LEPR

protein-coding

leptin receptor, the group of CD molecules|Immunoglobulin like domain containing

Gene summary

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).[provided by RefSeq, Nov 2010]

MANE transcript

NM_002303.6

Inheritance

ClinVar variants

P:55U:327B:154

Top phenotype

Leptin receptor deficiency

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr1:65,420,652-65,641,559

External References & Databases

Ensembl (ENSG00000116678)

Transcript & Mutation Effects

hg38 • Region Span ~220.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

obesity due to leptin receptor gene deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013992

Submitter: Orphanet

obesity due to leptin receptor gene deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013992

Submitter: Labcorp Genetics (formerly Invitae)

obesity due to leptin receptor gene deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013992

Submitter: Genomics England PanelApp

obesity due to leptin receptor gene deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013992

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Leptin receptor deficiencyAR

Manifestation: Allergy/Immunology/Infectious; Endocrine

Intervention: Allergy/Immunology/Infectious; Endocrine

Rationale: In addition to endocrine manifestations, individuals may be susceptible to infections (eg, respiratory infections), which, coupled with other manifestations (eg, severe obesity) can have severe sequelae such that prophylaxis and rapid treatment may be beneficial; Medical management of obesity with melanocortin-4 receptor (MC4R) agonist (setmelanotide) may be beneficial

Comments: Standard treatments for obesity, such as gastric surgery, have been described as beneficial

Refs: 8666155; 9537324; 17229951; 21306929; 23275530; 23616257; 35528826

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LEPR variants in ClinVar

13 Conditions Cataloged

LEPR-related disorderTotal: 479

not providedTotal: 157

Inborn genetic diseasesTotal: 97

Obesity due to leptin receptor gene deficiencyTotal: 59

not specifiedTotal: 44

Monogenic diabetesTotal: 13

Early onset severe obesityTotal: 6

ObesityTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002303.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			12 clinvar	116 clinvar	3 clinvar	131
missense	1 clinvar	11 clinvar	308 clinvar	34 clinvar	1 clinvar	355
nonsense	5 clinvar	12 clinvar	1 clinvar			18
start loss		1 clinvar				1
frameshift	6 clinvar	10 clinvar	3 clinvar			19
splice donor/acceptor (+/-2bp)	3 clinvar	6 clinvar	3 clinvar			12
Total	15	40	327	150	4	536

Highest pathogenic variant AF is 0.00038719253

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002303.6	RefSeq	NP_002294.2	18	MANE Select
ENST00000349533.11	Ensembl	ENSP00000330393.7	18	MANE Select
NM_001003679.3	RefSeq	NP_001003679.1	18	Standard
NM_001003680.3	RefSeq	NP_001003680.1	18	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
lepr	Danio rerio	Structure: secondary motor neuron Quality: branchiness abnormal

Gene / Model

Organism

Observed Phenotype

lepr

Danio rerio

Structure: secondary motor neuron

Quality: branchiness

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Adipocytokine signaling pathway - Homo sapiens (human)
Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human)
Jak-STAT signaling pathway - Homo sapiens (human)
AMPK signaling pathway - Homo sapiens (human)
Neuroactive ligand-receptor interaction - Homo sapiens (human)

Biological Process

angiogenesis
energy reserve metabolic process
phagocytosis
cell surface receptor signaling pathway
multicellular organism development

Molecular Function

transmembrane signaling receptor activity
cytokine receptor activity
protein binding
peptide hormone binding
cytokine binding

Cellular Component

extracellular region
external side of plasma membrane
integral component of membrane
basolateral plasma membrane
receptor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000349533
Coding exons: 18
Length: 220995
Individuals with no LoFs: 125718
Homozygous LoFs: 0
Heterozygous LoFs: 28
Defined: 125746
p: 0.000111

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.42	490	587	0.835	0.0000275	7702
Missense (PolyPhen)		88	133.57	0.65885		1797
Synonymous	0.266	204	209	0.977	0.0000103	2122
Loss of Function	5.77	9	55.3	0.163	0.00000242	755

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00012	0.00012	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor for hormone LEP/leptin (Probable) (PubMed:22405007). 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 (By similarity) (PubMed:9537324). 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 (PubMed:25060689, PubMed:12504075, PubMed:8805376). 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 (By similarity). {ECO:0000250|UniProtKB:P48356, ECO:0000269|PubMed:12504075, ECO:0000269|PubMed:22405007, ECO:0000269|PubMed:25060689, ECO:0000269|PubMed:8805376, ECO:0000269|PubMed:9537324, ECO:0000305|PubMed:25232147}.; FUNCTION: Isoform E: Antagonizes Isoform A and isoform B-mediated LEP binding and endocytosis. {ECO:0000250|UniProtKB:P48356}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:25751111, ECO:0000269|PubMed:9537324}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0824

Intolerance Scores

LoFtool: 0.609
RVIS EVS: -0.22
RVIS percentile EVS: 37.7

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.964

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium