Obesity due to leptin receptor gene deficiency

Summary

Obesity due to leptin receptor gene deficiency (MONDO:0013992) is a disease caused by LEPR (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: LEPR (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 74
• Phenotypes (HPO): 21

Clinical features

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0001513	Obesity	Obligate (100%)
HP:0003292	Decreased serum leptin	Obligate (100%)
HP:0000771	Gynecomastia	Very frequent (80-99%)
HP:0000786	Primary amenorrhea	Very frequent (80-99%)
HP:0000815	Hypergonadotropic hypogonadism	Very frequent (80-99%)
HP:0000842	Hyperinsulinemia	Very frequent (80-99%)
HP:0002591	Polyphagia	Very frequent (80-99%)
HP:0005419	Decreased T cell activation	Very frequent (80-99%)
HP:0008187	Absence of secondary sex characteristics	Very frequent (80-99%)
HP:0008214	Decreased serum estradiol	Very frequent (80-99%)
HP:0008724	Hypoplasia of the ovary	Very frequent (80-99%)
HP:0008734	Decreased testicular size	Very frequent (80-99%)
HP:0032218	Decreased proportion of CD4-positive T cells	Very frequent (80-99%)
HP:0040171	Decreased serum testosterone concentration	Very frequent (80-99%)
HP:0000712	Emotional lability	Frequent (30-79%)
HP:0000831	Insulin-resistant diabetes mellitus	Frequent (30-79%)
HP:0002155	Hypertriglyceridemia	Frequent (30-79%)
HP:0002788	Recurrent upper respiratory tract infections	Frequent (30-79%)
HP:0004926	Orthostatic hypotension due to autonomic dysfunction	Frequent (30-79%)
HP:0005616	Accelerated skeletal maturation	Frequent (30-79%)
HP:0008245	Pituitary hypothyroidism	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	obesity due to leptin receptor gene deficiency
Mondo ID	MONDO:0013992
OMIM	614963
Orphanet	179494
ICD-11	997823205
NCIT	C120386
UMLS	C3554225
MedGen	767139
GARD	0017083
NORD	109401
Is cancer (heuristic)	no

Also known as: LEPR Deficiency · obesity due to leptin receptor gene deficiency · obesity, morbid, due to leptin receptor deficiency

Data availability: 74 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › gonadal disorder › hypogonadism › hypogonadotropic hypogonadism › congenital hypogonadotropic hypogonadism › obesity due to leptin receptor gene deficiency

Related subtypes (24): brachytelephalangy-dysmorphism-Kallmann syndrome, hypogonadotropic hypogonadism 7 with or without anosmia, Prader-Willi syndrome, familial adrenal hypoplasia with absent pituitary luteinizing hormone, cerebellar ataxia-hypogonadism syndrome, CHARGE syndrome, ataxia-hypogonadism-choroidal dystrophy syndrome, Woodhouse-Sakati syndrome, Laurence-Moon syndrome, X-linked adrenal hypoplasia congenita, obesity due to prohormone convertase I deficiency, arhinia, choanal atresia, and microphthalmia, ANE syndrome, combined pituitary hormone deficiencies, genetic form, obesity due to congenital leptin deficiency, polyendocrine-polyneuropathy syndrome, hypogonadotropic hypogonadism-frontoparietal alopecia syndrome, hypogonadotropic hypogonadism-retinitis pigmentosa syndrome, Kallmann syndrome-heart disease syndrome, isolated congenital hypogonadotropic hypogonadism, Moebius syndrome-axonal neuropathy-hypogonadotropic hypogonadism syndrome, hypogonadotropic hypogonadism-severe microcephaly-sensorineural hearing loss-dysmorphism syndrome, Prader-Willi-like syndrome, Martsolf syndrome 1

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

74 retrieved; paginated sample, class counts are floors:

38 uncertain significance, 18 conflicting classifications of pathogenicity, 5 benign/likely benign, 4 benign, 4 pathogenic, 2 pathogenic/likely pathogenic, 2 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1679174	NM_002303.6(LEPR):c.133_136dup (p.Tyr46Ter)	LEPR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
453309	NM_002303.6(LEPR):c.3268_3269dup (p.Ser1090fs)	LEPR	Pathogenic	no assertion criteria provided
619954	NM_002303.6(LEPR):c.464A>C (p.Tyr155Ser)	LEPR	Pathogenic	no assertion criteria provided
631614	NM_002303.6(LEPR):c.1835G>A (p.Arg612His)	LEPR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
666597	Single allele	LEPR	Pathogenic	criteria provided, single submitter
8522	NM_002303.6(LEPR):c.2597+1G>A	LEPR	Pathogenic	no assertion criteria provided
3359113	NM_002303.6(LEPR):c.1967dup (p.Glu657fs)	LEPR	Likely pathogenic	criteria provided, single submitter
3779815	NM_002303.6(LEPR):c.3439dup (p.Thr1147fs)	LEPR	Likely pathogenic	criteria provided, single submitter
1901927	NM_002303.6(LEPR):c.575A>C (p.Glu192Ala)	LEPR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297986	NM_002303.6(LEPR):c.371A>G (p.Asp124Gly)	LEPR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297990	NM_002303.6(LEPR):c.921G>C (p.Gln307His)	LEPR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297997	NM_002303.6(LEPR):c.2698A>G (p.Ile900Val)	LEPR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
298001	NM_002303.6(LEPR):c.3078T>C (p.Asn1026=)	LEPR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3639329	NM_002303.6(LEPR):c.1232A>G (p.Tyr411Cys)	LEPR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
36466	NM_002303.6(LEPR):c.3417A>G (p.Ala1139=)	LEPR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
727197	NM_002303.6(LEPR):c.36T>C (p.His12=)	LEPR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
730209	NM_002303.6(LEPR):c.2370A>C (p.Ser790=)	LEPR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
874014	NM_002303.6(LEPR):c.1018A>G (p.Ile340Val)	LEPR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
874015	NM_002303.6(LEPR):c.1030G>A (p.Val344Ile)	LEPR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
875834	NM_002303.6(LEPR):c.371-9T>A	LEPR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
875835	NM_002303.6(LEPR):c.594G>A (p.Val198=)	LEPR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
875881	NM_002303.6(LEPR):c.2171T>C (p.Val724Ala)	LEPR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
875883	NM_002303.6(LEPR):c.2260G>A (p.Val754Met)	LEPR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
876875	NM_002303.6(LEPR):c.3041C>G (p.Ser1014Cys)	LEPR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
917430	NM_002303.6(LEPR):c.2918C>A (p.Thr973Asn)	LEPR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
931429	NM_002303.6(LEPR):c.2221G>A (p.Val741Met)	LEPR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1339320	NM_002303.6(LEPR):c.2674-5935A>C	LEPR	Uncertain significance	criteria provided, single submitter
1709580	NM_002303.6(LEPR):c.421A>G (p.Ile141Val)	LEPR	Uncertain significance	criteria provided, single submitter
2502174	NM_002303.6(LEPR):c.346A>C (p.Asn116His)	LEPR	Uncertain significance	criteria provided, single submitter
2502175	NM_002303.6(LEPR):c.976C>T (p.Arg326Cys)	LEPR	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LEPR	Orphanet:179494	Obesity due to leptin receptor gene deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LEPR	HGNC:6554	ENSG00000116678	P48357	Leptin receptor	gencc,clinvar
LEPROT	HGNC:29477	ENSG00000213625	O15243	Leptin receptor gene-related protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LEPR	Leptin receptor	Receptor for hormone LEP/leptin.
LEPROT	Leptin receptor gene-related protein	Negatively regulates leptin receptor (LEPR) cell surface expression, and thus decreases response to leptin.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LEPR	Antibody/Immunoglobulin	yes		Hematopoietin_rcpt_Gp130_CS, Hempt_rcpt_S_F1_CS, FN3_dom
LEPROT	Other/Unknown	no		Vps55/LEPROT

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
choroid plexus epithelium	1
trabecular bone tissue	1
trigeminal ganglion	1
metanephric glomerulus	1
renal glomerulus	1
visceral pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LEPR	272	broad	marker	trabecular bone tissue, choroid plexus epithelium, trigeminal ganglion
LEPROT	295	ubiquitous	marker	metanephric glomerulus, renal glomerulus, visceral pleura

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LEPR	2,243
LEPROT	587

Intra-cohort edges

A	B	Sources
LEPR	LEPROT	intact, string_interaction

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LEPR	P48357	9

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LEPROT	O15243	80.89

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by Leptin	1	1038.2×	1e-03	LEPR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
multicellular organism development	1	4213.0×	0.003	LEPR
regulation of transport	1	4213.0×	0.003	LEPR
sexual reproduction	1	2808.7×	0.003	LEPR
negative regulation of growth hormone receptor signaling pathway	1	1685.2×	0.003	LEPROT
regulation of bone remodeling	1	1404.3×	0.003	LEPR
leptin-mediated signaling pathway	1	1203.7×	0.003	LEPR
response to leptin	1	1203.7×	0.003	LEPR
bone growth	1	1203.7×	0.003	LEPR
regulation of feeding behavior	1	936.2×	0.004	LEPR
late endosome to vacuole transport via multivesicular body sorting pathway	1	766.0×	0.004	LEPROT
negative regulation of protein localization to cell surface	1	648.1×	0.004	LEPROT
energy reserve metabolic process	1	526.6×	0.005	LEPR
glial cell proliferation	1	443.5×	0.005	LEPR
negative regulation of receptor signaling pathway via JAK-STAT	1	443.5×	0.005	LEPROT
negative regulation of gluconeogenesis	1	401.2×	0.005	LEPR
cell surface receptor signaling pathway via STAT	1	280.9×	0.007	LEPR
glycogen metabolic process	1	263.3×	0.007	LEPR
obsolete positive regulation of protein targeting to mitochondrion	1	247.8×	0.007	LEPROT
T cell differentiation	1	191.5×	0.009	LEPR
gluconeogenesis	1	162.0×	0.010	LEPR
energy homeostasis	1	135.9×	0.011	LEPR
negative regulation of autophagy	1	129.6×	0.011	LEPR
phagocytosis	1	120.4×	0.011	LEPR
cholesterol metabolic process	1	98.0×	0.013	LEPR
transport across blood-brain barrier	1	89.6×	0.014	LEPR
positive regulation of cold-induced thermogenesis	1	81.8×	0.015	LEPR
cytokine-mediated signaling pathway	1	65.3×	0.017	LEPR
glucose homeostasis	1	65.3×	0.017	LEPR
cell surface receptor signaling pathway	1	32.0×	0.033	LEPR
angiogenesis	1	31.2×	0.033	LEPR

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LEPR	0	0
LEPROT	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
LEPR	3	Binding:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	LEPR
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	LEPROT

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
LEPR	3	—
LEPROT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.