HNF4A

Summary

HNF4A (hepatocyte nuclear factor 4 alpha, HGNC:5024) is a protein-coding gene on chromosome 20q13.12, encoding Hepatocyte nuclear factor 4-alpha (P41235). Transcriptional regulator which controls the expression of hepatic genes during the transition of endodermal cells to hepatic progenitor cells, facilitating the recruitment of RNA pol II to the promoters of target genes. It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is a nuclear transcription factor which binds DNA as a homodimer. The encoded protein controls the expression of several genes, including hepatocyte nuclear factor 1 alpha, a transcription factor which regulates the expression of several hepatic genes. This gene may play a role in development of the liver, kidney, and intestines. Mutations in this gene have been associated with monogenic autosomal dominant non-insulin-dependent diabetes mellitus type I. Alternative splicing of this gene results in multiple transcript variants encoding several different isoforms.

Source: NCBI Gene 3172 — RefSeq curated summary.

At a glance

• Gene–disease (curated): monogenic diabetes (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 93
• Clinical variants (ClinVar): 768 total — 72 pathogenic, 87 likely-pathogenic
• Phenotypes (HPO): 74
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 335 downstream targets (CollecTRI)
• MANE Select transcript: NM_175914

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5024
Approved symbol	HNF4A
Name	hepatocyte nuclear factor 4 alpha
Location	20q13.12
Locus type	gene with protein product
Status	Approved
Aliases	NR2A1, HNF4
Ensembl gene	ENSG00000101076
Ensembl biotype	protein_coding
OMIM	600281
Entrez	3172

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 15 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000316099, ENST00000316673, ENST00000372920, ENST00000415691, ENST00000443598, ENST00000457232, ENST00000609262, ENST00000609795, ENST00000619550, ENST00000681977, ENST00000682169, ENST00000682427, ENST00000683148, ENST00000683657, ENST00000684046, ENST00000684136, ENST00000684476, ENST00000894460

RefSeq mRNA: 10 — MANE Select: NM_175914 NM_000457, NM_001030003, NM_001030004, NM_001258355, NM_001287182, NM_001287183, NM_001287184, NM_175914, NM_178849, NM_178850

CCDS: CCDS13330, CCDS13331, CCDS42876, CCDS46604, CCDS46605, CCDS68131

Canonical transcript exons

ENST00000316673 — 10 exons

Exon	Start	End
ENSE00001526362	44429523	44432845
ENSE00001760101	44355699	44355853
ENSE00003531005	44407381	44407475
ENSE00003536662	44424018	44424254
ENSE00003593107	44413694	44413800
ENSE00003610134	44418425	44418512
ENSE00003622456	44414507	44414662
ENSE00003630078	44419721	44419876
ENSE00003640722	44406058	44406232
ENSE00003668514	44428335	44428487

Expression profiles

Bgee: expression breadth ubiquitous, 110 present calls, max score 96.03.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.3922 / max 233.4830, expressed in 129 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
184712	1.1660	93
184715	0.9123	84
184718	0.1844	46
184717	0.0549	26
184711	0.0412	22
184716	0.0181	14
184719	0.0153	7

Top tissues by expression

248 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	96.03	gold quality
mucosa of transverse colon	UBERON:0004991	95.82	gold quality
duodenum	UBERON:0002114	94.45	gold quality
liver	UBERON:0002107	93.63	gold quality
rectum	UBERON:0001052	93.31	gold quality
mucosa of sigmoid colon	UBERON:0004993	91.92	gold quality
colonic mucosa	UBERON:0000317	91.52	gold quality
jejunal mucosa	UBERON:0000399	90.26	gold quality
type B pancreatic cell	CL:0000169	87.90	gold quality
adult mammalian kidney	UBERON:0000082	87.70	gold quality
olfactory bulb	UBERON:0002264	87.41	gold quality
small intestine	UBERON:0002108	86.33	gold quality
small intestine Peyer’s patch	UBERON:0003454	85.91	gold quality
transverse colon	UBERON:0001157	85.32	gold quality
ileal mucosa	UBERON:0000331	84.18	silver quality
endometrium epithelium	UBERON:0004811	83.78	gold quality
Brodmann (1909) area 10	UBERON:0013541	83.63	gold quality
frontal pole	UBERON:0002795	83.41	gold quality
paraflocculus	UBERON:0005351	83.11	gold quality
islet of Langerhans	UBERON:0000006	82.80	gold quality
middle frontal gyrus	UBERON:0002702	82.46	gold quality
pancreas	UBERON:0001264	81.95	gold quality
jejunum	UBERON:0002115	81.77	gold quality
cervix squamous epithelium	UBERON:0006922	81.76	gold quality
body of pancreas	UBERON:0001150	81.66	gold quality
kidney	UBERON:0002113	81.54	gold quality
epithelial cell of pancreas	CL:0000083	81.30	silver quality
tendon of biceps brachii	UBERON:0008188	81.07	silver quality
colonic epithelium	UBERON:0000397	79.70	gold quality
triceps brachii	UBERON:0001509	79.50	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	16.72
E-MTAB-6075	no	43.70

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

335 targets.

Target	Regulation
ABCA1	Activation
ABCB1
ABCC2	Activation
ABCC6	Unknown
ABCG5	Repression
ABCG8	Repression
ACADM	Unknown
ACAT2	Unknown
ACMSD
ACOT13	Unknown
ADAM2
ADAMTS1	Unknown
ADGRG1
AFP	Activation
AGT	Activation
AKR1C4	Unknown
ALB	Repression
ALDH2	Repression
ALDH3A1	Unknown
ALDH6A1	Unknown
ALDOB	Unknown
ALPI
AMBP	Unknown
ANG	Unknown
ANK3	Unknown
ANKS4B
APC
APOA1	Unknown
APOA2	Unknown
APOA4	Unknown

JASPAR motifs

Motif	Name	Family
MA0114.1	HNF4A	RXR-related receptors (NR2)
MA0114.2	HNF4A	RXR-related receptors (NR2)
MA0114.4	HNF4A	RXR-related receptors (NR2)
MA0114.5	HNF4A	RXR-related receptors (NR2)
MA1494.1	HNF4A	RXR-related receptors (NR2)
MA1494.2	HNF4A	RXR-related receptors (NR2)

JASPAR matrix evidence (PMIDs): PMID:12385991, PMID:22383578, PMID:25164757

Upstream regulators (CollecTRI, top): CDX1, CEBPA, CREB1, EWSR1, FOXA1, FOXA2, FOXO1, GATA4, GATA6, HES6, HHEX, HNF1A, HNF1B, HNF4A, ISL1, NFATC1, NFKB, NR0B2, NR1H4, NR1I2, NR1I3, NR2F1, NR2F2, NR3C1, NR5A2, ONECUT1, RARA, RBPJ, RELA, RXRA, SOX17, SP1, SREBF2, SRY, TCF3, TP53, VDR

miRNA regulators (miRDB)

129 targeting HNF4A, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-34B-5P	99.78	67.56	1175
HSA-MIR-449C-5P	99.78	67.63	1168

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Control transcription of aldehyde dehydrogenase 2 (PMID:11811951)
• HNF4 alpha activates the insulin gene directly, through a previously unrecognized cis element (PMID:11994285)
• HNF-4alpha is involved in regulating cancer cell transmigration by modulating the Fas-FasL system (PMID:12036449)
• mutations in maturity-onset diabetes of the young (MODY) candidate genes in 22 Spanish families. (PMID:12050210)
• variation in the HNF4alpha enhancer element is not a common cause of susceptibility to type 2 diabetes (PMID:12083813)
• MODY is caused by a translocation at chromosome 20, resulting in an upstream disruption of the gene (PMID:12086970)
• spermine significantly enhanced the interaction between HNF4alpha and full-length DRIP205 in an AF-2, NR-box-dependent manner. Spermine enhanced the interaction of DRIP205 with the VDR , but decreased the interaction of both HNF4alpha and VDR with GRIP1 (PMID:12089346)
• These results support clinical findings that liver function can also be impaired in diabetic patients having hepatocyte nuclear factor 4alpha (HNF4alpha) mutations. (PMID:12110948)
• cooperative role with Sp1 or Sp3 leads to transcriptional activation of the human haem oxygenase-1 gene promoter in a hepatoma cell line (PMID:12133007)
• The missense mutation was located in the DNA binding domain of HNF4A, and identification of this mutation allowed for presymptomatic diagnosis in the younger generations and will improve medical follow-up of the predisposed individuals. (PMID:12203996)
• 2.7 A X-ray crystalography results suggest that the HNF4s may be transcription factors that are constitutively bound to fatty acids (PMID:12220494)
• These findings provide genetic evidence that HNF-1alpha serves as an upstream regulator of HNF-4alpha and interacts directly with the P2 promoter in human pancreatic cells. (PMID:12235114)
• Maturity-onset diabetes of the young resulting from a novel mutation in the HNF-4alpha gene. (PMID:12413008)
• the order of recruitment of factors to the HNF-4alpha regulatory regions upon the initial activation of the gene during enterocyte differentiation (PMID:12504020)
• regulates transcription of hepatitis B virus (PMID:12551987)
• Twenty different mutations in the HNF-4alpha, GCK and HNF-1alpha in 29 families. Three of 3, 10 of 11 and 1 of 6 of the mutations identified in HNF-4alpha, GCK and HNF-1alpha respectively, were new. (PMID:12627330)
• Results suggest that the transcriptional cross talk between the TGFbeta-regulated Smads 3 and 4 and hepatocyte nuclear factor-4 is mediated by specific functional domains in the two types of transcription factors. (PMID:12631740)
• HNF4 alpha isoforms originating from the P1 promoter exhibit stronger transcriptional activities and recruit coactivators more efficiently than isoforms driven by the P2 promoter. (PMID:12697672)
• Transdifferentiation to the hepatocytic phenotype in hepatoid adenocarcinoma tissue of the stomach was not directly associated with HNF-4alpha expression, thus suggesting that transdifferentiation proceeds by a complicated mechanism. (PMID:12701690)
• Hepatic expression of HNF-4 was impaired in advanced human cirrhosis and negatively correlated with WT1 mRNA levels (PMID:12829997)
• hepatocyte nuclear factor-4 binds to SREBP2 to enhance sterol isomerase gene expression in hepatocytes (PMID:12855700)
• HNF4-alpha, HNF3-beta and Sp1/Sp3 are important in regulation of prothrombin expression (PMID:12911579)
• HNF-4alpha plays an important role in the differentiation and maintenance of the matured human hepatocyte phenotype. (PMID:14563941)
• HNF-4alpha represents a potential modifier of the glycerol kinase deficiency phenotype (PMID:14654354)
• HNF-4alpha has a role in regulating gluconeogenic genes along with PGC-1 and SREBP-1 (PMID:14722127)
• identifed systematically the genes occupied by the transcriptional regulators HNF1alpha, HNF4alpha, and HNF6, together with RNA polymerase II in liver and pancreatic islets; results suggest how misregulation of HNF4alpha can contribute to type 2 diabetes (PMID:14988562)
• Human SNPs were identified across a 78-kb region around HNF4 alpha and evaluated in an association analysis of Ashkenazi Jewish type 2 diabetics and controls. (PMID:15047632)
• A study population of Ashkenazi Jewish origin suggests that variant(s) located near or within HNF4A increases susceptibility to type 2 diabetes. (PMID:15047633)
• residues of the ligand binding pocket are critical in hepatocyte nuclear factor-4alpha (PMID:15123688)
• stimulated expression of the precore RNA and the core RNA from the core promoter of both the wild-type (WT) Hepatitis B virus and the double mutant, although its effect on the former was more prominent (PMID:15194767)
• the V199I missense mutation located in the ligand binding/dimerization domain of HNF-4alpha contributes to type 2 diabetes in a Philippine-1 family (PMID:15281001)
• ligand-activated PXR interferes with HNF-4 signaling by targeting the common coactivator PGC-1, which underlies physiologically relevant inhibitory cross-talk between drug metabolism and cholesterol/glucose metabolism (PMID:15322103)
• HNF-4 and FXR, are closely involved in MTP gene expression, and the results provide evidence for a novel interaction between bile acids and lipoprotein metabolism. (PMID:15337761)
• Data show that nitric oxide and transforming growth factor-beta1 inhibit hepatocyte nuclear factor-4alpha function in HEPG2 cells. (PMID:15358161)
• HNF4alpha as a major factor for the control of UGT1A9 hepatic expression. (PMID:15470081)
• Association of the HNF4alpha P2 promoter haplotype with type 2 diabetes in a U.K. Caucasian population where there is no evidence of linkage to 20q. (PMID:15504983)
• HNF-4alpha is linked to late-onset type 2 diabetes. (PMID:15519277)
• A comparision of gene expression patterns induced by hepatic nuclear factors, HNF6, HNF4alpha and HNF1beta, in a pancreatic beta- cell line. (PMID:15520459)
• human microsomal triglyceride transfer protein is transcriptionally regulated by hepatocyte nuclear factor-4alpha (PMID:15547294)
• Variants in both the P1 and P2 promoters of HNF4A increase risk for typical type 2 diabetes. (PMID:15561969)

Cross-species orthologs

30 orthologs

Organism	Symbol	Gene ID
danio_rerio	hnf4a	ENSDARG00000021494
mus_musculus	Hnf4a	ENSMUSG00000017950
rattus_norvegicus	Hnf4a	ENSRNOG00000008895
drosophila_melanogaster	usp	FBGN0003964
drosophila_melanogaster	Hr78	FBGN0015239
drosophila_melanogaster	Hr83	FBGN0037436
caenorhabditis_elegans		WBGENE00003626
caenorhabditis_elegans		WBGENE00003650
caenorhabditis_elegans	nhr-69	WBGENE00003659
caenorhabditis_elegans		WBGENE00003683
caenorhabditis_elegans		WBGENE00003706
caenorhabditis_elegans		WBGENE00003719
caenorhabditis_elegans		WBGENE00003726
caenorhabditis_elegans		WBGENE00007547
caenorhabditis_elegans		WBGENE00008221
caenorhabditis_elegans		WBGENE00011097
caenorhabditis_elegans		WBGENE00011098
caenorhabditis_elegans		WBGENE00011099
caenorhabditis_elegans		WBGENE00011100
caenorhabditis_elegans		WBGENE00015395
caenorhabditis_elegans		WBGENE00015396
caenorhabditis_elegans		WBGENE00015397
caenorhabditis_elegans		WBGENE00015705
caenorhabditis_elegans		WBGENE00016975
caenorhabditis_elegans		WBGENE00017198
caenorhabditis_elegans		WBGENE00017787
caenorhabditis_elegans		WBGENE00020748
caenorhabditis_elegans		WBGENE00021848
caenorhabditis_elegans		WBGENE00022423
caenorhabditis_elegans		WBGENE00044354

Paralogs (11): NR2E1 (ENSG00000112333), NR2C1 (ENSG00000120798), RXRG (ENSG00000143171), NR2F6 (ENSG00000160113), HNF4G (ENSG00000164749), NR2F1 (ENSG00000175745), NR2C2 (ENSG00000177463), NR2F2 (ENSG00000185551), RXRA (ENSG00000186350), RXRB (ENSG00000204231), NR2E3 (ENSG00000278570)

Protein

Protein identifiers

Hepatocyte nuclear factor 4-alpha — P41235 (reviewed: P41235)

Alternative names: Nuclear receptor subfamily 2 group A member 1, Transcription factor 14, Transcription factor HNF-4

All UniProt accessions (13): P41235, A0A087WXV4, A0A804HI58, A0A804HIR4, A0A804HJ41, A0A804HJ81, A0A804HJJ6, A0A804HJL7, B9VVT8, F1D8S2, F1D8T0, F1D8T1, F8WBS7

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional regulator which controls the expression of hepatic genes during the transition of endodermal cells to hepatic progenitor cells, facilitating the recruitment of RNA pol II to the promoters of target genes. Activates the transcription of CYP2C38. Represses the CLOCK-BMAL1 transcriptional activity and is essential for circadian rhythm maintenance and period regulation in the liver and colon cells.

Subunit / interactions. Homodimerization is required for HNF4-alpha to bind to its recognition site. Interacts with CLOCK, BMAL1, CRY1, CRY2, PER1 and PER2. Interacts with NR0B2/SHP; the resulting heterodimer is transcriptionally inactive. Interacts with DDX3X; this interaction disrupts the interaction between HNF4 and NR0B2 that forms inactive heterodimers and enhances the formation of active HNF4 homodimers.

Subcellular location. Nucleus.

Post-translational modifications. Phosphorylated on tyrosine residue(s); phosphorylation is important for its DNA-binding activity. Phosphorylation may directly or indirectly play a regulatory role in the subnuclear distribution. Phosphorylation at Ser-313 by AMPK reduces the ability to form homodimers and bind DNA. Acetylation at Lys-458 lowers transcriptional activation by about two-fold.

Disease relevance. Maturity-onset diabetes of the young 1 (MODY1) [MIM:125850] A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. The disease is caused by variants affecting the gene represented in this entry. Type 2 diabetes mellitus (T2D) [MIM:125853] A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. Disease susceptibility may be associated with variants affecting the gene represented in this entry. Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young (FRTS4) [MIM:616026] An autosomal dominant disease characterized by Fanconi syndrome associated with a beta cell phenotype of neonatal hyperinsulinism with macrosomia and young onset diabetes. Fanconi syndrome is a proximal tubulopathy resulting in generalized aminoaciduria, low molecular weight proteinuria, glycosuria, hyperphosphaturia and hypouricemia. Some FRTS4 patients have nephrocalcinosis, renal impairment, hypercalciuria with relative hypocalcemia, and hypermagnesemia. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.

Miscellaneous. Binds fatty acids. Produced by alternative promoter usage. Produced by alternative splicing of isoform HNF4-Alpha-1. Produced by alternative splicing of isoform HNF4-Alpha-1. Produced by alternative splicing of isoform HNF4-Alpha-1. Produced by alternative promoter usage. Produced by alternative splicing of isoform HNF4-Alpha-7. Produced by alternative splicing of isoform HNF4-Alpha-7.

Similarity. Belongs to the nuclear hormone receptor family. NR2 subfamily.

Isoforms (7)

UniProt ID	Names	Canonical?
P41235-1	HNF4-Alpha-1, HNF-4B	yes
P41235-2	HNF4-Alpha-2, HNF4-A
P41235-3	HNF4-Alpha-3, HNF4-C
P41235-4	HNF4-Alpha-4
P41235-5	HNF4-Alpha-7
P41235-6	HNF4-Alpha-8
P41235-7	HNF4-Alpha-9

RefSeq proteins (10): NP_000448, NP_001025174, NP_001025175, NP_001245284, NP_001274111, NP_001274112, NP_001274113, NP_787110, NP_849180, NP_849181 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000536	Nucl_hrmn_rcpt_lig-bd	Domain
IPR001628	Znf_hrmn_rcpt	Domain
IPR001723	Nuclear_hrmn_rcpt	Family
IPR013088	Znf_NHR/GATA	Homologous_superfamily
IPR035500	NHR-like_dom_sf	Homologous_superfamily
IPR049635	HNF4_LBD	Domain
IPR049636	HNF4-like_DBD	Domain
IPR050274	Nuclear_hormone_rcpt_NR2	Family

Pfam: PF00104, PF00105

UniProt features (61 total): helix 17, modified residue 10, sequence variant 9, strand 6, splice variant 4, turn 3, cross-link 2, zinc finger region 2, mutagenesis site 2, chain 1, domain 1, DNA-binding region 1, sequence conflict 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
3CBB	X-RAY DIFFRACTION	2
8C1L	X-RAY DIFFRACTION	2
1PZL	X-RAY DIFFRACTION	2.1
3FS1	X-RAY DIFFRACTION	2.2
9IBR	X-RAY DIFFRACTION	2.78
4IQR	X-RAY DIFFRACTION	2.9
6CHT	X-RAY DIFFRACTION	3.17
4B7W	X-RAY DIFFRACTION	4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P41235-F1	74.83	0.56

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (12): 166, 167, 313, 429, 432, 436, 458, 234, 307, 142, 143, 144

Mutagenesis-validated functional residues (2):

Position	Phenotype
313	abolishes ampk-mediated phosphorylation.
313	phosphomimetic mutant that leads to reduced ability to bind dna.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-383280	Nuclear Receptor transcription pathway
R-HSA-9831926	Nephron development
R-HSA-210745	Regulation of gene expression in beta cells

MSigDB gene sets: 363 (showing top): GOBP_CIRCADIAN_RHYTHM, GOBP_ACYLGLYCEROL_HOMEOSTASIS, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, PID_HNF3B_PATHWAY, GOBP_STEROL_HOMEOSTASIS, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, GOBP_INSULIN_SECRETION, AREB6_03, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_GROWTH, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT

GO Biological Process (30): regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), lipid metabolic process (GO:0006629), xenobiotic metabolic process (GO:0006805), sex differentiation (GO:0007548), blood coagulation (GO:0007596), negative regulation of cell population proliferation (GO:0008285), response to glucose (GO:0009749), regulation of gastrulation (GO:0010470), regulation of lipid metabolic process (GO:0019216), signal transduction involved in regulation of gene expression (GO:0023019), cell differentiation (GO:0030154), negative regulation of cell growth (GO:0030308), glucose homeostasis (GO:0042593), cholesterol homeostasis (GO:0042632), regulation of circadian rhythm (GO:0042752), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), rhythmic process (GO:0048511), regulation of insulin secretion (GO:0050796), lipid homeostasis (GO:0055088), phospholipid homeostasis (GO:0055091), regulation of growth hormone receptor signaling pathway (GO:0060398), triglyceride homeostasis (GO:0070328), obsolete regulation of ornithine metabolic process (GO:0090368), regulation of DNA-templated transcription (GO:0006355), gene expression (GO:0010467), nuclear receptor-mediated steroid hormone signaling pathway (GO:0030518), intracellular receptor signaling pathway (GO:0030522)

GO Molecular Function (18): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), chromatin binding (GO:0003682), DNA-binding transcription factor activity (GO:0003700), nuclear receptor activity (GO:0004879), signaling receptor binding (GO:0005102), fatty acid binding (GO:0005504), zinc ion binding (GO:0008270), protein homodimerization activity (GO:0042803), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), sequence-specific double-stranded DNA binding (GO:1990837), nuclear steroid receptor activity (GO:0003707), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565), metal ion binding (GO:0046872)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Generic Transcription Pathway	1
Kidney development	1
Regulation of beta-cell development	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	4
DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
transcription by RNA polymerase II	2
negative regulation of cellular process	2
regulation of transcription by RNA polymerase II	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
binding	2
primary metabolic process	1
metabolic process	1
cellular response to xenobiotic stimulus	1
developmental process involved in reproduction	1
hemostasis	1
wound healing	1
coagulation	1
cell population proliferation	1
regulation of cell population proliferation	1
response to hexose	1
gastrulation	1
regulation of anatomical structure morphogenesis	1
regulation of embryonic development	1
lipid metabolic process	1
regulation of primary metabolic process	1
signal transduction	1
regulation of gene expression	1
cellular developmental process	1
regulation of cell growth	1
cell growth	1
negative regulation of growth	1
carbohydrate homeostasis	1
sterol homeostasis	1
circadian rhythm	1
regulation of biological process	1
negative regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
biological_process	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1

Protein interactions and networks

STRING

4264 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HNF4A	LEF1	Q9UJU2	999
HNF4A	CTNNB1	P35222	999
HNF4A	PPARGC1A	Q9UBK2	993
HNF4A	SMAD4	Q13485	987
HNF4A	BCL9	O00512	979
HNF4A	EP300	Q09472	978
HNF4A	NR0B2	Q15466	963
HNF4A	FOXO1	Q12778	947
HNF4A	SMAD3	P84022	941
HNF4A	CTBP1	Q13363	936
HNF4A	HNF1A	P20823	935
HNF4A	AXIN1	O15169	926
HNF4A	TLE1	Q04724	923
HNF4A	GSK3B	P49841	919
HNF4A	TCF7L2	Q9NQB0	908

IntAct

114 interactions, top by confidence:

A	B	Type	Score
HNF4A	PPARGC1A	psi-mi:“MI:0407”(direct interaction)	0.650
HNF4A	TP53	psi-mi:“MI:0914”(association)	0.600
HNF4A	TP53	psi-mi:“MI:0915”(physical association)	0.600
	HNF4A	psi-mi:“MI:0915”(physical association)	0.580
HNF4A		psi-mi:“MI:0915”(physical association)	0.580
	HNF4A	psi-mi:“MI:0914”(association)	0.580
HNF4A	PROX1	psi-mi:“MI:0915”(physical association)	0.580

BioGRID (353): HNF4A (Biochemical Activity), HNF4A (Biochemical Activity), SREBF1 (Affinity Capture-Western), CTNNB1 (Co-localization), NR1I2 (Two-hybrid), NR1I2 (Reconstituted Complex), HNF4A (Reconstituted Complex), NR0B2 (Reconstituted Complex), HNF4A (Two-hybrid), HNF4A (Two-hybrid), NR1I2 (Affinity Capture-Western), PPARGC1A (Affinity Capture-Western), HNF4A (Two-hybrid), HNF4A (Two-hybrid), DMD (Two-hybrid)

ESM2 similar proteins: A0P8Z4, O00482, O35507, O42101, O76202, O95718, P03372, P06211, P11475, P19785, P22449, P28701, P28705, P35396, P35398, P37234, P41235, P45448, P48443, P49698, P49867, P49884, P51128, P51129, P51448, P54779, P57783, P70033, Q03181, Q06726, Q0GFF6, Q0VC20, Q0ZAQ8, Q15406, Q29040, Q4V8R7, Q505F1, Q5BJR8, Q5REL6, Q61539

Diamond homologs: A2T7D9, A2T928, A3RGC1, G5EFF5, O00482, O13124, O18531, O35627, O42101, O42295, O42392, O42450, O54915, O57606, O75469, O97716, P03373, P04625, P10276, P10827, P10828, P11416, P11473, P13053, P13631, P15204, P18113, P18115, P18117, P18119, P18514, P18911, P22448, P33242, P33244, P37242, P41235, P48281, P49700, P49701

SIGNOR signaling

31 interactions.

A	Effect	B	Mechanism
PRKAA1	“down-regulates activity”	HNF4A	phosphorylation
HNF4A	“up-regulates quantity by expression”	G6PC1	“transcriptional regulation”
HNF4A	“up-regulates quantity by expression”	PCK1	“transcriptional regulation”
p38	up-regulates	HNF4A	phosphorylation
HNF4A	“up-regulates quantity by expression”	GK	“transcriptional regulation”
SRC	down-regulates	HNF4A	phosphorylation
AMPK	down-regulates	HNF4A	phosphorylation
HNF4A	“up-regulates quantity by expression”	AKR1C4	“transcriptional regulation”
NR3C1	“up-regulates quantity by expression”	HNF4A	“transcriptional regulation”
HNF4A	“down-regulates quantity by repression”	F12	“transcriptional regulation”
“all-trans-retinoic acid”	“down-regulates quantity by repression”	HNF4A
HNF4A	“up-regulates quantity by expression”	AFP	“transcriptional regulation”
HNF4A	“up-regulates quantity by expression”	C1QTNF5	“transcriptional regulation”
HNF4A	“down-regulates quantity by repression”	GFER	“transcriptional regulation”
HNF4A	“up-regulates quantity by expression”	PCSK9	“transcriptional regulation”
HNF4A	“up-regulates quantity by expression”	LDLR	“transcriptional regulation”
HNF4A	“down-regulates quantity by repression”	ABCG5	“transcriptional regulation”
HNF4A	“down-regulates quantity by repression”	ABCG8	“transcriptional regulation”
HNF4A	“up-regulates quantity by expression”	NPC1L1	“transcriptional regulation”
HNF4A	“up-regulates quantity by expression”	CYP27A1	“transcriptional regulation”
HNF4A	“up-regulates quantity by expression”	G6P	“transcriptional regulation”
MAPK3	“down-regulates activity”	HNF4A	phosphorylation
NR0B2	“down-regulates quantity by repression”	HNF4A	“transcriptional regulation”
PRKAA2	“down-regulates quantity by destabilization”	HNF4A	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 30 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Factors involved in megakaryocyte development and platelet production	5	14.4×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
regulation of circadian rhythm	5	43.2×	1e-05
positive regulation of gene expression	6	7.8×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

768 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	72
Likely pathogenic	87
Uncertain significance	272
Likely benign	119
Benign	55

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1299750	NM_175914.5(HNF4A):c.-181G>A	Pathogenic
1299753	NM_175914.5(HNF4A):c.48C>A (p.Tyr16Ter)	Pathogenic
1299754	NM_175914.5(HNF4A):c.48C>G (p.Tyr16Ter)	Pathogenic
1338424	NM_175914.5(HNF4A):c.325C>T (p.Gln109Ter)	Pathogenic
1436365	NM_175914.5(HNF4A):c.536G>A (p.Trp179Ter)	Pathogenic
1437566	NM_175914.5(HNF4A):c.562G>T (p.Glu188Ter)	Pathogenic
1457657	NM_175914.5(HNF4A):c.352C>T (p.Arg118Ter)	Pathogenic
1459983	NC_000020.10:g.(?42984253)(42984513_?)del	Pathogenic
156152	NM_175914.5(HNF4A):c.187C>T (p.Arg63Trp)	Pathogenic
1691373	NM_175914.5(HNF4A):c.47dup (p.Tyr16Ter)	Pathogenic
1700659	NM_175914.5(HNF4A):c.537G>A (p.Trp179Ter)	Pathogenic
1700662	NM_175914.5(HNF4A):c.1064-1G>T	Pathogenic
1700663	NM_175914.5(HNF4A):c.981G>A (p.Trp327Ter)	Pathogenic
1700669	NM_175914.5(HNF4A):c.1086dup (p.Ala363fs)	Pathogenic
1807419	NM_175914.5(HNF4A):c.50-1G>A	Pathogenic
2169620	NM_175914.5(HNF4A):c.874C>T (p.Gln292Ter)	Pathogenic
2427543	NC_000020.10:g.(?43047045)(43280248_?)del	Pathogenic
2574172	NM_175914.5(HNF4A):c.876_877insT (p.Val293fs)	Pathogenic
2578346	NM_175914.5(HNF4A):c.225-21A>G	Pathogenic
2581134	NM_175914.5(HNF4A):c.734G>A (p.Arg245His)	Pathogenic
2710007	NM_175914.5(HNF4A):c.1210C>T (p.Gln404Ter)	Pathogenic
2736967	NM_175914.5(HNF4A):c.199C>T (p.Arg67Trp)	Pathogenic
3068527	NM_175914.5(HNF4A):c.278G>C (p.Cys93Ser)	Pathogenic
3068530	NM_175914.5(HNF4A):c.320C>A (p.Ala107Asp)	Pathogenic
3068531	NM_175914.5(HNF4A):c.331G>T (p.Glu111Ter)	Pathogenic
3068532	NM_175914.5(HNF4A):c.421del (p.Arg141fs)	Pathogenic
3238969	NM_175914.5(HNF4A):c.583-1G>A	Pathogenic
3238975	NM_175914.5(HNF4A):c.1A>G (p.Met1Val)	Pathogenic
3238977	NM_175914.5(HNF4A):c.62C>A (p.Ser21Ter)	Pathogenic
3248362	NC_000020.10:g.(?43047045)(43047172_?)del	Pathogenic

SpliceAI

1648 predictions. Top by Δscore:

Variant	Effect	Δscore
20:44406050:T:TA	acceptor_gain	1.0000
20:44406057:GACAC:G	acceptor_gain	1.0000
20:44406230:CAGG:C	donor_loss	1.0000
20:44406231:AGGT:A	donor_loss	1.0000
20:44406232:GGTG:G	donor_loss	1.0000
20:44406233:G:C	donor_loss	1.0000
20:44406234:T:A	donor_loss	1.0000
20:44413692:A:AG	acceptor_gain	1.0000
20:44413693:G:GA	acceptor_gain	1.0000
20:44413693:GCC:G	acceptor_gain	1.0000
20:44414493:T:TA	acceptor_gain	1.0000
20:44414496:A:AG	acceptor_gain	1.0000
20:44414497:T:G	acceptor_gain	1.0000
20:44414501:TCGAA:T	acceptor_loss	1.0000
20:44414502:C:A	acceptor_gain	1.0000
20:44414503:GAA:G	acceptor_loss	1.0000
20:44414504:AAGAT:A	acceptor_loss	1.0000
20:44414505:A:AG	acceptor_gain	1.0000
20:44414505:A:AT	acceptor_loss	1.0000
20:44414506:G:GA	acceptor_gain	1.0000
20:44414506:GA:G	acceptor_gain	1.0000
20:44414506:GAT:G	acceptor_gain	1.0000
20:44414506:GATC:G	acceptor_gain	1.0000
20:44414506:GATCA:G	acceptor_gain	1.0000
20:44414661:AGG:A	donor_loss	1.0000
20:44414663:G:GC	donor_loss	1.0000
20:44414663:G:GG	donor_gain	1.0000
20:44416686:G:GT	donor_gain	1.0000
20:44418420:TTCA:T	acceptor_loss	1.0000
20:44418421:TCA:T	acceptor_loss	1.0000

AlphaMissense

2962 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:44406120:T:A	C60S	1.000
20:44406120:T:C	C60R	1.000
20:44406121:G:A	C60Y	1.000
20:44406121:G:C	C60S	1.000
20:44406121:G:T	C60F	1.000
20:44406122:T:G	C60W	1.000
20:44406127:T:A	I62N	1.000
20:44406127:T:G	I62S	1.000
20:44406129:T:A	C63S	1.000
20:44406129:T:C	C63R	1.000
20:44406130:G:A	C63Y	1.000
20:44406130:G:C	C63S	1.000
20:44406130:G:T	C63F	1.000
20:44406131:C:G	C63W	1.000
20:44406135:G:C	D65H	1.000
20:44406136:A:C	D65A	1.000
20:44406136:A:T	D65V	1.000
20:44406142:C:A	A67D	1.000
20:44406147:G:C	G69R	1.000
20:44406148:G:A	G69D	1.000
20:44406153:C:A	H71N	1.000
20:44406153:C:G	H71D	1.000
20:44406154:A:G	H71R	1.000
20:44406154:A:T	H71L	1.000
20:44406155:C:A	H71Q	1.000
20:44406155:C:G	H71Q	1.000
20:44406156:T:A	Y72N	1.000
20:44406156:T:C	Y72H	1.000
20:44406156:T:G	Y72D	1.000
20:44406157:A:G	Y72C	1.000

dbSNP variants (sampled 300 via entrez): RS1000108655 (20:44392261 G>A,C), RS1000146738 (20:44430187 T>A,C), RS1000214206 (20:44429141 C>T), RS1000224592 (20:44424553 G>A), RS1000245827 (20:44382017 T>G), RS1000303293 (20:44379890 T>A,C), RS1000341566 (20:44398335 G>A), RS1000406853 (20:44418427 G>A), RS1000408337 (20:44428060 A>G), RS1000456367 (20:44425599 G>A), RS1000462745 (20:44383599 T>G), RS1000473674 (20:44388171 C>G), RS1000515564 (20:44422743 C>T), RS1000519958 (20:44430387 A>C), RS1000550511 (20:44425940 G>A)

Disease associations

OMIM: gene MIM:600281 | disease phenotypes: MIM:125853, MIM:125850, MIM:616026, MIM:125851, MIM:606391, MIM:174050, MIM:600496

GenCC curated gene-disease

Disease	Classification	Inheritance
maturity-onset diabetes of the young type 1	Definitive	Autosomal dominant
diabetes mellitus, noninsulin-dependent	Strong	Autosomal dominant
Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young	Strong	Autosomal dominant
hyperinsulinism due to HNF4A deficiency	Supportive	Autosomal dominant
maturity-onset diabetes of the young	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
monogenic diabetes	Definitive	AD

Mondo (13): type 2 diabetes mellitus (MONDO:0005148), maturity-onset diabetes of the young type 1 (MONDO:0007452), Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young (MONDO:0014458), maturity-onset diabetes of the young type 2 (MONDO:0007453), monogenic diabetes (MONDO:0015967), maturity-onset diabetes of the young (MONDO:0018911), autosomal dominant polycystic liver disease (MONDO:0000447), familial hyperinsulinism (MONDO:0017182), hyperinsulinism (MONDO:0002177), hyperinsulinism due to HNF1A deficiency (MONDO:0017935), maturity-onset diabetes of the young type 3 (MONDO:0010894), hyperinsulinism due to HNF4A deficiency (MONDO:0016988), (MONDO:0007455)

Orphanet (7): MODY (Orphanet:552), HNF1B-related autosomal dominant tubulointerstitial kidney disease (Orphanet:93111), Rare genetic diabetes mellitus (Orphanet:183625), Isolated polycystic liver disease (Orphanet:2924), Familial hyperinsulinism (Orphanet:276525), Hyperinsulinism due to HNF1A deficiency (Orphanet:324575), Congenital hyperinsulinism due to HNF4A deficiency (Orphanet:263455)

HPO phenotypes

74 total (30 of 74 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000077	Abnormality of the kidney
HP:0000093	Proteinuria
HP:0000107	Renal cyst
HP:0000112	Nephropathy
HP:0000119	Abnormality of the genitourinary system
HP:0000121	Nephrocalcinosis
HP:0000488	Retinopathy
HP:0000713	Agitation
HP:0000819	Diabetes mellitus
HP:0000825	Hyperinsulinemic hypoglycemia
HP:0000831	Insulin-resistant diabetes mellitus
HP:0000842	Hyperinsulinemia
HP:0000855	Insulin resistance
HP:0000956	Acanthosis nigricans
HP:0000975	Hyperhidrosis
HP:0000980	Pallor
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001254	Lethargy
HP:0001259	Coma
HP:0001319	Neonatal hypotonia
HP:0001337	Tremor
HP:0001511	Intrauterine growth retardation
HP:0001513	Obesity
HP:0001520	Large for gestational age
HP:0001649	Tachycardia
HP:0001738	Exocrine pancreatic insufficiency
HP:0001942	Metabolic acidosis
HP:0001943	Hypoglycemia

GWAS associations

93 associations (top):

Study	Trait	p-value
GCST000290_8	HDL cholesterol	8.000000e-10
GCST000527_6	Ulcerative colitis	9.000000e-17
GCST000755_4	HDL cholesterol	1.000000e-15
GCST000760_39	Cholesterol, total	6.000000e-13
GCST000965_12	C-reactive protein levels	2.000000e-09
GCST001213_6	Type 2 diabetes	3.000000e-10
GCST001351_6	Type 2 diabetes	1.000000e-11
GCST001650_2	C-reactive protein	8.000000e-06
GCST001728_19	Ulcerative colitis	1.000000e-43
GCST002221_58	Cholesterol, total	1.000000e-24
GCST002223_36	HDL cholesterol	2.000000e-34
GCST002352_18	Type 2 diabetes	5.000000e-08
GCST002899_11	HDL cholesterol	5.000000e-20
GCST003194_7	Fibrinogen levels	1.000000e-10
GCST003523_24	Coenzyme Q10 levels	3.000000e-06
GCST003678_7	C-reactive protein levels or total cholesterol levels (pleiotropy)	1.000000e-20
GCST003679_21	C-reactive protein levels or LDL-cholesterol levels (pleiotropy)	4.000000e-14
GCST003680_11	C-reactive protein levels or HDL-cholesterol levels (pleiotropy)	4.000000e-28
GCST004121_17	Fibrinogen levels	2.000000e-09
GCST004122_34	Fibrinogen levels	7.000000e-09
GCST004604_45	Hematocrit	6.000000e-10
GCST004613_93	Sum neutrophil eosinophil counts	9.000000e-12
GCST004614_51	Granulocyte count	2.000000e-11
GCST004620_131	Sum basophil neutrophil counts	1.000000e-11
GCST004626_162	Myeloid white cell count	7.000000e-10
GCST004629_49	Neutrophil count	6.000000e-12
GCST004633_128	Neutrophil percentage of white cells	1.000000e-10
GCST004894_88	Type 2 diabetes	4.000000e-10
GCST005434_24	Pancreatic cancer	5.000000e-06
GCST005537_53	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	7.000000e-16

EFO canonical traits (22, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0004458	C-reactive protein measurement
EFO:0007836	coenzyme Q10 measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004348	hematocrit
EFO:0004833	neutrophil count
EFO:0004842	eosinophil count
EFO:0007987	granulocyte count
EFO:0005090	basophil count
EFO:0007990	neutrophil percentage of leukocytes
EFO:0004619	factor VII measurement
EFO:0004761	uric acid measurement
EFO:0009924	Drugs used in diabetes use measurement
EFO:0004329	alcohol drinking
EFO:0004531	urate measurement
EFO:0000195	metabolic syndrome
EFO:0004509	hemoglobin measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004615	apolipoprotein B measurement
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0004305	erythrocyte count

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D003924	Diabetes Mellitus, Type 2	C18.452.394.750.149; C19.246.300
D006946	Hyperinsulinism	C18.452.394.968
C562772	Mason-Type Diabetes (supp.)
C565101	Maturity-Onset Diabetes of the Young, Type 1 (supp.)
C563933	Maturity-Onset Diabetes of the Young, Type 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5398 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

7 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1884613	Metabolism/PK	3	efavirenz	HIV infectious disease
rs2071197	Efficacy,Metabolism/PK	4	lamotrigine	Epilepsy
rs2071197	Metabolism/PK	4	carbamazepine	Epilepsy
rs2273618	Toxicity	3	docetaxel	Anemia;Nasopharyngeal Neoplasms
rs3212198	Dosage	3	warfarin
rs3746574	Toxicity	3	docetaxel	Anemia;Nasopharyngeal Neoplasms
rs6130615	Toxicity	3	docetaxel	Anemia;Nasopharyngeal Neoplasms

PharmGKB variants

19 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1884613	HNF4A	3	1.50	1	efavirenz
rs2071197	HNF4A	4	-0.50	2	carbamazepine;lamotrigine
rs2273618	HNF4A	3	1.50	1	docetaxel
rs3212198	HNF4A	3	0.00	1	warfarin
rs3746574	HNF4A	3	1.50	1	docetaxel
rs6130615	HNF4A	3	1.50	1	docetaxel
rs3212183	HNF4A		0.00	0
rs11086926	HNF4A		0.00	0
rs3212185	HNF4A		0.00	0
rs2425637	HNF4A		0.00	0
rs3212197	HNF4A		0.00	0
rs6093976	HNF4A		0.00	0
rs6093978	HNF4A		0.00	0
rs745975	HNF4A		0.00	0
rs2425640	HNF4A		0.00	0
rs1800961	HNF4A		0.00	0
rs6031587	HNF4A		0.00	0
rs3212207	HNF4A		0.00	0
rs3212191	HNF4A		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: nhr — 2A. Hepatocyte nuclear factor-4 receptors

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
HNF4α inhibitor	Agonist	8.22	pEC50

Binding affinities (BindingDB)

163 measured of 219 human assays (233 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
(4-acetyloxy-3-chloranyl-2-morpholin-4-yl-naphthalen-1-yl) ethanoate	EC50	0.133 nM
N-[4-(methoxymethyl)-1-(2-thiophen-2-ylethyl)piperidin-4-yl]-N-phenyl-propanamide;2-oxidanylpropane-1,2,3-tricarboxylic acid	KI	50 nM
SMR000469200	KI	126 nM
MLS000122969	IC50	127 nM
2-{2-ethoxy-5-[(4-ethylpiperazine-1-)sulfonyl]phenyl}-5-methyl-7-propyl-3H,4H-imidazo[1,5-a][1,2,4]triazin-4-one	IC50	300 nM
(3Z,5E)-1-ethyl-3,5-bis(3-hydroxy-4-methoxy-benzylidene)-4-piperidone	EC50	380 nM
2-butyl-4-thiazolidinecarboxylic acid	IC50	814 nM
N-cyclohexyl-2-[3-(2-furanyl)-2-oxo-1-quinoxalinyl]-2-phenylacetamide	IC50	817 nM
SMR001821229	IC50	828 nM
cid_53383152	IC50	970 nM
5-hydroxy-4-[[4-(2-hydroxyethyl)-1-piperazinyl]methyl]-2-methyl-3-benzo[g]benzofurancarboxylic acid ethyl ester	IC50	1130 nM
7-methyl-1,3-dinitro-acridine	EC50	1190 nM
N-benzyl-2-(4-cyanophenyl)-2-[3-(furan-2-yl)-2-oxoquinoxalin-1-yl]acetamide	IC50	1300 nM
cid_53383173	IC50	1340 nM
cid_53383343	IC50	1400 nM
cid_53383347	IC50	1480 nM
N-cyclohexyl-2-[3-(2-furanyl)-2-oxo-1-quinoxalinyl]-2-(1-naphthalenyl)acetamide	IC50	1480 nM
cid_6377798	IC50	1560 nM
MLS000680483	IC50	1590 nM
(E)-2-cyano-3-[3-[(E)-2-cyano-3-(2-methoxyethylamino)-3-oxidanylidene-prop-1-enyl]phenyl]-N-(2-methoxyethyl)prop-2-enamide	EC50	1650 nM
N-tert-butyl-2-cyclopropyl-2-[3-(2-furanyl)-2-oxo-1-quinoxalinyl]acetamide	IC50	1720 nM
N-cyclohexyl-2-[3-(2-furanyl)-2-oxo-1-quinoxalinyl]-2-(4-methoxyphenyl)acetamide	IC50	1750 nM
N-tert-butyl-2-[3-(2-furanyl)-2-oxo-1-quinoxalinyl]-2-(4-methoxyphenyl)acetamide	IC50	1780 nM
MLS003674221	IC50	1810 nM
cid_53383334	IC50	1840 nM
N-tert-butyl-2-(2-fluorophenyl)-2-[3-(furan-2-yl)-2-oxoquinoxalin-1-yl]acetamide	IC50	1850 nM
MLS003674201	IC50	1860 nM
MLS003674212	IC50	1860 nM
MLS000779343	IC50	1870 nM
SMR000132574	IC50	1870 nM
1-(2-fluorophenyl)-5-{4-[(5-nitro-2-pyridinyl)oxy]benzylidene}-2,4,6(1H,3H,5H)-pyrimidinetrione	IC50	1880 nM
N-tert-butyl-2-[3-(furan-2-yl)-2-oxoquinoxalin-1-yl]-2-(4-phenylphenyl)acetamide	IC50	1910 nM
2-(1-benzofuran-2-yl)-2-[3-(furan-2-yl)-2-oxoquinoxalin-1-yl]-N-pentylacetamide	IC50	2000 nM
cid_53383163	IC50	2020 nM
MLS000517420	IC50	2170 nM
cid_53383333	IC50	2170 nM
2-(1-benzofuran-2-yl)-N-cyclohexyl-2-[3-(furan-2-yl)-2-oxidanylidene-quinoxalin-1-yl]ethanamide	IC50	2190 nM
N-cyclohexyl-2-[3-(furan-2-yl)-2-oxidanylidene-quinoxalin-1-yl]-2-quinolin-4-yl-ethanamide	IC50	2230 nM
2-(2-fluorophenyl)-2-[3-(furan-2-yl)-2-oxidanylidene-quinoxalin-1-yl]-N-(phenylmethyl)ethanamide	IC50	2240 nM
Cyclopentanone, 2-heptylidene-5-(1-pyrrolidinylmethyl)-, (E)-, hydrochloride	IC50	2250 nM
MLS000532188	IC50	2270 nM
N-tert-butyl-2-[3-(furan-2-yl)-2-oxoquinoxalin-1-yl]-2-naphthalen-1-ylacetamide	IC50	2270 nM
3-phenyl-1,4-benzodioxin-2-carboxaldehyde	EC50	2280 nM
MLS003674211	IC50	2400 nM
MLS003674210	IC50	2410 nM
N-(2,6-dimethylphenyl)-2-[3-(furan-2-yl)-2-oxidanylidene-quinoxalin-1-yl]-2-(4-methoxyphenyl)ethanamide	IC50	2420 nM
MLS003674174	IC50	2460 nM
MLS003674199	IC50	2480 nM
cid_53383516	IC50	2540 nM
cid_53383325	IC50	2560 nM

ChEMBL bioactivities

59 potent at pChembl≥5 of 63 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.22	EC50	6	nM	CHEMBL6188913
7.89	EC50	13	nM	CHEMBL6192782
7.85	EC50	14	nM	CHEMBL6189288
7.64	Kd	23	nM	CHEMBL6188913
7.52	EC50	30	nM	CHEMBL6188617
7.52	EC50	30	nM	CHEMBL6191813
7.40	EC50	40	nM	CHEMBL6191139
7.39	EC50	41	nM	CHEMBL6193595
7.30	EC50	50	nM	CHEMBL6191053
7.22	EC50	60	nM	CHEMBL508948
7.22	EC50	60	nM	CHEMBL6192960
7.02	Ki	96	nM	CHEMBL3719130
6.96	Ki	110	nM	CHEMBL3714906
6.89	EC50	130	nM	CHEMBL6189697
6.87	Ki	135	nM	CHEMBL3715206
6.85	EC50	140	nM	CHEMBL6191864
6.82	EC50	150	nM	CHEMBL6193200
6.79	Ki	163	nM	CHEMBL3716204
6.78	Ki	165	nM	CHEMBL3715006
6.67	Ki	215	nM	CHEMBL3717945
6.66	Ki	219	nM	CHEMBL3718791
6.63	Ki	234	nM	CHEMBL3719031
6.61	Ki	244	nM	CHEMBL3715067
6.60	EC50	250	nM	CHEMBL6188842
6.52	EC50	300	nM	CHEMBL6190077
6.50	IC50	320	nM	CHEMBL6192869
6.49	Ki	322	nM	CHEMBL3716364
6.48	EC50	330	nM	CHEMBL1834962
6.47	Ki	339	nM	CHEMBL3718230
6.44	Ki	364	nM	CHEMBL3718049
6.44	Kd	360	nM	CHEMBL6188913
6.40	IC50	400	nM	CHEMBL6190802
6.29	Ki	514	nM	CHEMBL3718438
6.24	Ki	580	nM	CHEMBL3717489
6.15	Ki	710	nM	CHEMBL3714833
6.14	Ki	721	nM	CHEMBL3716703
6.01	Ki	966	nM	CHEMBL3715185
6.00	Ki	1010	nM	CHEMBL3716661
5.97	Ki	1075	nM	CHEMBL3714795
5.92	Ki	1193	nM	CHEMBL3718949
5.92	EC50	1200	nM	CHEMBL6192519
5.91	EC50	1220	nM	CHEMBL7135
5.89	EC50	1300	nM	CHEMBL6188824
5.89	EC50	1280	nM	CHEMBL6980
5.85	Ki	1398	nM	CHEMBL3716417
5.83	EC50	1470	nM	CHEMBL7644
5.75	EC50	1800	nM	CHEMBL6190496
5.71	EC50	1950	nM	CHEMBL7258
5.68	EC50	2090	nM	CHEMBL7174
5.66	Ki	2170	nM	CHEMBL3714844

PubChem BioAssay actives

7 with measured affinity, of 48 total; 7 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-(2-nitrobenzo[e][1]benzofuran-1-yl)ethanol	455458: Agonist activity at human full length HNF4alpha nuclear receptor expressed in human HepG2/C3A cells co-transfected with LexADBD assessed as increase in transcriptional activity after 16 hrs by beta-galactosidase one hybrid assay	ec50	1.2200	uM
1-methyl-2-nitrobenzo[e][1]benzofuran	455458: Agonist activity at human full length HNF4alpha nuclear receptor expressed in human HepG2/C3A cells co-transfected with LexADBD assessed as increase in transcriptional activity after 16 hrs by beta-galactosidase one hybrid assay	ec50	1.2800	uM
4-methoxy-2-nitrobenzo[e][1]benzofuran	455458: Agonist activity at human full length HNF4alpha nuclear receptor expressed in human HepG2/C3A cells co-transfected with LexADBD assessed as increase in transcriptional activity after 16 hrs by beta-galactosidase one hybrid assay	ec50	1.4700	uM
2-nitrobenzo[e][1]benzofuran-7-ol	455458: Agonist activity at human full length HNF4alpha nuclear receptor expressed in human HepG2/C3A cells co-transfected with LexADBD assessed as increase in transcriptional activity after 16 hrs by beta-galactosidase one hybrid assay	ec50	1.9500	uM
2-nitrobenzo[e][1]benzofuran	455458: Agonist activity at human full length HNF4alpha nuclear receptor expressed in human HepG2/C3A cells co-transfected with LexADBD assessed as increase in transcriptional activity after 16 hrs by beta-galactosidase one hybrid assay	ec50	2.0900	uM
8-methoxy-2-nitrobenzo[e][1]benzofuran	455458: Agonist activity at human full length HNF4alpha nuclear receptor expressed in human HepG2/C3A cells co-transfected with LexADBD assessed as increase in transcriptional activity after 16 hrs by beta-galactosidase one hybrid assay	ec50	2.3300	uM
7-methoxy-2-nitrobenzo[e][1]benzofuran	455458: Agonist activity at human full length HNF4alpha nuclear receptor expressed in human HepG2/C3A cells co-transfected with LexADBD assessed as increase in transcriptional activity after 16 hrs by beta-galactosidase one hybrid assay	ec50	2.5700	uM

CTD chemical–gene interactions

90 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
perfluorooctanoic acid	increases expression, decreases activity, decreases expression	7
sodium arsenite	decreases expression, increases expression	5
Dexamethasone	affects binding, increases reaction, increases activity, increases expression, decreases reaction	4
Rifampin	increases reaction, decreases expression, affects binding, increases activity, affects cotreatment (+2 more)	4
Cyclosporine	decreases expression, increases expression	4
perfluorooctane sulfonic acid	decreases expression	3
Benzo(a)pyrene	affects methylation, decreases expression	3
U 0126	increases reaction, increases expression, affects binding, decreases reaction, increases phosphorylation	2
lithocholic acid acetate	affects binding, decreases reaction, increases reaction, increases phosphorylation	2
Calcitriol	decreases activity, increases activity, decreases reaction, increases reaction, increases phosphorylation (+2 more)	2
Copper	affects cotreatment, decreases expression	2
Estradiol	decreases reaction, affects cotreatment, increases reaction, decreases expression, affects binding	2
Tretinoin	decreases activity, decreases expression, increases reaction, affects expression, affects binding (+1 more)	2
Aflatoxin B1	affects expression, decreases expression	2
Palmitic Acid	affects cotreatment, affects expression, decreases expression	2
PF-06840003	decreases expression, decreases reaction	1
fluorotelomer sulfonic acids	decreases expression	1
dicrotophos	increases expression	1
allyl isothiocyanate	affects cotreatment, decreases reaction, increases expression, increases reaction	1
propionaldehyde	decreases expression	1
bisphenol A	decreases expression	1
deoxynivalenol	increases expression, affects cotreatment, affects expression	1
quercitrin	decreases expression	1
terbufos	increases methylation	1
beta-lapachone	decreases expression	1
butyraldehyde	decreases expression	1
potassium bromate	decreases expression, increases expression	1
nonylphenol	decreases expression, decreases reaction, increases expression, affects reaction, decreases acetylation	1
ochratoxin A	decreases expression	1
4-hydroxy-2-nonenal	decreases expression	1

ChEMBL screening assays

106 unique, capped per target: 97 binding, 9 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1015274	Binding	Increase in transcriptional activity of HNF-4alpha ligand binding domain expressed in human Hep G2 cells co-transfected with Gal4-DBD by luciferase reporter gene assay	Crystal structure of the peroxisome proliferator-activated receptor gamma (PPARgamma) ligand binding domain complexed with a novel partial agonist: a new region of the hydrophobic pocket could be exploited for drug design. — J Med Chem
CHEMBL1065340	Functional	Agonist activity at human full length HNF4alpha nuclear receptor expressed in human HepG2/C3A cells co-transfected with LexADBD assessed as increase in transcriptional activity at 12.5 uM by beta-galactosidase one hybrid assay relative to c	Identification of small molecule regulators of the nuclear receptor HNF4alpha based on naphthofuran scaffolds. — Bioorg Med Chem

Cellosaurus cell lines

78 cell lines: 49 transformed cell line, 10 finite cell line, 9 induced pluripotent stem cell, 7 cancer cell line, 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0I31	GM10155	Transformed cell line	Female
CVCL_A2U9	SEES3-1V human HNF4A, clone1	Embryonic stem cell	Male
CVCL_A2V0	SEES3-1V human HNF4A, clone2	Embryonic stem cell	Male
CVCL_A2V1	SEES3-1V human HNF4A, clone3	Embryonic stem cell	Male
CVCL_AI24	GM01243	Transformed cell line	Male
CVCL_AI25	GM01244	Transformed cell line	Male
CVCL_AI26	GM01430	Finite cell line	Male
CVCL_AI27	GM01496	Finite cell line	Male
CVCL_AI28	GM01497	Finite cell line	Female
CVCL_AI29	GM01498	Transformed cell line	Female

Clinical trials (associated diseases)

318 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04239586	PHASE4	UNKNOWN	Switching From Insulin to Sulfonylurea in Diabetes Associated With Variants in MODY Genes
NCT00006163	PHASE4	COMPLETED	Computer-assisted Diabetes Self-management Interventions
NCT00036504	PHASE4	COMPLETED	Efficacy and Safety of Twice-Daily Insulin Lispro Low Mixture Compared to a Once-Daily Long Acting Insulin Comparator in Patients Who Have Been Using One or More Oral Antihyperglycemic Agents Without Insulin
NCT00044460	PHASE4	COMPLETED	Efficacy and Safety In Poorly Controlled Type 2 Diabetics
NCT00095446	PHASE4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	PHASE4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00110370	PHASE4	COMPLETED	Comparing Pre-Mixed Insulin With Insulin Glargine Combined With Rapid-Acting Insulin in Patients With Type 2 Diabetes
NCT00110448	PHASE4	COMPLETED	Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial
NCT00118950	PHASE4	COMPLETED	Effect of Metformin Versus Repaglinide Treatment in Non-Obese Type 2 Diabetic Patients Uncontrolled by Diet
NCT00118963	PHASE4	COMPLETED	Effect of Repaglinide Versus Metformin Treatment in Non-Obese Patients With Type-2-Diabetes
NCT00121966	PHASE4	COMPLETED	South Danish Diabetes Study: Evaluation of the Antidiabetic Treatment of Type 2 Diabetes Mellitus
NCT00123604	PHASE4	COMPLETED	Vascular Effects of Carvedilol Versus Metoprolol in Hypertensive Patients With Type 2 Diabetes
NCT00123643	PHASE4	COMPLETED	Vascular Effects of Rosiglitazone Versus Glyburide in Type 2 Diabetic Patients
NCT00124397	PHASE4	COMPLETED	Atorvastatin and Endothelial Function in Type 2 Diabetes Mellitus (ATTEND-Study)
NCT00129233	PHASE4	COMPLETED	Comparison of Valsartan With Amlodipine in Hypertensive Patients With Glucose Intolerance
NCT00133718	PHASE4	COMPLETED	A 2 Year Trial of Patients With Type 2 Diabetes Focusing on Cardiovascular Diagnostics and Metabolic Control
NCT00135070	PHASE4	TERMINATED	Hospital In-Patient Insulin Study
NCT00141232	PHASE4	COMPLETED	Evaluating Atorvastatin With Omega-3 Fatty Acids in Cardiovascular Risk Reduction in Patients With Type 2 Diabetes
NCT00144144	PHASE4	UNKNOWN	A Study on Ca Blocker Versus AII Antagonists in Hypertension With Type 2 Diabetes
NCT00149331	PHASE4	COMPLETED	The Effects of Two Education Strategies About Insulin on Patient Preferences and Perceptions About Insulin Therapy
NCT00162357	PHASE4	COMPLETED	Post-PCI:Cardiac Imaging in Patients With Diabetes to Detect Coronary Artery Blockages Previously Opened by Angioplasty
NCT00174681	PHASE4	COMPLETED	Tulip Study: Testing the Usefulness of Lantus When Initiated Prematurely In Patients With Type 2 Diabetes
NCT00174824	PHASE4	COMPLETED	Comparison of Insulin Glargine and NPH Human Insulin in Progression of Diabetic Retinopathy in Type 2 Diabetic Patients
NCT00177398	PHASE4	COMPLETED	Effect of Glargine Insulin on Glucose Control in Hospitalized Patients Who Receive Tube Feedings
NCT00179400	PHASE4	COMPLETED	The Role of Acute Combined PPAR Alpha and Gamma Stimulation on Insulin Action in Humans
NCT00184561	PHASE4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	PHASE4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00191178	PHASE4	COMPLETED	Effects of Insulin in Perceived Mood Symptoms in Patients With Type 2 Diabetes
NCT00191282	PHASE4	COMPLETED	Hyperglycemia and Cardiovascular Outcomes With Type 2 Diabetes
NCT00191464	PHASE4	COMPLETED	Long-Term Effects of Insulin Plus Metformin Regimens on the Overall and Postprandial Glycemic Control of Patients With Type 2 Diabetes
NCT00192803	PHASE4	UNKNOWN	Non-Insulin Dependent Diabetes Mellitus (NIDDM) and Angiotensin Converting Enzyme 2 (ACE2): Diabetic Patients Treated With Antihypertensive Drugs
NCT00202033	PHASE4	COMPLETED	Impact of Self-Monitoring Blood Glucose Frequency on Glycemic Control in Patients With Type 2 Diabetes
NCT00205660	PHASE4	COMPLETED	Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole
NCT00212290	PHASE4	COMPLETED	Insulin Resistance and Central Nervous System (CNS) Function in Type 2 Diabetes
NCT00212303	PHASE4	COMPLETED	Exercise Training in Type 2 Diabetes and Hypertension
NCT00225342	PHASE4	WITHDRAWN	Study Protocol for Rosiglitazone Versus Gliclazide in Diabetics With Angina
NCT00238472	PHASE4	COMPLETED	A Pilot Study to Evaluate the Effects of Nateglinide vs. Glibenclamide on Renal Hemodynamics and Albumin Excretion
NCT00239538	PHASE4	COMPLETED	SMOOTH - Blood Pressure Control in Diabetic/Obese Patients
NCT00240253	PHASE4	COMPLETED	A Study Evaluating the Efficacy and Safety of Adding Symlin® to Lantus® (Insulin Glargine) in Subjects With Type 2 Diabetes
NCT00240422	PHASE4	COMPLETED	Trial to Compare the Effects of Either Telmisartan (40-80 mg PO Once Daily) or Ramipril (5-10 mg PO Once Daily) on Renal Endothelial Dysfunction in Hypertensive Patients With Type 2 Diabetes