtl	1.5e-10	+0.56	1:65495616:C:T
Adipose Visceral Omentum	eqtl	2.0e-10	-0.19	1:65472197:A:T
Cells EBV-transformed lymphocytes	eqtl	4.5e-09	+0.77	1:65429130:G:A
Thyroid	sqtl	9.8e-08	+0.38	1:65433313:C:T
Skin Sun Exposed Lower leg	eqtl	1.6e-06	-0.20	1:65466502:T:A
Brain Cerebellar Hemisphere	eqtl	2.1e-06	-0.28	1:65472197:A:T
Esophagus Muscularis	eqtl	3.7e-06	-0.20	1:65524739:C:T
Heart Atrial Appendage	eqtl	4.2e-06	-0.20	1:65479167:T:C
Brain Caudate basal ganglia	eqtl	1.2e-05	-0.23	1:65483257:C:A
Esophagus Gastroesophageal Junction	eqtl	1.6e-05	-0.20	1:65435525:G:A
Colon Sigmoid	eqtl	1.9e-05	+0.21	1:65504812:T:C
Brain Cerebellum	eqtl	2.6e-05	+0.27	1:65424553:C:T
Heart Left Ventricle	eqtl	2.7e-05	-0.19	1:65473475:A:G
Skin Sun Exposed Lower leg	sqtl	9.0e-05	-0.33	1:65532158:G:A
Muscle Skeletal	eqtl	1.5e-04	+0.28	1:65429130:G:A
Spleen	eqtl	1.5e-04	+0.32	1:65526143:C:CGG
Artery Coronary	eqtl	2.1e-04	-0.28	1:65465711:G:C

FANTOM5 promoters

showing 10 of 12 alternative TSS:

Promoter ID	TPM avg	Samples expressed
3289	37.2493	1818
3302	7.2785	595
3297	1.8867	358
3293	0.5272	205
3301	0.4727	198
3288	0.2603	79
3295	0.2458	114
3299	0.0800	36
3298	0.0471	20
3294	0.0462	16

Top tissues by expression

showing 100 of 291 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
trabecular bone tissue	UBERON:0002483	98.83	gold quality
choroid plexus epithelium	UBERON:0003911	98.53	gold quality
trigeminal ganglion	UBERON:0001675	98.41	gold quality
pericardium	UBERON:0002407	97.86	gold quality
skin of hip	UBERON:0001554	97.10	gold quality
oral cavity	UBERON:0000167	96.76	gold quality
pharyngeal mucosa	UBERON:0000355	96.52	gold quality
lower lobe of lung	UBERON:0008949	96.25	gold quality
upper leg skin	UBERON:0004262	95.75	gold quality
urethra	UBERON:0000057	95.49	gold quality
calcaneal tendon	UBERON:0003701	95.48	gold quality
cardia of stomach	UBERON:0001162	94.89	gold quality
dorsal root ganglion	UBERON:0000044	94.79	gold quality
mammary duct	UBERON:0001765	94.78	gold quality
vena cava	UBERON:0004087	94.53	gold quality
cardiac muscle of right atrium	UBERON:0003379	94.20	gold quality
liver	UBERON:0002107	93.69	gold quality
synovial joint	UBERON:0002217	93.20	gold quality
cauda epididymis	UBERON:0004360	92.73	gold quality
visceral pleura	UBERON:0002401	92.50	gold quality
mammalian vulva	UBERON:0000997	92.49	gold quality
epithelium of mammary gland	UBERON:0003244	92.39	gold quality
body of tongue	UBERON:0011876	92.09	gold quality
thoracic mammary gland	UBERON:0005200	92.03	gold quality
mammary gland	UBERON:0001911	91.97	gold quality
mucosa of paranasal sinus	UBERON:0005030	91.82	gold quality
pleura	UBERON:0000977	91.17	gold quality
right lobe of liver	UBERON:0001114	90.42	gold quality
parietal pleura	UBERON:0002400	90.27	gold quality
seminal vesicle	UBERON:0000998	90.18	gold quality
tongue	UBERON:0001723	90.14	gold quality
superficial temporal artery	UBERON:0001614	89.85	gold quality
germinal epithelium of ovary	UBERON:0001304	89.81	gold quality
trachea	UBERON:0003126	89.28	gold quality
tibial nerve	UBERON:0001323	88.99	gold quality
superior surface of tongue	UBERON:0007371	88.96	gold quality
upper arm skin	UBERON:0004263	88.74	gold quality
lung	UBERON:0002048	88.32	gold quality
cranial nerve II	UBERON:0000941	88.27	gold quality
nipple	UBERON:0002030	87.65	gold quality
periodontal ligament	UBERON:0008266	87.51	gold quality
adult organism	UBERON:0007023	87.33	gold quality
blood vessel layer	UBERON:0004797	87.14	gold quality
renal glomerulus	UBERON:0000074	86.96	gold quality
pigmented layer of retina	UBERON:0001782	86.94	gold quality
endometrium	UBERON:0001295	86.92	gold quality
gall bladder	UBERON:0002110	86.78	gold quality
metanephric glomerulus	UBERON:0004736	86.48	gold quality
right lung	UBERON:0002167	86.46	gold quality
left ovary	UBERON:0002119	86.39	gold quality
adipose tissue	UBERON:0001013	86.36	gold quality
fundus of stomach	UBERON:0001160	86.30	gold quality
connective tissue	UBERON:0002384	86.28	gold quality
colonic epithelium	UBERON:0000397	85.93	gold quality
penis	UBERON:0000989	85.85	gold quality
saphenous vein	UBERON:0007318	85.77	gold quality
right ovary	UBERON:0002118	85.61	gold quality
ovary	UBERON:0000992	85.56	gold quality
adipose tissue of abdominal region	UBERON:0007808	85.41	gold quality
myometrium	UBERON:0001296	85.13	gold quality
peritoneum	UBERON:0002358	85.08	gold quality
omental fat pad	UBERON:0010414	85.06	gold quality
upper lobe of lung	UBERON:0008948	84.64	gold quality
uterus	UBERON:0000995	84.48	gold quality
tendon	UBERON:0000043	84.02	gold quality
upper lobe of left lung	UBERON:0008952	83.95	gold quality
decidua	UBERON:0002450	83.74	gold quality
coronary artery	UBERON:0001621	83.68	gold quality
body of stomach	UBERON:0001161	83.25	gold quality
left coronary artery	UBERON:0001626	83.20	gold quality
urinary bladder	UBERON:0001255	83.15	gold quality
smooth muscle tissue	UBERON:0001135	83.03	gold quality
subcutaneous adipose tissue	UBERON:0002190	82.96	gold quality
stomach	UBERON:0000945	82.87	gold quality
body of uterus	UBERON:0009853	82.77	gold quality
tibial artery	UBERON:0007610	82.69	gold quality
popliteal artery	UBERON:0002250	82.68	gold quality
right coronary artery	UBERON:0001625	82.61	gold quality
islet of Langerhans	UBERON:0000006	82.57	gold quality
mucosa of urinary bladder	UBERON:0001259	82.40	gold quality
female reproductive system	UBERON:0000474	82.31	gold quality
endocervix	UBERON:0000458	82.14	gold quality
minor salivary gland	UBERON:0001830	82.08	gold quality
lymph node	UBERON:0000029	82.00	gold quality
renal medulla	UBERON:0000362	81.95	gold quality
mouth mucosa	UBERON:0003729	81.93	gold quality
layer of synovial tissue	UBERON:0007616	81.76	gold quality
myocardium	UBERON:0002349	81.66	gold quality
aorta	UBERON:0000947	81.41	gold quality
metanephros	UBERON:0000081	81.17	gold quality
descending thoracic aorta	UBERON:0002345	81.09	gold quality
mucosa of stomach	UBERON:0001199	80.93	gold quality
monocyte	CL:0000576	79.95	gold quality
epithelial cell of pancreas	CL:0000083	79.88	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.75	gold quality
ascending aorta	UBERON:0001496	79.61	gold quality
thoracic aorta	UBERON:0001515	79.60	gold quality
mononuclear cell	CL:0000842	79.53	gold quality
pylorus	UBERON:0001166	79.49	gold quality
saliva-secreting gland	UBERON:0001044	79.45	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	1370.94
E-MTAB-5061	yes	572.20
E-GEOD-81608	yes	492.26
E-GEOD-81547	yes	408.38
E-ENAD-27	yes	402.20
E-GEOD-83139	yes	358.98
E-MTAB-10287	yes	65.16
E-CURD-112	yes	9.17
E-MTAB-10137	yes	4.00
E-GEOD-124858	no	184.03
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Tissue enriched

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Putamen	tissue	175.2
Pons	tissue	174.2
Thalamus	tissue	145.9
Cerebral cortex	tissue	145.3	not detected
Motor cortex	tissue	145.3
Prefrontal cortex	tissue	128.6
Spinal cord	tissue	122.3
Liver	tissue	121.9	not detected
Midbrain	tissue	114.2
Insular cortex	tissue	113.0
Substantia nigra	tissue	112.2
Amygdala	tissue	111.0
Occipital cortex	tissue	109.6
Superior colliculi	tissue	109.4
Medulla oblongata	tissue	107.7
Basal ganglia	tissue	99.4	not detected
Hippocampal formation	tissue	98.0
Ventral forebrain	tissue	96.9
Entorhinal cortex	tissue	93.7
Temporal cortex	tissue	93.0
Retrosplenial cortex	tissue	92.9
Septum	tissue	89.7
Hypothalamus	tissue	88.7
Retrosplenial and cingulate cortex	tissue	88.4
Periaqueductal gray	tissue	87.5
Somatosensory cortex	tissue	84.2
Cerebellum	tissue	53.0	not detected
Choroid plexus	tissue	52.0	high
Olfactory bulb	tissue	44.5
Corpus callosum	tissue	41.5
Tongue	tissue	30.0
Endometrium 1	tissue	23.1	not detected
Adipose tissue	tissue	22.7	not detected
Lung	tissue	21.2	not detected
Ovary	tissue	21.1	not detected
Cervix	tissue	20.3	not detected
Breast	tissue	19.3	not detected
Smooth muscle	tissue	17.5	not detected
Fallopian tube	tissue	15.2	not detected
Skin 1	tissue	14.3	not detected
Gallbladder	tissue	13.8	not detected
Pituitary gland	tissue	10.9
Nucleus accumbens	tissue	9.1
Hippocampus	tissue	9.1	not detected
Lymph node	tissue	8.9	not detected
Esophagus	tissue	8.7	not detected
Urinary bladder	tissue	8.5	not detected
Prostate	tissue	8.5	not detected
Locus coeruleus	tissue	8.3
Postcentral gyrus	tissue	8.0
Stomach 1	tissue	7.3	not detected
Kidney	tissue	7.3	not detected
Seminal vesicle	tissue	6.8	not detected
Adrenal gland	tissue	6.8	not detected
Heart muscle	tissue	6.5	not detected
Epididymis	tissue	6.3	not detected
Colon	tissue	5.5	not detected
Tonsil	tissue	5.4	not detected
Small intestine	tissue	5.3	not detected
Placenta	tissue	5.0	not detected

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Ventral spinal cord (122.3), Ventral hippocampus (98.0), Dorsal hippocampus (91.0), Dorsal spinal cord (88.7), Subiculum (85.8).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIF1A, KAT5, MT3, PPARG

miRNA regulators (miRDB)

Targeting LEPR by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

22 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-3156-3P	99.76	66.72	939
HSA-MIR-200A-5P	99.76	69.10	949
HSA-MIR-200B-5P	99.76	69.05	948
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-3618	99.69	68.57	1012
HSA-MIR-3147	99.52	66.34	388
HSA-MIR-150-3P	99.43	70.51	920
HSA-MIR-372-5P	99.41	69.11	2299
HSA-MIR-302A-5P	99.39	68.21	1913
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-5197-3P	98.71	67.05	1905
HSA-MIR-10226	98.25	66.50	811
HSA-MIR-660-5P	98.16	68.27	680
HSA-MIR-4457	98.09	67.12	1274
HSA-MIR-4275	97.96	68.42	1549
HSA-MIR-585-5P	97.54	69.02	955
HSA-MIR-5591-3P	96.23	67.03	489
HSA-MIR-4522	95.76	66.23	742

Functional genomics

gnomAD constraint: pLI 9.32e-05, LOEUF 0.589, missense Z 2.07 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000349533 — one region, missense o/e 0.89. ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• A human liver cell line expresses the leptin receptor long form Ob-Rb in sufficient quantity to respond to leptin signalling in terms of STAT activation. (PMID:11448122)
• Cultured human articular chondrocytes express functional leptin receptor Ob-R, a receptor present on chondrocytes in native human cartilage. (PMID:11549273)
• Sleep apnea syndrome is associated with plasma soluble leptin receptor and insulin resistance independently of body mass index. (PMID:11896492)
• leptin receptors are expressed in breast cancer; data suggests they may be implicated in mammary cell proliferation and in breast cancer pathogenesis (PMID:11911959)
• the levels of mRNA for the long and total forms of leptin receptors were suppressed in association with the severity of endometriosis (PMID:11994543)
• results suggest that DNA sequence variations in the leptin receptor gene could affect substrate oxidation (PMID:12006639)
• presence of the long leptin receptor isoform in the absorptive cells of the small intestine, suggesting that leptin could have a physiological role in the regulation of nutrient absorption (PMID:12010881)
• confirmation of expression in primary osteoblasts (PMID:12054170)
• relationship of soluble leptin receptor with the degree of adiposity suggests that high SLR levels may enhance leptin action in lean subjects more than in obese subjects (PMID:12075576)
• regulation of circulating levels by gender, adiposity, sex steroids and leptin (PMID:12086939)
• Leptin receptor (Ob-R) expression is induced in peripheral blood mononuclear cells by in vitro activation and in vivo in HIV-infected patients, consistent with the suggested role of leptin in modulating the immune response. (PMID:12100031)
• during weight loss leptin levels decreased, whereas soluble leptin receptor levels and the receptor bound fraction of leptin increased (PMID:12105280)
• modifications in ciruclating levels across the eating disorder spectrum (PMID:12140788)
• Serum leptin and leptin binding activity in children and adolescents with hypothalamic dysfunction. (PMID:12199340)
• cloning, expression and purification of a recombinant leptin-binding domain (PMID:12226096)
• regulated shedding of the ectodomain of membrane-spanning leptin receptors may represent a novel mechanism of modulating leptin’s biological activity (PMID:12270921)
• transforming growth factor beta effects an increase in formation (PMID:12359239)
• high levels of soluble leptin receptor in emaciation may reflect an up-regulation to suppress leptin action during energy deficiency and with free leptin index is a tool to investigate the leptin axis during growth and sexual maturation (PMID:12364439)
• term pregnancy human umbilical cord and fetal membranes co-express leptin and its receptor genes (PMID:12396559)
• Significantly increased in anorexia nervosa patients. Increase unaffected by partial refeeding. Possible etiological role of increased soluble leptin receptor levels in anorexia nervosa by affecting leptin central and/or peripherial effects. (PMID:12489569)
• Human natural killer cell lines express leptin receptors. (PMID:12504075)
• the tumor clones in childhood acute lymphoblastic leukemia do not express the leptin receptor (PMID:12512839)
• higher leptin levels for those with a leptin receptor Lys109Arg or Gln223Arg mutation may imply that these subjects have a modified functional leptin receptor (PMID:12634434)
• Skillful mechanism where a change in the serum SLEPR level regulates, in part, the biological activity of leptin in the circulation. (PMID:12660261)
• in living cells approximately 60% of the leptin receptor exists as constitutive dimers at physiological expression levels in the absence of leptin (PMID:12734179)
• Serum adiponectin and soluble leptin receptor levels might be influenced by common regulatory factors and challenge the notion that cortisol may have a direct inhibitory effect on adiponectin in humans. (PMID:12788897)
• low serum leptin, high serum TGF-beta1 and sOb-R levels, and elevated urine leptin concentrations were observed at the onset of minimal change nephrotic syndrome (PMID:12898374)
• Possibility that soluble leptin receptor is a minor component of leptin binding capacity in the plasma of pregnant women. (PMID:14599116)
• role of the soluble leptin receptor (sOB-R) in maintaining serum leptin levels in nephrotic patients (PMID:14602796)
• Ob-R gene may serve as a novel modifier gene for hypercholesterolemia in Japanese men. (PMID:14625131)
• Hints for a peripheral role of leptin in the male genital tract, possibly, by an interaction between leptin and spermatozoa via sperm leptin receptors. (PMID:14636218)
• Soluble leptin receptor levels are not altered by the cyclic hormone status in the menstrual cycle. (PMID:14967380)
• LEPR single nucleotide polymorphisms contribute to variation in obesity phenotypes. (PMID:14970363)
• The leptin receptor is aberrantly expressed in bladder cancer tissue and is possibly involved in the carcinogenesis of bladder cancer. (PMID:14972512)
• Lower expression levels of leptin receptor short form (Ob-Ra) were observed in most endometrial cancer tissues, especially in the poorly differentiated ones. (PMID:14984939)
• Expression of leptin receptor in arcuate nucleus resulted in normalization of estrous cycle length, increased ovarian follicular development, and decreased serum progesterone levels. (PMID:14998906)
• plasma SLR levels are independently regulated by many different physiological and pathophysiological conditions and SLR may modulate the actions of leptin (PMID:15016839)
• low levels of expression of leptin receptors at the cell surface results from partial retention in the biosynthetic pathway, coupled to constitutive removal from the plasma membrane via ligand-independent, constitutive endocytosis (PMID:15123629)
• Secretory endometrium is target for leptin, and oocytes and preimplantation embryos possess OB-R mRNA. Leptin may be necessary for embryonic development. Leptin mRNA expressed at blastocysts stage. Possible function in blastocyst-endometrial dialogue. (PMID:15126576)
• Leptin receptor polymorphism (Gln223 Arg) has association with peak bone mass in young women. (PMID:15130412)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	lepr	ENSDARG00000070961
mus_musculus	Lepr	ENSMUSG00000057722
rattus_norvegicus	Lepr	ENSRNOG00000023664

Paralogs (23): CRLF1 (ENSG00000006016), IL12RB2 (ENSG00000081985), IL5RA (ENSG00000091181), IL12RB1 (ENSG00000096996), IL27RA (ENSG00000104998), EBI3 (ENSG00000105246), GHR (ENSG00000112964), PRLR (ENSG00000113494), LIFR (ENSG00000113594), CSF3R (ENSG00000119535), CNTFR (ENSG00000122756), IL13RA2 (ENSG00000123496), IL13RA1 (ENSG00000131724), IL6ST (ENSG00000134352), IL11RA (ENSG00000137070), OSMR (ENSG00000145623), IL2RG (ENSG00000147168), IL6R (ENSG00000160712), IL23R (ENSG00000162594), IL31RA (ENSG00000164509), IL3RA (ENSG00000185291), CSF2RA (ENSG00000198223), CRLF2 (ENSG00000205755)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:104993) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 226 distinct phenotype terms.

Mouse phenotype (MP)	Records
obese	18
increased body weight	17
increased circulating insulin level	16
hyperglycemia	14
increased circulating leptin level	12
increased circulating glucose level	9
increased circulating triglyceride level	6
infertility	6
abnormal glucose homeostasis	5
decreased circulating insulin level	5
increased total body fat amount	5
abnormal eating behavior	4
polyphagia	4
reduced female fertility	4
male infertility	4
insulin resistance	4
decreased circulating glucose level	4
increased food intake	4
abnormal circulating glucose level	3
decreased locomotor activity	3
increased circulating HDL cholesterol level	3
hepatic steatosis	3
decreased circulating triglyceride level	3
increased circulating cholesterol level	3
abnormal oxygen consumption	3

+201 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Macaca mulatta	Q9MYL0	95.6%	Diamond
Sus scrofa	O02671	84.1%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
PDE4B-AS1	ncRNA	101927139
PDE4B	protein-coding	5142
LEPROT	protein-coding	54741
DNAJC6-AS1	ncRNA	102724416
DNAJC6	protein-coding	9829
AK4	protein-coding	205
SGIP1	protein-coding	84251

Protein

Protein identifiers

Leptin receptor — P48357 (reviewed: P48357)

Alternative names: HuB219, OB receptor

All UniProt accessions (1): P48357

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for hormone LEP/leptin. On ligand binding, mediates LEP central and peripheral effects through the activation of different signaling pathways such as JAK2/STAT3 and MAPK cascade/FOS. In the hypothalamus, LEP acts as an appetite-regulating factor that induces a decrease in food intake and an increase in energy consumption by inducing anorexinogenic factors and suppressing orexigenic neuropeptides, also regulates bone mass and secretion of hypothalamo-pituitary-adrenal hormones. In the periphery, increases basal metabolism, influences reproductive function, regulates pancreatic beta-cell function and insulin secretion, is pro-angiogenic and affects innate and adaptive immunity. Control of energy homeostasis and melanocortin production (stimulation of POMC and full repression of AgRP transcription) is mediated by STAT3 signaling, whereas distinct signals regulate NPY and the control of fertility, growth and glucose homeostasis. Involved in the regulation of counter-regulatory response to hypoglycemia by inhibiting neurons of the parabrachial nucleus. Has a specific effect on T lymphocyte responses, differentially regulating the proliferation of naive and memory T -ells. Leptin increases Th1 and suppresses Th2 cytokine production. May transport LEP across the blood-brain barrier. Binds LEP and mediates LEP endocytosis. Does not induce phosphorylation of and activate STAT3. Antagonizes Isoform A and isoform B-mediated LEP binding and endocytosis.

Subunit / interactions. Present as a mixture of monomers and dimers. The phosphorylated receptor binds a number of SH2 domain-containing proteins such as JAK2, STAT3, PTPN11, and SOCS3. Interaction with SOCS3 inhibits JAK/STAT signaling and MAPK cascade.

Subcellular location. Cell membrane. Basolateral cell membrane Secreted.

Tissue specificity. Isoform A is expressed in fetal liver and in hematopoietic tissues and choroid plexus. In adults highest expression in heart, liver, small intestine, prostate and ovary. Low level in lung and kidney. Isoform B is highly expressed in hypothalamus, but also in skeletal muscle. Detected in fundic and antral epithelial cells of the gastric mucosa. Isoform B and isoform A are expressed by NK cells (at protein level).

Post-translational modifications. On ligand binding, phosphorylated on two conserved C-terminal tyrosine residues (isoform B only) by JAK2. Tyr-986 is required for complete binding and activation of PTPN11, ERK/FOS activation,for interaction with SOCS3 and SOCS3 mediated inhibition of leptin signaling. Phosphorylation on Tyr-1141 is required for STAT3 binding/activation. Phosphorylation of Tyr-1079 has a more accessory role.

Disease relevance. Leptin receptor deficiency (LEPRD) [MIM:614963] A rare disease characterized by normal levels of serum leptin, hyperphagia and severe obesity from an early age. Additional features include alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The cytoplasmic domain may be essential for intracellular signal transduction by activation of JAK tyrosine kinase and STATs. The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding. The box 1 motif is required for JAK interaction and/or activation.

Similarity. Belongs to the type I cytokine receptor family. Type 2 subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
P48357-1	B, 13.2, OBRb	yes
P48357-2	A, 6.4, HuB219.3
P48357-3	C, 12.1, OBRa
P48357-4	D, HuB219.2
P48357-5	E

RefSeq proteins (6): NP_001003679, NP_001003680, NP_001185616, NP_001185617, NP_001185618, NP_002294* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003529	Hematopoietin_rcpt_Gp130_CS	Conserved_site
IPR003531	Hempt_rcpt_S_F1_CS	Conserved_site
IPR003961	FN3_dom	Domain
IPR007110	Ig-like_dom	Domain
IPR010457	IgC2-like_lig-bd	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036116	FN3_sf	Homologous_superfamily
IPR041182	LEP-R_IGD	Domain

Pfam: PF00041, PF06328, PF18589

UniProt features (91 total): glycosylation site 18, strand 15, sequence variant 11, disulfide bond 10, splice variant 7, domain 5, helix 5, modified residue 4, region of interest 3, mutagenesis site 3, short sequence motif 2, topological domain 2, sequence conflict 2, signal peptide 1, chain 1, transmembrane region 1, turn 1

Structure

Experimental structures (PDB)

9 structures by resolution:

PDB	Title	Method	Resolution (Å)
3V6O	Leptin Receptor-antibody complex	X-RAY DIFFRACTION	1.95
6E2P	Structure of human JAK2 FERM/SH2 in complex with Leptin Receptor	X-RAY DIFFRACTION	2.83
8X85	Structure of leptin-LepR dimer	ELECTRON MICROSCOPY	3.58
7Z3Q	Crystal structure of the human leptin:LepR-CRH2 encounter complex to 3.6 A resolution.	X-RAY DIFFRACTION	3.62
8X81	Structure of leptin-LepR trimer with a large gap	ELECTRON MICROSCOPY	3.77
8X80	Structure of leptin-LepR trimer with a small gap	ELECTRON MICROSCOPY	3.88
8AVE	Human leptin in complex with the human LEP-R ectodomain fused to a C-terminal trimeric …	ELECTRON MICROSCOPY	5.62
8AVF	Human leptin in complex with the human LEP-R ectodomain fused to a C-terminal trimeric …	ELECTRON MICROSCOPY	6.45
8AVO	Human leptin in complex with the human LEP-R ectodomain fused to a C-terminal trimeric …	ELECTRON MICROSCOPY	6.84

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48357-F1	66.49	0.22

Antibody-complex structures (SAbDab)

1 antibodies co-crystallized with this protein: 3V6O

Human Protein Atlas

Protein class: CD markers, Predicted membrane proteins, Plasma proteins, Cancer-related genes, Mutational cancer driver genes, Candidate cardiovascular disease genes, Disease related genes, FDA approved drug targets, Biotech drugs, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): vesicles; basal body; cytosol; plasma membrane; primary cilium

Antibody reliability (HPA): IH approved · IF approved

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 (4)

Type	Positions
Phosphoserine	882
Phosphotyrosine	986, 1079, 1141

Disulfide bonds (10)

Type	Positions
Disulfide bond	37–90, 89–99, 131–142, 186–196, 188–193, 352–412, 413–418, 436–447, 473–528, 488–498

Glycosylation sites (18)

Type	Positions
N-linked (glcnac…) asparagine	23, 41, 56, 73, 81, 98, 187, 206, 276, 347, 397, 516, 624, 659, 688, 697, 728, 750

Mutagenesis-validated functional residues (3)

Position	Phenotype
986	greatly reduced ptpn11 binding; no ptpn11 phosphorylation; no effect on stat3 phosphorylation.
1078–1079	no effect on ptpn11 nor stat3 phosphorylation.
1141	no effect on ptpn11 phosphorylation; no stat3 phosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 1; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

1 pathway:

ID	Pathway	Evidence
R-HSA-2586552	Signaling by Leptin	electronic

MSigDB gene sets: 389 (showing top): GOBP_REGULATION_OF_AUTOPHAGY, WANG_CLIM2_TARGETS_UP, GOBP_BEHAVIOR, KEGG_ADIPOCYTOKINE_SIGNALING_PATHWAY, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_RESPONSE_TO_PEPTIDE, YAO_HOXA10_TARGETS_VIA_PROGESTERONE_UP, MODULE_64, GOZGIT_ESR1_TARGETS_DN, GOBP_GROWTH, GOCC_CELL_SURFACE, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_1

GO Biological Process (23): angiogenesis (GO:0001525), energy reserve metabolic process (GO:0006112), phagocytosis (GO:0006909), cell surface receptor signaling pathway (GO:0007166), multicellular organism development (GO:0007275), positive regulation of cell population proliferation (GO:0008284), negative regulation of autophagy (GO:0010507), cytokine-mediated signaling pathway (GO:0019221), sexual reproduction (GO:0019953), T cell differentiation (GO:0030217), leptin-mediated signaling pathway (GO:0033210), glucose homeostasis (GO:0042593), response to leptin (GO:0044321), regulation of bone remodeling (GO:0046850), regulation of transport (GO:0051049), regulation of feeding behavior (GO:0060259), energy homeostasis (GO:0097009), cell surface receptor signaling pathway via STAT (GO:0097696), bone growth (GO:0098868), positive regulation of cold-induced thermogenesis (GO:0120162), transport across blood-brain barrier (GO:0150104), system development (GO:0048731), regulation of cytokine production involved in inflammatory response (GO:1900015)

GO Molecular Function (8): transmembrane signaling receptor activity (GO:0004888), cytokine receptor activity (GO:0004896), peptide hormone binding (GO:0017046), cytokine binding (GO:0019955), leptin receptor activity (GO:0038021), identical protein binding (GO:0042802), protein binding (GO:0005515), signaling receptor activity (GO:0038023)

GO Cellular Component (6): extracellular region (GO:0005576), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), basolateral plasma membrane (GO:0016323), signaling receptor complex (GO:0043235), membrane (GO:0016020)

Reactome top-level categories

1 top-level categories:

Category	Pathways
Signal Transduction	1

GO top-level categories

53 GO namespaces:

Category	Terms
cell surface receptor signaling pathway	2
cytokine-mediated signaling pathway	2
protein binding	2
cellular anatomical structure	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
energy derivation by oxidation of organic compounds	1
endocytosis	1
signal transduction	1
multicellular organismal process	1
anatomical structure development	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
autophagy	1
negative regulation of catabolic process	1
regulation of autophagy	1
cellular response to cytokine stimulus	1
reproductive process	1
lymphocyte differentiation	1
T cell activation	1
cellular response to leptin stimulus	1
carbohydrate homeostasis	1
response to hormone	1
regulation of tissue remodeling	1
bone remodeling	1
transport	1
regulation of localization	1
feeding behavior	1
regulation of behavior	1
multicellular organismal-level homeostasis	1
organ growth	1
bone development	1
positive regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
signaling receptor activity	1
transmembrane signaling receptor activity	1
cytokine binding	1
immune receptor activity	1
hormone binding	1
cytokine receptor activity	1
leptin-mediated signaling pathway	1
binding	1
molecular transducer activity	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
basal plasma membrane	1
plasma membrane region	1
protein-containing complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 10 of 37 annotations. The rest are phylogenetic / computational / electronic (IEA).

10 experimentally-supported GO terms:

GO term	NS	Evidence
angiogenesis	BP	mutant phenotype
cell surface receptor signaling pathway via STAT	BP	direct assay
leptin-mediated signaling pathway	BP	direct assay
negative regulation of autophagy	BP	direct assay
regulation of transport	BP	direct assay
plasma membrane	CC	direct assay
signaling receptor complex	CC	direct assay
identical protein binding	MF	physical interaction
leptin receptor activity	MF	direct assay
peptide hormone binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 1,914 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LEPR	LEP	P41159	976
LEPR	POMC	P01189	881
LEPR	MC4R	P32245	875
LEPR	AGRP	O00253	870
LEPR	INS	P01308	866
LEPR	NPY	P01303	854
LEPR	STAT3	P40763	832
LEPR	LEPROT	O15243	827
LEPR	CARTPT	Q16568	789
LEPR	JAK2	O60674	768
LEPR	ADIPOQ	Q15848	755
LEPR	PCSK1	P29120	733
LEPR	STAP2	Q9UGK3	719
LEPR	LEPROTL1	O95214	707
LEPR	GHRL	Q9UBU3	701

IntAct

Human interaction partners of LEPR in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

10 partners by confidence:

Partner	Interaction type	MIscore	Records
LEP	direct interaction	0.700	3
GHSR	colocalization	0.610	3
HCRTR1	colocalization	0.580	2
LEPROT	physical association	0.540	2
PTPN11	association	0.530	2
GRB2	physical association	0.400	3
CSNK2B	physical association	0.370	1
PIN1	physical association	0.000	1
PTPRC	dephosphorylation reaction	0.000	1
PTPRJ	dephosphorylation reaction	0.000	1

BioGRID (48 interactions; top human partners by supporting records): USP8 (Proximity Label-MS; 4 records), BTNL8 (Affinity Capture-MS; 3 records), PTPN11 (Protein-RNA; 3 records), ATP6V0D1 (Affinity Capture-MS; 2 records), CDCP1 (Affinity Capture-MS; 2 records), FAM19A4 (Affinity Capture-MS; 2 records), NDN (Two-hybrid; 2 records), SCGB1D1 (Affinity Capture-MS; 2 records), SOCS3 (Reconstituted Complex; 2 records), AGO4 (Affinity Capture-MS), ANKLE2 (Affinity Capture-MS), AS3MT (Affinity Capture-MS), CSNK2B (Two-hybrid), DEFB107A (Affinity Capture-MS), ETAA1 (Synthetic Lethality)

SIGNOR signaling

showing 11 of 12 signaling interactions:

A	Effect	B	Mechanism
LEPR	“up-regulates activity”	JAK2	binding
LEPR	“up-regulates activity”	STAT3	phosphorylation
JAK2	“up-regulates activity”	LEPR	phosphorylation
LEPR	“up-regulates activity”	STAT3	binding
LEPR	“up-regulates activity”	PTPN11	binding
LEPR	“down-regulates activity”	AMPK
LEP	up-regulates	LEPR	binding
LEPR	“up-regulates quantity”	POMC
LEPR	“down-regulates quantity”	NPY
LEPR	“down-regulates quantity”	AGRP
LEPR	“up-regulates activity”	SH2B1	binding

Protein complexes (CORUM) (2)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

2 complexes by size:

Complex	Subunits	Members
★ LEPR (long)-SNX4 complex	2	LEPR, SNX4
★ Leptin receptor	1	LEPR

Ligand–receptor pairs (CellPhoneDB) (1)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

1 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
LEP	receptor

Disease & clinical

Genetic variants

Variant evidence for LEPR: 556 ClinVar records (40 pathogenic / likely pathogenic); 1 CIViC cancer variant; 5 PharmGKB clinical annotations; 77 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	21
Uncertain significance	244
Likely benign	165
Benign	54

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 40 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
421140	NM_002303.6(LEPR):c.93G>A (p.Trp31Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
1525833	NM_002303.6(LEPR):c.995-2A>G	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
596629	NM_002303.6(LEPR):c.479del (p.His160fs)	Pathogenic	criteria provided, single submitter	2
3030911	NM_002303.6(LEPR):c.1986_1990del (p.Leu663fs)	Pathogenic	criteria provided, single submitter	2
3351054	NM_002303.6(LEPR):c.1990T>A (p.Trp664Arg)	Pathogenic	criteria provided, single submitter	2
596614	NM_002303.6(LEPR):c.2296A>T (p.Lys766Ter)	Pathogenic	criteria provided, single submitter	1
2498024	NM_002303.6(LEPR):c.1874G>A (p.Trp625Ter)	Pathogenic	criteria provided, single submitter	1
2814341	NM_002303.6(LEPR):c.253dup (p.Thr85fs)	Pathogenic	criteria provided, single submitter	1
3653406	NM_002303.6(LEPR):c.395G>A (p.Trp132Ter)	Pathogenic	criteria provided, single submitter	1
4726995	NM_002303.6(LEPR):c.359_360del (p.Phe120fs)	Pathogenic	criteria provided, single submitter	1
4732471	NM_002303.6(LEPR):c.2396-2A>C	Pathogenic	criteria provided, single submitter	1
4811500	NM_002303.6(LEPR):c.1846del (p.Arg615_Leu616insTer)	Pathogenic	criteria provided, single submitter	1
453309	NM_002303.6(LEPR):c.3268_3269dup (p.Ser1090fs)	Likely pathogenic	criteria provided, single submitter	2
3340175	NM_002303.6(LEPR):c.2051A>C (p.His684Pro)	Likely pathogenic	criteria provided, single submitter	2
36465	NM_002303.6(LEPR):c.2880C>G (p.Asn960Lys)	Likely pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore LEPR’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 32 predictions of 2,992):

Position(s)	Effect	Δscore	Sites
1:65429835–65429836	acceptor_gain	1.0000	2
1:65429846–65429847	acceptor_gain	1.0000	2
1:65596446	acceptor_gain	1.0000
1:65598805–65598806	donor_loss	1.0000	3
1:65633260	donor_gain	1.0000
1:65420741–65420742	donor_loss	0.9900	5
1:65425300	acceptor_gain	0.9900
1:65425301–65425302	acceptor_loss	0.9900	6
1:65425379–65425380	donor_loss	0.9900	6
1:65596446–65596447	acceptor_loss	0.9900	5

AlphaMissense

1,089 missense substitutions predicted likely pathogenic (of 7,731 scored), across 327 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M445	9	0.893	0.981
S623	8	0.877	0.995
F500	8	0.853	0.981
C447	7	0.989	0.996
C436	7	0.987	0.995
C498	7	0.972	0.992
W883	7	0.970	0.995
W558	7	0.964	0.995
C473	7	0.962	0.980
C488	7	0.959	0.986
W368	7	0.953	0.994
W449	7	0.950	0.993
C412	7	0.949	0.985
C413	7	0.946	0.973
C418	7	0.942	0.978
C352	7	0.940	0.990
W774	7	0.939	0.988
W257	7	0.935	0.989
W512	7	0.933	0.986
W625	7	0.932	0.989

HPA cancer prognostics

RNA cancer specificity: Cancer enriched (Liver Hepatocellular Carcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	5.17e-07

Disease associations

OMIM: gene MIM:601007 | disease phenotypes: MIM:614963 (Leptin receptor deficiency)

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
obesity due to leptin receptor gene deficiency	Strong	Autosomal recessive	4

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (2 panels, 2 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

2 panels:

Panel	Rating
Hypogonadotropic hypogonadism (GMS)	green
Severe early-onset obesity	green

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

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

HPO phenotypes

32 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000712	Emotional lability
HP:0000718	Aggressive behavior
HP:0000771	Gynecomastia
HP:0000786	Primary amenorrhea
HP:0000815	Hypergonadotropic hypogonadism
HP:0000819	Diabetes mellitus
HP:0000823	Delayed puberty
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000831	Insulin-resistant diabetes mellitus
HP:0000842	Hyperinsulinemia
HP:0001249	Intellectual disability
HP:0001513	Obesity
HP:0002155	Hypertriglyceridemia
HP:0002591	Polyphagia
HP:0002788	Recurrent upper respiratory tract infections
HP:0002958	Immune dysregulation
HP:0003292	Decreased serum leptin
HP:0003593	Infantile onset
HP:0004322	Short stature
HP:0004926	Orthostatic hypotension due to autonomic dysfunction
HP:0005419	Decreased T cell activation
HP:0005616	Accelerated skeletal maturation
HP:0008187	Absence of secondary sex characteristics
HP:0008214	Decreased serum estradiol
HP:0008245	Pituitary hypothyroidism
HP:0008724	Hypoplasia of the ovary
HP:0008734	Decreased testicular size
HP:0012286	Abnormal hypothalamus morphology
HP:0032218	Decreased total CD4+ T cell proportion
HP:0040171	Decreased serum testosterone concentration
HP:0100738	Abnormal eating behavior

GWAS associations

showing 30 of 77 associations:

Study	Trait	p-value
GCST006585_1648	Blood protein levels	0.000000e+00
GCST007614_38	C-reactive protein levels	2e-183
GCST007614_24	C-reactive protein levels	2e-162
GCST007615_68	C-reactive protein levels	1e-153
GCST007615_34	C-reactive protein levels	6e-133
GCST007615_33	C-reactive protein levels	2e-89
GCST000965_8	C-reactive protein levels	4e-62
GCST007615_32	C-reactive protein levels	5e-49
GCST011350_2	C-reactive protein levels	4e-44
GCST007614_29	C-reactive protein levels	2e-39
GCST004614_134	Granulocyte count	4e-37
GCST003681_1	C-reactive protein levels or triglyceride levels (pleiotropy)	8e-36
GCST004626_163	Myeloid white cell count	8e-36
GCST90002398_434	Neutrophil count	4e-23
GCST90002400_418	Plateletcrit	6e-22
GCST009291_1	BMI at 6 months old	2e-21
GCST000178_2	C-reactive protein	7e-21
GCST90002407_6	White blood cell count	1e-20
GCST009294_1	BMI at 1 year old	3e-20
GCST004629_32	Neutrophil count	5e-20
GCST004620_126	Sum basophil neutrophil counts	8e-20
GCST004613_62	Sum neutrophil eosinophil counts	9e-20
GCST004614_133	Granulocyte count	1e-19
GCST90002399_90	Neutrophil percentage of white cells	4e-19
GCST004626_162	Myeloid white cell count	8e-19
GCST010989_131	Body size at age 10	1e-18
GCST012480_1	C-reactive protein levels	4e-18
GCST90011900_119	Serum alkaline phosphatase levels	1e-17
GCST90002390_479	Mean corpuscular hemoglobin	3e-17
GCST90002399_89	Neutrophil percentage of white cells	6e-17

EFO canonical traits (from GWAS)

25 canonical traits:

EFO ID	Trait name
EFO:0004458	C-reactive protein measurement
EFO:0004635	leptin receptor measurement
EFO:0004703	age at menarche
EFO:0004530	triglyceride measurement
EFO:0007888	age at voice drop
EFO:0004833	neutrophil count
EFO:0004842	eosinophil count
EFO:0007987	granulocyte count
EFO:0005090	basophil count
EFO:0004527	mean corpuscular hemoglobin
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0004340	body mass index
EFO:0005937	longitudinal BMI measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004509	hemoglobin measurement
EFO:0007989	monocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes
EFO:0007985	platelet crit
EFO:0004309	platelet count
EFO:0004736	aspartate aminotransferase measurement
EFO:0004533	alkaline phosphatase measurement
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5913 (SINGLE PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the LEPR protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

2 curated-mechanism drugs:

Drug	Modality	Max phase
METRELEPTIN	Protein	4
MIBAVADEMAB	Antibody	2

CIViC curated variants (1)

Named clinical variants curated in CIViC for this gene (the catalogue beneath the predictive evidence above):

UNDEREXPRESSION.

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

5 annotations by evidence level (1 strongest → 4):

Variant	Association	Level	Drugs	Phenotypes
rs1137101	Efficacy	3	simvastatin	Coronary Disease
rs1137101	Efficacy	3	simvastatin	Hyperlipidemias
rs1137101	Toxicity	3	valproic acid	Epilepsy
rs1137101	Toxicity	3	antipsychotics
rs1805094	Efficacy	3	atorvastatin	Acute coronary syndrome

PharmGKB variants

2 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

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

13 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs1805094	atorvastatin	Other	Genotype GG is associated with increased bone marrow density in the lumbar spine when treated with atorvastatin in people with Acute coronary syndrome.	PMID:19023160
rs1137101	valproic acid	Toxicity	Genotypes AA + AG is associated with increased Weight gain when treated with valproic acid in people with Epilepsy as compared to genotype GG.	PMID:25740917
rs1137101	clozapine	Toxicity	Genotypes AG + GG is associated with increased likelihood of Metabolic Syndrome when treated with clozapine in people with Schizophrenia as compared to genotype AA.	PMID:27681143
rs1045895	apremilast	Efficacy	Genotypes AA + AG is associated with decreased clinical benefit to apremilast in people with Psoriasis as compared to genotype GG.	PMID:38540428
rs1137101	valproic acid	Toxicity	Genotypes AG + GG is associated with increased severity of Weight gain when treated with valproic acid in people with Epilepsy as compared to genotype AA.	PMID:39539630
rs1137101	valproic acid	Toxicity	Genotypes AG + GG is associated with increased likelihood of Alopecia when treated with valproic acid in people with Epilepsy as compared to genotype AA.	PMID:39539630
rs6657868	clozapine	Toxicity	Genotypes AG + GG is associated with increased risk of Pneumonia when treated with clozapine in people with Schizophrenia or Schizoaffective disorder as compared to genotype AA.	PMID:40081291
rs9436746	clozapine	Toxicity	Genotypes AC + CC is associated with increased risk of Pneumonia when treated with clozapine in people with Schizophrenia or Schizoaffective disorder as compared to genotype AA.	PMID:40081291
rs1137101	clozapine	Toxicity	Genotype AA is associated with increased risk of Pneumonia when treated with clozapine in people with Schizophrenia or Schizoaffective disorder as compared to genotypes AG + GG.	PMID:40081291
rs1805096	clozapine	Toxicity	Genotype GG is associated with increased risk of Pneumonia when treated with clozapine in people with Schizophrenia or Schizoaffective disorder as compared to genotypes AA + AG.	PMID:40081291
rs1137101	antipsychotics	Other	Allele G is associated with increased likelihood of Obesity when treated with antipsychotics in women as compared to allele A.	PMID:21510767
rs1137101	simvastatin	Efficacy	Genotype GG is associated with decreased response to simvastatin in men with Hyperlipidemias as compared to genotypes AA + AG.	PMID:14625131
rs1137101	simvastatin	Efficacy	Genotype GG is associated with increased percentage change in HDL-C levels when treated with simvastatin in people with Coronary Disease as compared to genotype AA.	PMID:18854995

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — IL-6 receptor family

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
leptin	Agonist	10.19	pKd

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	4
methylmercuric chloride	decreases expression, increases expression	2
bisphenol A	decreases methylation, increases expression	2
trichostatin A	decreases expression	2
methacrylaldehyde	increases abundance, affects cotreatment, increases expression, increases oxidation	2
Acrolein	affects cotreatment, increases expression, increases oxidation, increases abundance	2
Air Pollutants	increases expression, increases oxidation, affects cotreatment, increases abundance	2
Arsenic	affects methylation, decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Ozone	increases abundance, affects cotreatment, increases expression, increases oxidation	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
Tetrachlorodibenzodioxin	increases expression, affects expression	2
Simvastatin	affects response to substance	2
Particulate Matter	increases expression, decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases expression, increases oxidation, increases abundance	1
pirinixic acid	affects binding, increases activity, increases expression	1
lead acetate	decreases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
1-aminomethylphosphonic acid	decreases expression	1
pentanal	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	increases expression, affects cotreatment	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1291112	Binding	Displacement of [125I]-Leptin from leptin receptor at 1 to 3 uM	Conformationally constrained NR2B selective NMDA receptor antagonists derived from ifenprodil: Synthesis and biological evaluation of tetrahydro-3-benzazepine-1,7-diols. — *Bioorg Med Chem*

Cellosaurus cell lines

7 cell lines: 4 cancer cell line, 1 hybrid cell line, 1 transformed cell line, 1 factor-dependent cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_4457	SN-56/OBR	Hybrid cell line
CVCL_D7TH	Ubigene A-549 LEPR KO	Cancer cell line	Male
CVCL_D8P6	Ubigene HCT 116 LEPR KO	Cancer cell line	Male
CVCL_D9II	Ubigene HEK293 LEPR KO	Transformed cell line	Female
CVCL_E0GF	Ubigene HeLa LEPR KO	Cancer cell line	Female
CVCL_K248	Baf3/WSX E63x7 sort	Factor-dependent cell line
CVCL_SV45	HAP1 LEPR (-)	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT00328926	Phase 4	TERMINATED	Luveris® (Lutropin Alfa for Injection) in Women With Hypogonadotropic Hypogonadism (Luteinizing Hormone [LH] Less Than [<] 1.2 International Unit Per Liter [IU/L])
NCT01403532	Phase 4	COMPLETED	Sequential Therapy for Hypogonadotropic Hypogonadism
NCT01454011	Phase 4	COMPLETED	The Effect of Testosterone Replacement on the High Density Lipoprotein Cholesterol Subgroups
NCT01601327	Phase 4	COMPLETED	Effects of Medications in Patients With Hypogonadism
NCT02310074	Phase 4	UNKNOWN	Efficacy and Safety of Pulsatile Gonadotropin Releasing Hormone Pump Treatment in Patients With Idiopathic Hypogonadotropic Hypogonadism
NCT02880280	Phase 4	UNKNOWN	Human Menopausal Gonadotropin Combining With Human Chorionic Gonadotropin Treat Congenital Hypogonadotropic Hypogonadism
NCT03490513	Phase 4	COMPLETED	Aromatase Inhibitors and Weight Loss in Severely Obese Men With Hypogonadism
NCT04456296	Phase 4	COMPLETED	A Study of the Effect of Testosterone Replacement Therapy on Blood Pressure in Adult Male Participants With Hypogonadism
NCT05205837	Phase 4	TERMINATED	A Randomized, Double-blinded, Clinical, Placebo-controlled Trial on the Effects of Therapy With Letrozole and hUman Choriongonadotropin in Male Hypogonadism Induced by Illicit Use of Anabolic Androgenic Steroids- The LUCAS Trial
NCT00076362	Phase 4	COMPLETED	Pediatric Hypothalamic Obesity
NCT00079547	Phase 4	COMPLETED	The Safety and Effectiveness of Low and High Carbohydrate Diets
NCT00115063	Phase 4	TERMINATED	LOSS- Louisiana Obese Subjects Study
NCT00134303	Phase 4	COMPLETED	Trial Comparing Metformin Versus Placebo in Non Alcoholic Steatohepatitis (NASH) Patients Receiving Bariatric Surgery for Obesity
NCT00143936	Phase 4	COMPLETED	The Safety and Efficacy of Low and High Carbohydrate Diets
NCT00143962	Phase 4	COMPLETED	Comparison of Two Approaches to Weight Loss Follow-Up Study
NCT00152360	Phase 4	COMPLETED	The Effect of Xenical on Weight and Risk Factors
NCT00176306	Phase 4	COMPLETED	Levofloxacin Pharmacokinetics (PK) in the Severely Obese
NCT00203450	Phase 4	COMPLETED	Zonegran for the Treatment of Weight Gain Associated With Psychotropic Medication Use: A Placebo-Controlled Trial
NCT00205504	Phase 4	COMPLETED	Oral Contraceptives in the Metabolic Syndrome
NCT00229229	Phase 4	TERMINATED	Comparison of 4 Diets in the Management of Overweight Patients With Vascular Disease
NCT00234988	Phase 4	COMPLETED	A Phase IV, Multi-Center, Open-Label Trial of Sibutramine in Combination With a Hypocaloric Diet in Obese and Overweight Thai Subjects.
NCT00264589	Phase 4	COMPLETED	Exercise Training and Cardiovascular Function in Obesity and in Type 2 Diabetes
NCT00288873	Phase 4	COMPLETED	Characterization of Hyperparathyroidism and Vitamin D Deficiency in Obesity
NCT00298857	Phase 4	TERMINATED	A Pharmacokinetic Study to Compare the Dosing of Valproic Acid in Subjects With Different Body Weights
NCT00315146	Phase 4	COMPLETED	Optimizing Body Composition for Function in Older Adults
NCT00319202	Phase 4	TERMINATED	Clinical Trial to Assess the Effects of Candesartan on the Carbohydrate Metabolism of Obese Subjects
NCT00327912	Phase 4	UNKNOWN	Laparoscopic Roux-en-Y Gastric Bypass Versus Laparoscopic Biliopancreatic Diversion (BPD)- Duodenal Switch for Superobesity
NCT00352287	Phase 4	COMPLETED	Study to Determine the Effects of Human Growth Hormone and Pioglitazone in Overweight, Prediabetic Adults
NCT00353054	Phase 4	COMPLETED	Effect of Calcium/Vitamin D Supplementation on Body Weight and Fat Loss.
NCT00390637	Phase 4	COMPLETED	Diet, Obesity and Genes (DiOGenes)
NCT00415688	Phase 4	COMPLETED	Lifestyle Modification for Obesity-Related Type 2 Diabetes
NCT00433641	Phase 4	COMPLETED	Weight Loss in Response to Sibutramine (MERIDIA) is Influenced by the Inherited Genes
NCT00440375	Phase 4	COMPLETED	Effects of Rosiglitazone on Bone in Postmenopausal Diabetic Women
NCT00453557	Phase 4	COMPLETED	Mechanism of Growth Hormone Effects on Adipose Tissue
NCT00456885	Phase 4	COMPLETED	The Effect of Exenatide on Weight and Hunger in Obese, Healthy Women
NCT00463112	Phase 4	COMPLETED	Effect of Diet Plus Sibutramine on Hormonal and Metabolic Features in Overweight and Obese Women With PCOS
NCT00512187	Phase 4	COMPLETED	Moderate Weight Loss Makes Obese Patients With Severe Chronic Plaque Psoriasis Responsive to Sub-Optimal Dose of Cyclosporine: an Investigator Blinded, Controlled, Randomized Clinical Trial
NCT00516919	Phase 4	COMPLETED	Study of Behavioral Weight Loss Therapy for Obesity and Binge Eating in Monolingual Hispanic Persons
NCT00522470	Phase 4	COMPLETED	Effects of Rosiglitazone on Serum Ghrelin and Peptide YY Levels
NCT00537810	Phase 4	COMPLETED	Treatment of Binge Eating in Obese Patients in Primary Care
NCT00538486	Phase 4	COMPLETED	A Randomized, Double-Blind, Active Control Trial Comparing Effects of Telmisartan, Candesartan and Amlodipine, Alone or Plus Metformin, on Non-Diabetic, Obese Hypertensive Patients
NCT00584389	Phase 4	TERMINATED	The Effect of Rimonabant on Energy Expenditure, Fat Metabolism and Body Composition
NCT00585182	Phase 4	COMPLETED	Study to Evaluate Weight-based Enoxaparin Dosing in Obese Medical Patients at Risk for DVT
NCT00632840	Phase 4	COMPLETED	Pharmacological Regulation of Fat Transport in Metabolic Syndrome
NCT00636142	Phase 4	COMPLETED	Effects of Infliximab on Insulin Sensitivity and Beta Cell Function in Insulin Resistant Human Obesity
NCT00675987	Phase 4	COMPLETED	A Randomized Clinical Trial To Study Losartan On Endothelial Dysfunction and Insulin Resistance In Obese Patients
NCT00694811	Phase 4	COMPLETED	Effects of Re-Feeding Duration on Weight Maintenance After Weight Loss With Very-Low-Energy Diets (VLEDs)
NCT00699413	Phase 4	TERMINATED	Supplements for Controlling Resistance to Insulin
NCT00729963	Phase 4	COMPLETED	Sibutramine Versus Continuous Positive Airway Pressure (CPAP)in Obstructive Sleep Apnea (OSA) Patients
NCT00752726	Phase 4	COMPLETED	Effect of Orlistat in Body Composition
NCT00770328	Phase 4	COMPLETED	The Effects of Pentoxifylline on PAI-1 in an Obese Population
NCT00775164	Phase 4	WITHDRAWN	Pioglitazone Therapy in Obese Children With Insulin Resistance: A Randomized, Controlled Pilot Study
NCT00775814	Phase 4	COMPLETED	Efficacy of Candesartan on Reducing Blood Pressure in Insulin-Resistant, Obese Patients With Hypertension.
NCT00779844	Phase 4	TERMINATED	Anesthesic Propofol and Remifentanil Requirements in Obese Patients
NCT00788840	Phase 4	COMPLETED	Detemir Energy Expenditure Study
NCT00790946	Phase 4	UNKNOWN	Kagoshima Collaborate Trial in Metabolic Syndrome (KACT Study)
NCT00841217	Phase 4	COMPLETED	Regulation of Lipoprotein Transport in Metabolic Syndrome
NCT00845559	Phase 4	WITHDRAWN	The Effects of Exenatide on Post-Meal Sugar Peaks and Vascular Health in Obese/Pre-Diabetic Young Adults
NCT00847262	Phase 4	COMPLETED	Trial Comparing Metabolic Effects of Telmisartan and Amlodipine on Hypertensive Patients With Obesity and Diabetes
NCT00852384	Phase 4	COMPLETED	Non Invasive Pressure Support Ventilation (NIPPV) Versus Recruitment Maneuver (RM) and Preoxygenation