ACTH-independent macronodular adrenal hyperplasia 3

Summary

ACTH-independent macronodular adrenal hyperplasia 3 (MONDO:0700299) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	ACTH-independent macronodular adrenal hyperplasia 3
Mondo ID	MONDO:0700299
OMIM	620990
UMLS	C5975485
MedGen	1875015
GARD	0027386
Is cancer (heuristic)	no

Also known as: ACTH-independent macronodular adrenal hyperplasia-3 · AIMAH3 · Cushing syndrome, food-dependent

Data availability: 4 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › Cushing syndrome due to macronodular adrenal hyperplasia › ACTH-independent macronodular adrenal hyperplasia 3

Related subtypes (2): ACTH-independent macronodular adrenal hyperplasia 2, ACTH-independent macronodular adrenal hyperplasia 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

4 retrieved; paginated sample, class counts are floors:

4 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3366856	NM_001009999.3(KDM1A):c.1849dup (p.Val617fs)	KDM1A	Pathogenic	no assertion criteria provided
3366857	NM_001009999.3(KDM1A):c.352-1G>A	KDM1A	Pathogenic	no assertion criteria provided
3366858	NM_001009999.3(KDM1A):c.811C>T (p.Arg271Ter)	KDM1A	Pathogenic	no assertion criteria provided
3366859	NM_001009999.3(KDM1A):c.1984C>T (p.Gln662Ter)	KDM1A	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KDM1A	Orphanet:189427	Cushing syndrome due to bilateral macronodular adrenocortical disease
KDM1A	Orphanet:477993	Palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome

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
KDM1A	HGNC:29079	ENSG00000004487	O60341	Lysine-specific histone demethylase 1A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KDM1A	Lysine-specific histone demethylase 1A	Histone demethylase that can demethylate both ‘Lys-4’ (H3K4me) and ‘Lys-9’ (H3K9me) of histone H3, thereby acting as a coactivator or a corepressor, depending on the context.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KDM1A	Transcription factor	no	1.14.11.65	Amino_oxidase, SWIRM, Homeodomain-like_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
cortical plate	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KDM1A	287	ubiquitous	marker	ganglionic eminence, ventricular zone, cortical plate

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KDM1A	6,235

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KDM1A	O60341	128

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. 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
NR1H2 and NR1H3-mediated signaling	1	393.8×	0.021	KDM1A
RHO GTPases activate PKNs	1	317.2×	0.021	KDM1A
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	1	308.6×	0.021	KDM1A
HDMs demethylate histones	1	228.4×	0.021	KDM1A
PTEN Regulation	1	228.4×	0.021	KDM1A
Regulation of PTEN gene transcription	1	178.4×	0.021	KDM1A
Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3	1	167.9×	0.021	KDM1A
ESR-mediated signaling	1	128.3×	0.021	KDM1A
HDACs deacetylate histones	1	120.2×	0.021	KDM1A
Negative Regulation of CDH1 Gene Transcription	1	120.2×	0.021	KDM1A
Potential therapeutics for SARS	1	114.2×	0.021	KDM1A
Signaling by Nuclear Receptors	1	102.0×	0.021	KDM1A
Intracellular signaling by second messengers	1	91.4×	0.021	KDM1A
Chromatin organization	1	81.6×	0.021	KDM1A
Estrogen-dependent gene expression	1	75.6×	0.021	KDM1A
Chromatin modifying enzymes	1	72.3×	0.021	KDM1A
RHO GTPase Effectors	1	68.0×	0.021	KDM1A
PIP3 activates AKT signaling	1	66.8×	0.021	KDM1A
Factors involved in megakaryocyte development and platelet production	1	66.4×	0.021	KDM1A
SARS-CoV Infections	1	55.4×	0.024	KDM1A
Hemostasis	1	36.0×	0.035	KDM1A
Signaling by Rho GTPases	1	34.2×	0.035	KDM1A
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	33.5×	0.035	KDM1A
Viral Infection Pathways	1	30.8×	0.037	KDM1A
Infectious disease	1	24.8×	0.044	KDM1A
Disease	1	13.1×	0.079	KDM1A
Signal Transduction	1	10.2×	0.098	KDM1A

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
guanine metabolic process	1	8426.0×	0.002	KDM1A
negative regulation of transcription initiation-coupled chromatin remodeling	1	5617.3×	0.002	KDM1A
response to fungicide	1	2808.7×	0.003	KDM1A
negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator	1	2407.4×	0.003	KDM1A
positive regulation of cell size	1	1296.3×	0.003	KDM1A
negative regulation of DNA damage response, signal transduction by p53 class mediator	1	1123.5×	0.003	KDM1A
negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	1	1053.2×	0.003	KDM1A
regulation of double-strand break repair via homologous recombination	1	991.3×	0.003	KDM1A
regulation of androgen receptor signaling pathway	1	991.3×	0.003	KDM1A
muscle cell development	1	936.2×	0.003	KDM1A
neuron maturation	1	802.5×	0.003	KDM1A
positive regulation of neural precursor cell proliferation	1	766.0×	0.003	KDM1A
DNA repair-dependent chromatin remodeling	1	674.1×	0.003	KDM1A
cellular response to gamma radiation	1	601.9×	0.003	KDM1A
positive regulation of neuroblast proliferation	1	581.1×	0.003	KDM1A
positive regulation of stem cell proliferation	1	526.6×	0.003	KDM1A
epigenetic regulation of gene expression	1	383.0×	0.004	KDM1A
positive regulation of epithelial to mesenchymal transition	1	318.0×	0.005	KDM1A
cellular response to UV	1	295.6×	0.005	KDM1A
cellular response to cAMP	1	290.6×	0.005	KDM1A
positive regulation of protein ubiquitination	1	213.3×	0.006	KDM1A
cerebral cortex development	1	205.5×	0.006	KDM1A
regulation of protein localization	1	205.5×	0.006	KDM1A
positive regulation of cold-induced thermogenesis	1	163.6×	0.007	KDM1A
positive regulation of neuron projection development	1	137.0×	0.008	KDM1A
negative regulation of transcription by RNA polymerase II	1	17.7×	0.061	KDM1A
positive regulation of transcription by RNA polymerase II	1	14.9×	0.070	KDM1A
regulation of transcription by RNA polymerase II	1	11.7×	0.086	KDM1A

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.

Symbol	Example approved molecule
KDM1A	OSIMERTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KDM1A	38	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
OSIMERTINIB	4	KDM1A
TRANYLCYPROMINE	4	KDM1A
COLISTIN	4	KDM1A
PHENELZINE	4	KDM1A
DIOSMIN	4	KDM1A
CAPSAICIN	4	KDM1A
BERBERINE	4	KDM1A
PACLITAXEL	4	KDM1A
AMSACRINE	4	KDM1A
ERLOTINIB	4	KDM1A
PROMAZINE	4	KDM1A
FENOLDOPAM	4	KDM1A
CHLORPROMAZINE	4	KDM1A
RALOXIFENE	4	KDM1A
CURCUMIN	3	KDM1A
RESVERATROL	3	KDM1A
PERAZINE	3	KDM1A
RUTIN	3	KDM1A
ENTINOSTAT	3	KDM1A
BOMEDEMSTAT	3	KDM1A
HESPERIDIN	3	KDM1A
ICARITIN	3	KDM1A
QUERCETIN	3	KDM1A
ICARIIN	3	KDM1A
IADADEMSTAT	2	KDM1A
FENETHAZINE	2	KDM1A
ISOQUERCETIN	2	KDM1A
DOMATINOSTAT	2	KDM1A
SECLIDEMSTAT	2	KDM1A
ACETOSIDE	2	KDM1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
KDM1A	1,089	Binding:1075, Functional:7, ADMET:7

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KDM1A	1.14.11.65, 1.14.11.66, 1.14.11.67, 1.14.99.66	[histone H3]-dimethyl-L-lysine9 demethylase, [histone H3]-trimethyl-L-lysine9 demethylase, [histone H3]-trimethyl-L-lysine4 demethylase, [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
KDM1A	1,089

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.

Compound	Max phase	Cohort target (bioactivity)
OSIMERTINIB	4	KDM1A
TRANYLCYPROMINE	4	KDM1A
COLISTIN	4	KDM1A
PHENELZINE	4	KDM1A
DIOSMIN	4	KDM1A
CAPSAICIN	4	KDM1A
BERBERINE	4	KDM1A
PACLITAXEL	4	KDM1A
AMSACRINE	4	KDM1A
ERLOTINIB	4	KDM1A
PROMAZINE	4	KDM1A
FENOLDOPAM	4	KDM1A
CHLORPROMAZINE	4	KDM1A
RALOXIFENE	4	KDM1A
CURCUMIN	3	KDM1A
RESVERATROL	3	KDM1A
PERAZINE	3	KDM1A
RUTIN	3	KDM1A
ENTINOSTAT	3	KDM1A
BOMEDEMSTAT	3	KDM1A
HESPERIDIN	3	KDM1A
ICARITIN	3	KDM1A
QUERCETIN	3	KDM1A
ICARIIN	3	KDM1A
IADADEMSTAT	2	KDM1A
FENETHAZINE	2	KDM1A
ISOQUERCETIN	2	KDM1A
DOMATINOSTAT	2	KDM1A
SECLIDEMSTAT	2	KDM1A
ACETOSIDE	2	KDM1A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KDM1A
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.