hyperinsulinism due to UCP2 deficiency

Summary

hyperinsulinism due to UCP2 deficiency (MONDO:0017183) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• Phenotypes (HPO): 26

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0000825	Hyperinsulinemic hypoglycemia	Very frequent (80-99%)
HP:0001985	Hypoketotic hypoglycemia	Very frequent (80-99%)
HP:0001988	Recurrent hypoglycemia	Very frequent (80-99%)
HP:0012051	Reactive hypoglycemia	Very frequent (80-99%)
HP:0030796	Increased C-peptide level	Very frequent (80-99%)
HP:0031084	Excessive insulin response to glucagon test	Very frequent (80-99%)
HP:0040299	Decreased circulating free fatty acid level	Very frequent (80-99%)
HP:0000713	Agitation	Frequent (30-79%)
HP:0000980	Pallor	Frequent (30-79%)
HP:0001069	Episodic hyperhidrosis	Frequent (30-79%)
HP:0001520	Large for gestational age	Frequent (30-79%)
HP:0001649	Tachycardia	Frequent (30-79%)
HP:0001962	Palpitations	Frequent (30-79%)
HP:0002329	Drowsiness	Frequent (30-79%)
HP:0012759	Neurodevelopmental abnormality	Frequent (30-79%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0001279	Syncope	Occasional (5-29%)
HP:0001325	Hypoglycemic coma	Occasional (5-29%)
HP:0001639	Hypertrophic cardiomyopathy	Occasional (5-29%)
HP:0002133	Status epilepticus	Occasional (5-29%)
HP:0002173	Hypoglycemic seizures	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0002591	Polyphagia	Occasional (5-29%)
HP:0007185	Loss of consciousness	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0031224	Diffuse pancreatic islet hyperplasia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperinsulinism due to UCP2 deficiency
Mondo ID	MONDO:0017183
Orphanet	276556
SNOMED CT	721834007
UMLS	C4303082
MedGen	928751
GARD	0021054
Is cancer (heuristic)	no

Also known as: hyperinsulinemic hypoglycemia due to UCP2 deficiency

Data availability: 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › pancreas disorder › endocrine pancreas disorder › islet cell adenomatosis › congenital isolated hyperinsulinism › diazoxide-sensitive diffuse hyperinsulinism › hyperinsulinism due to UCP2 deficiency

Related subtypes (7): hyperinsulinism-hyperammonemia syndrome, hyperinsulinemic hypoglycemia, familial, 4, exercise-induced hyperinsulinism, hyperinsulinism due to HNF4A deficiency, autosomal dominant hyperinsulinism due to SUR1 deficiency, autosomal dominant hyperinsulinism due to Kir6.2 deficiency, hyperinsulinism due to HNF1A deficiency

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · 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
UCP2	Moderate	Autosomal dominant	hyperinsulinism due to UCP2 deficiency	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
UCP2	Orphanet:276556	Hyperinsulinism due to UCP2 deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
UCP2	HGNC:12518	ENSG00000175567	P55851	Dicarboxylate carrier SLC25A8	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
UCP2	Dicarboxylate carrier SLC25A8	Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria, a process driven by mitochondrial motive force with an overall impact on glycolysis,…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Transporter	1	77.8×	0.013

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
UCP2	Transporter	yes		MCP, MCP_transmembrane, MCP_dom_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	1
epithelium of bronchus	1
granulocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
UCP2	291	ubiquitous	marker	granulocyte, bronchial epithelial cell, epithelium of bronchus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
UCP2	2,154

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
UCP2	P55851	62.63

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 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
The fatty acid cycling model	1	2284.0×	4e-04	UCP2

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
C4-dicarboxylate transport	1	16852.0×	0.001	UCP2
cellular response to lead ion	1	5617.3×	0.001	UCP2
negative regulation of calcium import into the mitochondrion	1	5617.3×	0.001	UCP2
response to superoxide	1	3370.4×	0.002	UCP2
negative regulation of insulin secretion involved in cellular response to glucose stimulus	1	1685.2×	0.002	UCP2
mitochondrial transmembrane transport	1	1685.2×	0.002	UCP2
L-glutamine metabolic process	1	1296.3×	0.002	UCP2
response to dexamethasone	1	1203.7×	0.002	UCP2
long-chain fatty acid transport	1	1123.5×	0.002	UCP2
mitochondrial fission	1	1053.2×	0.002	UCP2
response to fatty acid	1	1053.2×	0.002	UCP2
adaptive thermogenesis	1	1053.2×	0.002	UCP2
response to cold	1	561.7×	0.003	UCP2
regulation of mitochondrial membrane potential	1	543.6×	0.003	UCP2
liver regeneration	1	510.7×	0.003	UCP2
macrophage differentiation	1	468.1×	0.003	UCP2
reactive oxygen species metabolic process	1	468.1×	0.003	UCP2
glycolytic process	1	383.0×	0.004	UCP2
cellular response to amino acid starvation	1	318.0×	0.004	UCP2
proton transmembrane transport	1	312.1×	0.004	UCP2
cellular response to glucose stimulus	1	267.5×	0.004	UCP2
cellular response to insulin stimulus	1	170.2×	0.007	UCP2
positive regulation of cold-induced thermogenesis	1	163.6×	0.007	UCP2
negative regulation of neuron apoptotic process	1	110.9×	0.009	UCP2
response to hypoxia	1	95.8×	0.010	UCP2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
UCP2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
D	Druggable family + AlphaFold only, no drug	1	UCP2
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
UCP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.