insulin-resistance syndrome type A

Summary

insulin-resistance syndrome type A (MONDO:0012520) is a disease caused by INSR (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: INSR (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 239
• Phenotypes (HPO): 7

Clinical features

Signs & symptoms

Clinical features (HPO)

7 HPO clinical features (Orphanet curated; top 7 by frequency):

HPO ID	Term	Frequency
HP:0000823	Delayed puberty	Very frequent (80-99%)
HP:0000962	Hyperkeratosis	Very frequent (80-99%)
HP:0001482	Subcutaneous nodule	Very frequent (80-99%)
HP:0002230	Generalized hirsutism	Very frequent (80-99%)
HP:0005616	Accelerated skeletal maturation	Very frequent (80-99%)
HP:0005978	Type II diabetes mellitus	Very frequent (80-99%)
HP:0007440	Generalized hyperpigmentation	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	insulin-resistance syndrome type A
Mondo ID	MONDO:0012520
MeSH	C562710
OMIM	610549
Orphanet	2297
ICD-11	343459534
NCIT	C131836
UMLS	C0342278
MedGen	501111
GARD	0003008
Is cancer (heuristic)	no

Also known as: insulin resistant diabetes mellitus with acanthosis nigricans and hyperandrogenism · insulin-resistant acanthosis nigricans, type A · type A insulin resistance syndrome

Data availability: 239 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 › insulin-resistance syndrome type A

Related subtypes (11): gastrin secretion abnormality, abnormality of glucagon secretion, hyperinsulinism, post-surgical hypoinsulinemia, pancreatic cholera, diabetes mellitus, aggressive insulitis, benign insulitis, pancreatic neuroendocrine neoplasm, islet cell adenomatosis, insulin-resistance syndrome type B

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

239 retrieved; paginated sample, class counts are floors:

105 uncertain significance, 43 benign, 37 conflicting classifications of pathogenicity, 19 benign/likely benign, 18 likely benign, 12 pathogenic, 3 likely pathogenic, 2 uncertain significance/uncertain risk allele

ClinVar	Variant (HGVS)	Gene	Classification	Review
377384	NM_000208.2:c.[1465A>G;3160G>A]		Pathogenic	no assertion criteria provided
14679	NM_000208.4(INSR):c.3104G>T (p.Gly1035Val)	INSR	Pathogenic	no assertion criteria provided
14683	NM_000208.4(INSR):c.3680G>C (p.Trp1227Ser)	INSR	Pathogenic	no assertion criteria provided
14684	NM_000208.4(INSR):c.2286G>T (p.Arg762Ser)	INSR	Pathogenic	no assertion criteria provided
14685	INSR, EX17, ALU	INSR	Pathogenic	no assertion criteria provided
14687	NM_000208.4(INSR):c.3481G>A (p.Ala1161Thr)	INSR	Pathogenic	no assertion criteria provided
14692	NM_000208.4(INSR):c.3079C>T (p.Arg1027Ter)	INSR	Pathogenic	criteria provided, single submitter
14694	NM_000208.4(INSR):c.479G>A (p.Trp160Ter)	INSR	Pathogenic	no assertion criteria provided
14696	NM_000208.3(INSR):c.2683-542_2842+544del	INSR	Pathogenic	no assertion criteria provided
14704	NM_000208.4(INSR):c.3485C>A (p.Ala1162Glu)	INSR	Pathogenic	no assertion criteria provided
14708	NM_000208.4(INSR):c.3602G>A (p.Arg1201Gln)	INSR	Pathogenic	criteria provided, single submitter
4073618	NM_000208.4(INSR):c.3734T>A (p.Val1245Glu)	INSR	Pathogenic	criteria provided, single submitter
14697	NM_000208.4(INSR):c.3059G>A (p.Arg1020Gln)	INSR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382020	NM_000208.4(INSR):c.3601C>G (p.Arg1201Gly)	INSR	Likely pathogenic	criteria provided, single submitter
3602110	NM_000208.4(INSR):c.3488G>A (p.Arg1163Lys)	INSR	Likely pathogenic	criteria provided, single submitter
435517	NM_000208.4(INSR):c.3775G>A (p.Asp1259Asn)	INSR	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
502299	NM_000208.4(INSR):c.2498G>A (p.Arg833Gln)	INSR	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
1032927	NM_000208.4(INSR):c.2842+4A>T	INSR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1049578	NM_000208.4(INSR):c.1550A>G (p.Glu517Gly)	INSR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14695	NM_000208.4(INSR):c.1466A>G (p.Asn489Ser)	INSR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14707	NM_000208.4(INSR):c.3034G>A (p.Val1012Met)	INSR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
195041	NM_000208.4(INSR):c.190T>C (p.Leu64=)	INSR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211190	NM_000208.4(INSR):c.2243C>T (p.Ser748Leu)	INSR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211194	NM_000208.4(INSR):c.2736G>A (p.Arg912=)	INSR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211195	NM_000208.4(INSR):c.2838C>G (p.Asp946Glu)	INSR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
282255	NM_000208.4(INSR):c.2665C>T (p.Arg889Trp)	INSR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286286	NM_000208.4(INSR):c.151G>A (p.Glu51Lys)	INSR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
289211	NM_000208.4(INSR):c.41T>C (p.Leu14Pro)	INSR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330390	NM_000208.4(INSR):c.*2318G>A	INSR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330438	NM_000208.4(INSR):c.4082A>G (p.Tyr1361Cys)	INSR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 25 · 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
INSR	Definitive	Autosomal dominant	insulin-resistance syndrome type A	19

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
INSR	Orphanet:2297	Insulin-resistance syndrome type A
INSR	Orphanet:263458	Hyperinsulinism due to INSR deficiency
INSR	Orphanet:508	Donohue syndrome
INSR	Orphanet:769	Rabson-Mendenhall syndrome
LMNA	Orphanet:154	Familial isolated dilated cardiomyopathy
LMNA	Orphanet:157973	Congenital muscular dystrophy due to LMNA mutation
LMNA	Orphanet:1662	Restrictive dermopathy
LMNA	Orphanet:168796	Heart-hand syndrome, Slovenian type
LMNA	Orphanet:2229	Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome
LMNA	Orphanet:2348	Familial partial lipodystrophy, Dunnigan type
LMNA	Orphanet:280365	Autosomal semi-dominant severe lipodystrophic laminopathy
LMNA	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
LMNA	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
LMNA	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
LMNA	Orphanet:300751	Familial dilated cardiomyopathy with conduction defect due to LMNA mutation
LMNA	Orphanet:363618	LMNA-related cardiocutaneous progeria syndrome
LMNA	Orphanet:54260	Left ventricular noncompaction
LMNA	Orphanet:675396	Epithelioid hemangioma
LMNA	Orphanet:740	Hutchinson-Gilford progeria syndrome
LMNA	Orphanet:79084	Familial partial lipodystrophy, Köbberling type
LMNA	Orphanet:79474	Atypical Werner syndrome
LMNA	Orphanet:90153	Mandibuloacral dysplasia with type A lipodystrophy
LMNA	Orphanet:98853	Autosomal dominant Emery-Dreifuss muscular dystrophy
LMNA	Orphanet:98855	Autosomal recessive Emery-Dreifuss muscular dystrophy
LMNA	Orphanet:98856	Charcot-Marie-Tooth disease type 2B1

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
INSR	HGNC:6091	ENSG00000171105	P06213	Insulin receptor	gencc,clinvar
LMNA	HGNC:6636	ENSG00000160789	P02545	Prelamin-A/C	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
INSR	Insulin receptor	Receptor tyrosine kinase which mediates the pleiotropic actions of insulin.
LMNA	Prelamin-A/C	Lamins are intermediate filament proteins that assemble into a filamentous meshwork, and which constitute the major components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane.

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
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
INSR	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
LMNA	Other/Unknown	no		Lamin_tail_dom, IF_conserved, Lamin_tail_dom_sf

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
buccal mucosa cell	1
palpebral conjunctiva	1
visceral pleura	1
mucosa of stomach	1
nipple	1
skin of abdomen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
INSR	296	ubiquitous	marker	buccal mucosa cell, palpebral conjunctiva, visceral pleura
LMNA	295	ubiquitous	marker	nipple, mucosa of stomach, skin of abdomen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LMNA	7,173
INSR	4,446

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
INSR	P06213	88
LMNA	P02545	28

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Breakdown of the nuclear lamina	1	1903.3×	0.011	LMNA
IRS activation	1	1142.0×	0.011	INSR
Signal attenuation	1	519.1×	0.011	INSR
Signaling by Insulin receptor	1	439.2×	0.011	INSR
Depolymerization of the Nuclear Lamina	1	380.7×	0.011	LMNA
Insulin receptor signalling cascade	1	335.9×	0.011	INSR
Initiation of Nuclear Envelope (NE) Reformation	1	300.5×	0.011	LMNA
IRE1alpha activates chaperones	1	259.6×	0.011	LMNA
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	1	259.6×	0.011	LMNA
Nuclear Envelope Breakdown	1	228.4×	0.011	LMNA
Insulin receptor recycling	1	190.3×	0.012	INSR
Unfolded Protein Response (UPR)	1	178.4×	0.012	LMNA
Negative regulation of the PI3K/AKT network	1	139.3×	0.014	INSR
Oncogenic MAPK signaling	1	124.1×	0.015	LMNA
XBP1(S) activates chaperone genes	1	107.7×	0.016	LMNA
Signaling by BRAF and RAF1 fusions	1	85.2×	0.019	LMNA
Meiotic synapsis	1	70.5×	0.022	LMNA
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	48.4×	0.030	INSR
Intracellular signaling by second messengers	1	45.7×	0.030	INSR
PIP3 activates AKT signaling	1	33.4×	0.039	INSR
Diseases of signal transduction by growth factor receptors and second messengers	1	28.4×	0.043	LMNA
Signaling by Receptor Tyrosine Kinases	1	25.8×	0.045	INSR
Cellular responses to stress	1	18.4×	0.061	LMNA
Cellular responses to stimuli	1	15.7×	0.068	LMNA
Disease	1	6.5×	0.153	LMNA
Signal Transduction	1	5.1×	0.187	INSR

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
positive regulation of meiotic cell cycle	1	4213.0×	0.005	INSR
regulation of female gonad development	1	4213.0×	0.005	INSR
DNA double-strand break attachment to nuclear envelope	1	2808.7×	0.005	LMNA
establishment or maintenance of microtubule cytoskeleton polarity	1	2106.5×	0.005	LMNA
positive regulation of protein-containing complex disassembly	1	2106.5×	0.005	INSR
positive regulation of developmental growth	1	2106.5×	0.005	INSR
nuclear pore localization	1	1685.2×	0.005	LMNA
positive regulation of respiratory burst	1	1685.2×	0.005	INSR
negative regulation of mesenchymal cell proliferation	1	1404.3×	0.005	LMNA
protein localization to nuclear envelope	1	1053.2×	0.006	LMNA
regulation of protein localization to nucleus	1	1053.2×	0.006	LMNA
negative regulation of cardiac muscle hypertrophy in response to stress	1	936.2×	0.006	LMNA
exocrine pancreas development	1	842.6×	0.006	INSR
ventricular cardiac muscle cell development	1	766.0×	0.006	LMNA
male sex determination	1	702.2×	0.006	INSR
dendritic spine maintenance	1	648.1×	0.006	INSR
neuron projection maintenance	1	561.7×	0.007	INSR
nuclear envelope organization	1	495.6×	0.007	LMNA
positive regulation of glycogen biosynthetic process	1	495.6×	0.007	INSR
amyloid-beta clearance	1	468.1×	0.007	INSR
regulation of telomere maintenance	1	421.3×	0.007	LMNA
negative regulation of release of cytochrome c from mitochondria	1	401.2×	0.007	LMNA
nuclear migration	1	366.4×	0.007	LMNA
positive regulation of receptor internalization	1	351.1×	0.007	INSR
adrenal gland development	1	337.0×	0.007	INSR
positive regulation of glycolytic process	1	337.0×	0.007	INSR
positive regulation of mitotic nuclear division	1	271.8×	0.009	INSR
positive regulation of nitric oxide biosynthetic process	1	227.7×	0.010	INSR
positive regulation of D-glucose import across plasma membrane	1	227.7×	0.010	INSR
double-strand break repair via nonhomologous end joining	1	210.7×	0.010	LMNA

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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.

Symbol	Example approved molecule
INSR	FEDRATINIB
LMNA	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LMNA	823	4
INSR	36	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	INSR
SORAFENIB	4	INSR
NERATINIB	4	INSR
INFIGRATINIB PHOSPHATE	4	INSR
INFIGRATINIB	4	INSR
ENTRECTINIB	4	INSR
CERITINIB	4	INSR
OSIMERTINIB	4	INSR
BRIGATINIB	4	INSR
NINTEDANIB	4	INSR
SUNITINIB	4	INSR, LMNA
LAPATINIB	4	INSR
CRIZOTINIB	4	INSR
BEPRIDIL	4	LMNA
PHENYLBUTAZONE	4	LMNA
CEFOTAXIME SODIUM	4	LMNA
DIENESTROL	4	LMNA
IFOSFAMIDE	4	LMNA
PROGESTERONE	4	LMNA
CLOTRIMAZOLE	4	LMNA
DAPSONE	4	LMNA
AMINOCAPROIC ACID	4	LMNA
FLUCONAZOLE	4	LMNA
COLCHICINE	4	LMNA
NABUMETONE	4	LMNA
OXAPROZIN	4	LMNA
BUMETANIDE	4	LMNA
GLIPIZIDE	4	LMNA
BROMFENAC	4	LMNA
ROPIVACAINE	4	LMNA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
INSR	954	Binding:900, Functional:49, ADMET:4, Toxicity:1
LMNA	12	Binding:9, Functional:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
INSR	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
INSR	954

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

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.

Compound	Max phase	Cohort target (bioactivity)
FEDRATINIB	4	INSR
SORAFENIB	4	INSR
NERATINIB	4	INSR
INFIGRATINIB PHOSPHATE	4	INSR
INFIGRATINIB	4	INSR
ENTRECTINIB	4	INSR
CERITINIB	4	INSR
OSIMERTINIB	4	INSR
BRIGATINIB	4	INSR
NINTEDANIB	4	INSR
SUNITINIB	4	INSR, LMNA
LAPATINIB	4	INSR
CRIZOTINIB	4	INSR
BEPRIDIL	4	LMNA
PHENYLBUTAZONE	4	LMNA
CEFOTAXIME SODIUM	4	LMNA
DIENESTROL	4	LMNA
IFOSFAMIDE	4	LMNA
PROGESTERONE	4	LMNA
CLOTRIMAZOLE	4	LMNA
DAPSONE	4	LMNA
AMINOCAPROIC ACID	4	LMNA
FLUCONAZOLE	4	LMNA
COLCHICINE	4	LMNA
NABUMETONE	4	LMNA
OXAPROZIN	4	LMNA
BUMETANIDE	4	LMNA
GLIPIZIDE	4	LMNA
BROMFENAC	4	LMNA
ROPIVACAINE	4	LMNA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	INSR, LMNA
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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.