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hyperinsulinism due to INSR deficiency

disease
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Also known as HHF5hyperinsulinemic hypoglycemia due to INSR deficiencyhyperinsulinemic hypoglycemia due to insulin receptor deficiencyhyperinsulinemic hypoglycemia, familial, 5hyperinsulinemic hypoglycemia, familial, type 5

Summary

hyperinsulinism due to INSR deficiency (MONDO:0012381) is a disease caused by INSR (GenCC Strong), with 1 cohort gene.

At a glance

  • Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
  • Causal gene: INSR (GenCC Strong)
  • Cohort genes: 1
  • ClinVar variants: 60
  • Phenotypes (HPO): 9

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

TypeClassValueGeographyValidation
Cases/families10WorldwideValidated
Point prevalence<1 / 1 000 000WorldwideValidated

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO IDTermFrequency
HP:0000825Hyperinsulinemic hypoglycemiaObligate (100%)
HP:0001943HypoglycemiaVery frequent (80-99%)
HP:0001988Recurrent hypoglycemiaVery frequent (80-99%)
HP:0008283Fasting hyperinsulinemiaVery frequent (80-99%)
HP:0030794Abnormal C-peptide levelVery frequent (80-99%)
HP:0001250SeizureFrequent (30-79%)
HP:0012378FatigueFrequent (30-79%)
HP:0000855Insulin resistanceOccasional (5-29%)
HP:0001259ComaOccasional (5-29%)

Identifiers

Disease identifiers

FieldValue
Canonical namehyperinsulinism due to INSR deficiency
Mondo IDMONDO:0012381
MeSHC566494
OMIM609968
Orphanet263458
DOIDDOID:0070220
SNOMED CT721235003
UMLSC1864952
MedGen355335
GARD0017256
Is cancer (heuristic)no

Also known as: HHF5 · hyperinsulinemic hypoglycemia due to INSR deficiency · hyperinsulinemic hypoglycemia due to insulin receptor deficiency · hyperinsulinemic hypoglycemia, familial, 5 · hyperinsulinemic hypoglycemia, familial, type 5

Data availability: 60 ClinVar variants · 5 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 › hyperinsulinism › familial hyperinsulinism › hyperinsulinism due to INSR deficiency

Related subtypes (2): adult-onset non-insulinoma persistent hyperinsulinemic hypoglycemia, congenital isolated hyperinsulinism

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

60 retrieved; paginated sample, class counts are floors:

18 conflicting classifications of pathogenicity, 17 benign/likely benign, 14 uncertain significance, 4 likely pathogenic, 4 pathogenic, 2 uncertain significance/uncertain risk allele, 1 benign

ClinVarVariant (HGVS)GeneClassificationReview
14708NM_000208.4(INSR):c.3602G>A (p.Arg1201Gln)INSRPathogeniccriteria provided, single submitter
211189NM_000208.4(INSR):c.1610+2T>CINSRPathogeniccriteria provided, single submitter
3340447NM_000208.4(INSR):c.3196C>T (p.Arg1066Ter)INSRPathogeniccriteria provided, single submitter
3896504NM_000208.4(INSR):c.3058C>T (p.Arg1020Ter)INSRPathogeniccriteria provided, multiple submitters, no conflicts
14697NM_000208.4(INSR):c.3059G>A (p.Arg1020Gln)INSRLikely pathogeniccriteria provided, multiple submitters, no conflicts
3340446NM_000208.4(INSR):c.3610G>A (p.Ala1204Thr)INSRLikely pathogeniccriteria provided, single submitter
3382020NM_000208.4(INSR):c.3601C>G (p.Arg1201Gly)INSRLikely pathogeniccriteria provided, single submitter
816941NM_000208.4(INSR):c.1573C>T (p.Arg525Ter)INSRLikely pathogeniccriteria provided, multiple submitters, no conflicts
435517NM_000208.4(INSR):c.3775G>A (p.Asp1259Asn)INSRUncertain significance/Uncertain risk allelecriteria provided, multiple submitters, no conflicts
502299NM_000208.4(INSR):c.2498G>A (p.Arg833Gln)INSRUncertain significance/Uncertain risk allelecriteria provided, multiple submitters, no conflicts
1049578NM_000208.4(INSR):c.1550A>G (p.Glu517Gly)INSRConflicting classifications of pathogenicitycriteria provided, conflicting classifications
14695NM_000208.4(INSR):c.1466A>G (p.Asn489Ser)INSRConflicting classifications of pathogenicitycriteria provided, conflicting classifications
195041NM_000208.4(INSR):c.190T>C (p.Leu64=)INSRConflicting classifications of pathogenicitycriteria provided, conflicting classifications
211194NM_000208.4(INSR):c.2736G>A (p.Arg912=)INSRConflicting classifications of pathogenicitycriteria provided, conflicting classifications
211195NM_000208.4(INSR):c.2838C>G (p.Asp946Glu)INSRConflicting classifications of pathogenicitycriteria provided, conflicting classifications
282255NM_000208.4(INSR):c.2665C>T (p.Arg889Trp)INSRConflicting classifications of pathogenicitycriteria provided, conflicting classifications
289211NM_000208.4(INSR):c.41T>C (p.Leu14Pro)INSRConflicting classifications of pathogenicitycriteria provided, conflicting classifications
330455NM_000208.4(INSR):c.2573C>T (p.Thr858Met)INSRConflicting classifications of pathogenicitycriteria provided, conflicting classifications
330462NM_000208.4(INSR):c.2295C>T (p.Gly765=)INSRConflicting classifications of pathogenicitycriteria provided, conflicting classifications
330474NM_000208.4(INSR):c.909G>A (p.Gln303=)INSRConflicting classifications of pathogenicitycriteria provided, conflicting classifications
330480NM_000208.4(INSR):c.39G>C (p.Pro13=)INSRConflicting classifications of pathogenicitycriteria provided, conflicting classifications
3891392NM_000208.4(INSR):c.2716G>A (p.Ala906Thr)INSRConflicting classifications of pathogenicitycriteria provided, conflicting classifications
435514NM_000208.4(INSR):c.225C>T (p.Asp75=)INSRConflicting classifications of pathogenicitycriteria provided, conflicting classifications
549552NM_000208.4(INSR):c.2388G>C (p.Arg796Ser)INSRConflicting classifications of pathogenicitycriteria provided, conflicting classifications
631539NM_000208.4(INSR):c.3143G>A (p.Gly1048Asp)INSRConflicting classifications of pathogenicitycriteria provided, conflicting classifications
739582NM_000208.4(INSR):c.2793G>A (p.Ala931=)INSRConflicting classifications of pathogenicitycriteria provided, conflicting classifications
742862NM_000208.4(INSR):c.624A>G (p.Arg208=)INSRConflicting classifications of pathogenicitycriteria provided, conflicting classifications
892834NM_000208.4(INSR):c.2829C>T (p.Tyr943=)INSRConflicting classifications of pathogenicitycriteria provided, conflicting classifications
194702NM_000208.4(INSR):c.3193C>G (p.Leu1065Val)INSRUncertain significancecriteria provided, multiple submitters, no conflicts
1954970NM_000208.4(INSR):c.640C>A (p.His214Asn)INSRUncertain significancecriteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 4 · 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.

GeneClassificationInheritanceDiseaseRecords
INSRStrongAutosomal dominanthyperinsulinism due to INSR deficiency19

Orphanet rare-disease linkage (cohort genes)

GeneOrphanet IDRare disease
INSROrphanet:2297Insulin-resistance syndrome type A
INSROrphanet:263458Hyperinsulinism due to INSR deficiency
INSROrphanet:508Donohue syndrome
INSROrphanet:769Rabson-Mendenhall syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

SubsetGenes
multi_evidence1

Cohort genes (full)

SymbolHGNCEnsemblUniProtNameEvidence
INSRHGNC:6091ENSG00000171105P06213Insulin receptorgencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

SymbolProtein nameFunction (lead sentence)
INSRInsulin receptorReceptor tyrosine kinase which mediates the pleiotropic actions of insulin.

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.

FamilyGenesFoldFDR
Kinase127.7×0.036

Per-gene assignment

SymbolFamilyDruggable?ECInterPro (top 3)
INSRKinaseyes2.7.10.1Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom

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)

BucketGenes
narrow (1-5 tissues)0
moderate (6-20)0
broad (>20)1
unknown0

Top tissues across cohort

TissueCohort genes
buccal mucosa cell1
palpebral conjunctiva1
visceral pleura1

Per-gene tissue summary (top 30)

SymbolBgee breadthFANTOM5 breadthSCXATop tissues
INSR296ubiquitousmarkerbuccal mucosa cell, palpebral conjunctiva, visceral pleura

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

SymbolInteractor count
INSR4,446

Structural data

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

Cohort genes with PDB structures (top 30)

SymbolUniProtPDB entries
INSRP0621388

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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.

PathwayCohort genesFoldFDRSample cohort genes
IRS activation12284.0×0.004INSR
Signal attenuation11038.2×0.004INSR
Signaling by Insulin receptor1878.5×0.004INSR
Insulin receptor signalling cascade1671.8×0.004INSR
Insulin receptor recycling1380.7×0.006INSR
Negative regulation of the PI3K/AKT network1278.5×0.007INSR
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling196.8×0.015INSR
Intracellular signaling by second messengers191.4×0.015INSR
PIP3 activates AKT signaling166.8×0.018INSR
Signaling by Receptor Tyrosine Kinases151.7×0.021INSR
Signal Transduction110.2×0.098INSR

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 termCohort genesFoldFDRSample cohort genes
positive regulation of meiotic cell cycle18426.0×0.002INSR
regulation of female gonad development18426.0×0.002INSR
positive regulation of protein-containing complex disassembly14213.0×0.002INSR
positive regulation of developmental growth14213.0×0.002INSR
positive regulation of respiratory burst13370.4×0.002INSR
exocrine pancreas development11685.2×0.004INSR
male sex determination11404.3×0.004INSR
dendritic spine maintenance11296.3×0.004INSR
neuron projection maintenance11123.5×0.004INSR
positive regulation of glycogen biosynthetic process1991.3×0.004INSR
amyloid-beta clearance1936.2×0.004INSR
positive regulation of receptor internalization1702.2×0.004INSR
adrenal gland development1674.1×0.004INSR
positive regulation of glycolytic process1674.1×0.004INSR
positive regulation of mitotic nuclear division1543.6×0.005INSR
positive regulation of nitric oxide biosynthetic process1455.5×0.005INSR
positive regulation of D-glucose import across plasma membrane1455.5×0.005INSR
symbiont entry into host cell1401.2×0.006INSR
heart morphogenesis1374.5×0.006INSR
regulation of embryonic development1330.4×0.006INSR
receptor internalization1324.1×0.006INSR
cellular response to growth factor stimulus1318.0×0.006INSR
learning1280.9×0.006INSR
receptor-mediated endocytosis1221.7×0.007INSR
insulin receptor signaling pathway1221.7×0.007INSR
epidermis development1210.7×0.007INSR
memory1183.2×0.008INSR
transport across blood-brain barrier1179.3×0.008INSR
cellular response to insulin stimulus1170.2×0.008INSR
male gonad development1156.0×0.009INSR

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

SymbolExample approved molecule
INSRFEDRATINIB

Top cohort targets by molecule count

SymbolMoleculesMax phase
INSR364

Drugs targeting cohort genes (top 30)

MoleculeMax phaseTargets in cohort
FEDRATINIB4INSR
SORAFENIB4INSR
NERATINIB4INSR
INFIGRATINIB PHOSPHATE4INSR
INFIGRATINIB4INSR
ENTRECTINIB4INSR
CERITINIB4INSR
OSIMERTINIB4INSR
BRIGATINIB4INSR
NINTEDANIB4INSR
SUNITINIB4INSR
LAPATINIB4INSR
CRIZOTINIB4INSR
LINSITINIB3INSR
LINIFANIB3INSR
DOVITINIB3INSR
LESTAURTINIB3INSR
FORETINIB2INSR
SU-0148132INSR
CENISERTIB2INSR
ILORASERTIB2INSR
OSI-6322INSR
R-4062INSR
TOZASERTIB2INSR
BMS-7548072INSR
ELLAGIC ACID2INSR
PF-005622711INSR
KW-24491INSR
RG-15301INSR
XL-2281INSR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

SymbolAssaysType breakdown
INSR954Binding:900, Functional:49, ADMET:4, Toxicity:1

Cohort enzymes (BRENDA EC)

SymbolEC numbersNames
INSR2.7.10.1receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

SymbolChEMBL assays
INSR954

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

30 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.

CompoundMax phaseCohort target (bioactivity)
FEDRATINIB4INSR
SORAFENIB4INSR
NERATINIB4INSR
INFIGRATINIB PHOSPHATE4INSR
INFIGRATINIB4INSR
ENTRECTINIB4INSR
CERITINIB4INSR
OSIMERTINIB4INSR
BRIGATINIB4INSR
NINTEDANIB4INSR
SUNITINIB4INSR
LAPATINIB4INSR
CRIZOTINIB4INSR
LINSITINIB3INSR
LINIFANIB3INSR
DOVITINIB3INSR
LESTAURTINIB3INSR
FORETINIB2INSR
SU-0148132INSR
CENISERTIB2INSR
ILORASERTIB2INSR
OSI-6322INSR
R-4062INSR
TOZASERTIB2INSR
BMS-7548072INSR
ELLAGIC ACID2INSR
PF-005622711INSR
KW-24491INSR
RG-15301INSR
XL-2281INSR

Druggability pyramid

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

TierDefinitionGenesSymbols
AApproved (phase 4 drug)1INSR
BPhased (≥1) drug, not yet approved0
CDruggable family + PDB, no drug0
DDruggable family + AlphaFold only, no drug0
EDifficult family or no structure, no drug0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

Generated
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This page pulls from 70 datasets indexed by BioBTree:

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