HADH

Summary

HADH (hydroxyacyl-CoA dehydrogenase, HGNC:4799) is a protein-coding gene on chromosome 4q25, encoding Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial (Q16836). Mitochondrial fatty acid beta-oxidation enzyme that catalyzes the third step of the beta-oxidation cycle for medium and short-chain 3-hydroxy fatty acyl-CoAs (C4 to C10).

This gene is a member of the 3-hydroxyacyl-CoA dehydrogenase gene family. The encoded protein functions in the mitochondrial matrix to catalyze the oxidation of straight-chain 3-hydroxyacyl-CoAs as part of the beta-oxidation pathway. Its enzymatic activity is highest with medium-chain-length fatty acids. Mutations in this gene cause one form of familial hyperinsulinemic hypoglycemia. The human genome contains a related pseudogene of this gene on chromosome 15.

Source: NCBI Gene 3033 — RefSeq curated summary.

At a glance

• Gene–disease (curated): obsolete hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 388 total — 17 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 45
• Druggable target: yes
• MANE Select transcript: NM_005327

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4799
Approved symbol	HADH
Name	hydroxyacyl-CoA dehydrogenase
Location	4q25
Locus type	gene with protein product
Status	Approved
Aliases	HADH1, SCHAD
Ensembl gene	ENSG00000138796
Ensembl biotype	protein_coding
OMIM	601609
Entrez	3033

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 15 protein_coding, 11 nonsense_mediated_decay, 8 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000309522, ENST00000403312, ENST00000505878, ENST00000507260, ENST00000510728, ENST00000511742, ENST00000514776, ENST00000515462, ENST00000603302, ENST00000626637, ENST00000638559, ENST00000638621, ENST00000638648, ENST00000639013, ENST00000639146, ENST00000639335, ENST00000639698, ENST00000639784, ENST00000640048, ENST00000640060, ENST00000640201, ENST00000640586, ENST00000640752, ENST00000681992, ENST00000682067, ENST00000682086, ENST00000682197, ENST00000682373, ENST00000684696, ENST00000876844, ENST00000923928, ENST00000923929, ENST00000923930, ENST00000944999, ENST00000945000, ENST00000945001

RefSeq mRNA: 3 — MANE Select: NM_005327 NM_001184705, NM_001331027, NM_005327

CCDS: CCDS3678, CCDS54790, CCDS82943

Canonical transcript exons

ENST00000309522 — 8 exons

Exon	Start	End
ENSE00000333879	108009759	108009887
ENSE00000841666	108014431	108014588
ENSE00000841669	108027688	108027760
ENSE00001196027	107989889	107990064
ENSE00001561694	108034239	108035171
ENSE00003532965	108033176	108033292
ENSE00003593016	108019540	108019666
ENSE00003618844	108023474	108023563

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 98.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.2478 / max 1236.3931, expressed in 1802 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
49199	22.7505	1780
49200	16.3494	1703
49198	0.1368	32
49203	0.0058	2
49202	0.0053	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	98.88	gold quality
heart right ventricle	UBERON:0002080	98.82	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.81	gold quality
mucosa of transverse colon	UBERON:0004991	98.62	gold quality
type B pancreatic cell	CL:0000169	98.57	gold quality
diaphragm	UBERON:0001103	98.41	gold quality
nephron tubule	UBERON:0001231	98.41	gold quality
vastus lateralis	UBERON:0001379	98.39	gold quality
body of tongue	UBERON:0011876	98.29	gold quality
left ventricle myocardium	UBERON:0006566	98.21	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.17	gold quality
jejunal mucosa	UBERON:0000399	98.14	gold quality
quadriceps femoris	UBERON:0001377	98.14	gold quality
cardiac ventricle	UBERON:0002082	98.07	gold quality
heart left ventricle	UBERON:0002084	98.05	gold quality
skeletal muscle tissue	UBERON:0001134	97.89	gold quality
gastrocnemius	UBERON:0001388	97.78	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.77	gold quality
jejunum	UBERON:0002115	97.75	gold quality
rectum	UBERON:0001052	97.66	gold quality
duodenum	UBERON:0002114	97.64	gold quality
choroid plexus epithelium	UBERON:0003911	97.61	gold quality
right lobe of liver	UBERON:0001114	97.59	gold quality
muscle organ	UBERON:0001630	97.59	gold quality
skeletal muscle organ	UBERON:0014892	97.59	gold quality
muscle tissue	UBERON:0002385	97.57	gold quality
biceps brachii	UBERON:0001507	97.55	gold quality
apex of heart	UBERON:0002098	97.55	gold quality
muscle of leg	UBERON:0001383	97.42	gold quality
triceps brachii	UBERON:0001509	97.37	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-GEOD-81547	yes	1714.56
E-GEOD-83139	yes	1414.55
E-MTAB-5061	yes	1241.76
E-ENAD-27	yes	1159.05
E-HCAD-31	yes	1060.62
E-GEOD-81608	yes	912.38
E-CURD-112	yes	38.55
E-ANND-3	yes	12.38

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXA2

miRNA regulators (miRDB)

40 targeting HADH, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-7978	99.86	66.90	856
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-4658	99.77	64.94	514
HSA-MIR-6790-5P	99.77	65.24	505
HSA-MIR-4645-3P	99.76	69.33	993
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-9851-3P	99.63	69.68	1110
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-548G-3P	99.48	68.67	2159
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-593-5P	99.34	69.50	965
HSA-MIR-2116-5P	99.32	69.34	1273
HSA-MIR-5100	99.11	67.52	1098

Literature-anchored findings (GeneRIF, showing 18)

• To investigate its function in this catalytic dyad, Glu(170) was replaced with glutamine (E170Q), and the mutant enzyme was characterized. Substrate and cofactor binding were unaffected by the mutation; E170Q exhibited diminished catalytic activity (PMID:11451959)
• SCHAD deficiency can result in persistent hyperinsulinemic hypoglycemia of infancy (PMID:14693719)
• Unlikely that variation in HADHSC plays a major role in the pathogenesis of type 2 diabetes in the examined cohorts. (PMID:17065362)
• This case indicates that mutations of the HADH gene should be sought in hyperinsulinemic patients in whom diffuse form of hyperinsulinemic hypoglycemia. (PMID:19318379)
• Congenital hyperinsulinism due to mutations in HNF4A and HADH. (PMID:20931292)
• We recommend that HADH sequence analysis is considered in all patients with diazoxide-responsive hyperinsulinemic hypoglycemia when recessive inheritance is suspected (PMID:21252247)
• Clinical, biochemical and molecular findings of four new Caucasian patients with HADH deficiency. (PMID:21347589)
• Loss of function mutations in 3-Hydroxyacyl-CoA Dehydrogenase (HADH) cause leucine sensitive hyperinsulinaemic hypoglycaemia. (PMID:22583614)
• Next-generation sequencing reveals deep intronic cryptic ABCC8 and HADH splicing founder mutations causing hyperinsulinism by pseudoexon activation. (PMID:23273570)
• in a cohort of hyperinsulinemic hypoglycemia patients from Isfahan, Iran, 78% were noted to have disease-causing mutations: 48% had HADH mutations and 26% had ABCC8 mutations. (PMID:26268944)
• We present clinical and laboratory findings together with the long-term clinical course of a case with a deep intronic HADH splicing mutation (c.636+471G>T) causing neonatal-onset hyperinsulinemic hypoglycemia with mild progression (PMID:26316438)
• Paretic muscle in hemiparetic stroke survivors had lower HAD concentration. (PMID:26361074)
• The most frequently seen mutations in Turkish patients with congenital hyperinsulinism (CHI) were ATP binding cassette subfamily C member 8 (ABCC8) gene, followed by 3-hydroxyacyl CoA dehydrogenase (HADH) and kcnj11 channel (KCNJ11) genes. (PMID:27181376)
• Functional evaluation of 16 SCHAD missense variants: Only amino acid substitutions causing congenital hyperinsulinism of infancy lead to loss-of-function phenotypes in vitro. (PMID:32876354)
• Differentially expressed genes PCCA, ECHS1, and HADH are potential prognostic biomarkers for gastric cancer. (PMID:33881965)
• Genetic pathogenesis, diagnosis, and treatment of short-chain 3-hydroxyacyl-coenzyme A dehydrogenase hyperinsulinism. (PMID:34736508)
• Abnormal expression of HADH, an enzyme of fatty acid oxidation, affects tumor development and prognosis (Review). (PMID:36239258)
• Patients with the G1528C mutation of 3-hyroxyacyl-CoA dehydrogenase exhibit hepatomegaly and steatosis of the liver, as well as accumulation of fat in the myocardium, renal tubules, and skeletal muscle (PMID:9185222)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hadh	ENSDARG00000030765
mus_musculus	Hadh	ENSMUSG00000027984
rattus_norvegicus	Hadh	ENSRNOG00000010697
caenorhabditis_elegans		WBGENE00001157
caenorhabditis_elegans		WBGENE00001158

Paralogs (3): HADHA (ENSG00000084754), EHHADH (ENSG00000113790), CRYL1 (ENSG00000165475)

Protein

Protein identifiers

Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial — Q16836 (reviewed: Q16836)

Alternative names: Medium and short-chain L-3-hydroxyacyl-coenzyme A dehydrogenase, Short-chain 3-hydroxyacyl-CoA dehydrogenase

All UniProt accessions (18): Q16836, A0A0A0MSE2, A0A0D9SFP2, A0A140VK76, A0A1W2PNM1, A0A1W2PP40, A0A1W2PQ55, A0A1W2PQ78, A0A1W2PQC2, A0A1W2PQV5, A0A1W2PRM6, A0A1W2PRT2, A0A804HJK7, A0A804HJW7, A0A804HKJ2, A0A804HLB5, E9PF18, J3KR89

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial fatty acid beta-oxidation enzyme that catalyzes the third step of the beta-oxidation cycle for medium and short-chain 3-hydroxy fatty acyl-CoAs (C4 to C10). Plays a role in the control of insulin secretion by inhibiting the activation of glutamate dehydrogenase 1 (GLUD1), an enzyme that has an important role in regulating amino acid-induced insulin secretion. Plays a role in the maintenance of normal spermatogenesis through the reduction of fatty acid accumulation in the testes.

Subunit / interactions. Homodimer. Interacts with GLUD1; this interaction inhibits the activation of glutamate dehydrogenase 1 (GLUD1).

Subcellular location. Mitochondrion matrix.

Tissue specificity. Expressed in liver, kidney, pancreas, heart and skeletal muscle.

Post-translational modifications. Succinylation at Lys-81, adjacent to a coenzyme A binding site. Desuccinylated by SIRT5.

Disease relevance. 3-alpha-hydroxyacyl-CoA dehydrogenase deficiency (HADH deficiency) [MIM:231530] An autosomal recessive, metabolic disorder with various clinical presentations including hypoglycemia, hepatoencephalopathy, myopathy or cardiomyopathy, and in some cases sudden death. The disease is caused by variants affecting the gene represented in this entry. Hyperinsulinemic hypoglycemia, familial, 4 (HHF4) [MIM:609975] A form of hyperinsulinemic hypoglycemia, a clinically and genetically heterogeneous disorder characterized by inappropriate insulin secretion from the pancreatic beta-cells in the presence of low blood glucose levels. HHF4 clinical features include hypoglycemic coma, mental retardation due to repeated episodes of hypoglycemia, and seizures. HHF4 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Lipid metabolism; fatty acid beta-oxidation.

Similarity. Belongs to the 3-hydroxyacyl-CoA dehydrogenase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q16836-1	1	yes
Q16836-2	2
Q16836-3	3

RefSeq proteins (3): NP_001171634, NP_001317956, NP_005318* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006108	3HC_DH_C	Domain
IPR006176	3-OHacyl-CoA_DH_NAD-bd	Domain
IPR006180	3-OHacyl-CoA_DH_CS	Conserved_site
IPR008927	6-PGluconate_DH-like_C_sf	Homologous_superfamily
IPR013328	6PGD_dom2	Homologous_superfamily
IPR022694	3-OHacyl-CoA_DH	Family
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily
IPR052242	Mito_3-hydroxyacyl-CoA_DH	Family

Pfam: PF00725, PF02737

Enzyme classification (BRENDA):

• EC 1.1.1.35 — 3-hydroxyacyl-CoA dehydrogenase (BRENDA: 24 organisms, 99 substrates, 16 inhibitors, 84 Km, 49 kcat entries)

Substrate kinetics (BRENDA)

27 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ACETOACETYL-COA	0.003–0.263	22
NAD+	0.0001–29.5	9
NADH	0.0009–50	9
(S)-3-HYDROXYBUTYRYL-COA	0.0001–43.5	7
(R)-3-HYDROXYACYL-COA	0.0505–0.1157	4
ACETOACETYL-PANTETHEINE	0.08–1.19	4
3-ACETOACETYL-COA	0.0096–65.6	3
(S)-3-HYDROXYBUTANOYL-COA	0.06–0.2	2
(S)-3-HYDROXYHEXANOYL-COA	0.0286–0.34	2
(S)-3-HYDROXYOCTANOYL-COA	0.0163–0.35	2
3-ACETOACYL-COA	0.0094–0.0175	2
3-OXOHEXANOYL-COA	0.0083–0.016	2
3-OXOOCTANOYL-COA	0.0065–0.0125	2
(3BETA,5ALPHA,17BETA)-ANDROSTANE-3,17-DIOL	0.034	1
(S)-3-HYDROXYDECANOYL-COA	0.088	1

Catalyzed reactions (Rhea), 4 shown:

• a (3S)-3-hydroxyacyl-CoA + NAD(+) = a 3-oxoacyl-CoA + NADH + H(+) (RHEA:22432)
• (3S)-3-hydroxybutanoyl-CoA + NAD(+) = acetoacetyl-CoA + NADH + H(+) (RHEA:30799)
• (3S)-hydroxyhexadecanoyl-CoA + NAD(+) = 3-oxohexadecanoyl-CoA + NADH + H(+) (RHEA:31159)
• (3S)-hydroxydecanoyl-CoA + NAD(+) = 3-oxodecanoyl-CoA + NADH + H(+) (RHEA:31187)

UniProt features (80 total): modified residue 23, helix 17, strand 11, binding site 10, sequence variant 7, turn 5, splice variant 2, sequence conflict 2, transit peptide 1, chain 1, site 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
1F0Y	X-RAY DIFFRACTION	1.8
3HAD	X-RAY DIFFRACTION	2
3RQS	X-RAY DIFFRACTION	2
1M76	X-RAY DIFFRACTION	2.15
1IL0	X-RAY DIFFRACTION	2.2
2HDH	X-RAY DIFFRACTION	2.2
1F14	X-RAY DIFFRACTION	2.3
1F17	X-RAY DIFFRACTION	2.3
1M75	X-RAY DIFFRACTION	2.3
1F12	X-RAY DIFFRACTION	2.4
1LSJ	X-RAY DIFFRACTION	2.5
1LSO	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16836-F1	96.90	0.93

Functional residue map

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

Catalytic / active sites (1): 170 (important for catalytic activity)

Ligand- & substrate-binding residues (10): 173; 305; 34–39; 57; 73; 80; 122; 127; 149; 149

Post-translational modifications (23): 80, 81, 81, 87, 87, 125, 127, 136, 136, 179, 185, 185, 192, 192, 202, 202, 206, 212, 212, 241 …

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-77310	Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA
R-HSA-77346	Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA
R-HSA-77348	Beta oxidation of octanoyl-CoA to hexanoyl-CoA
R-HSA-77350	Beta oxidation of hexanoyl-CoA to butanoyl-CoA
R-HSA-77352	Beta oxidation of butanoyl-CoA to acetyl-CoA
R-HSA-9837999	Mitochondrial protein degradation

MSigDB gene sets: 472 (showing top): GOBP_LIPID_MODIFICATION, MORF_DNMT1, chr4q25, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_FATTY_ACID_CATABOLIC_PROCESS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, PID_HNF3B_PATHWAY, GOBP_INSULIN_SECRETION, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, MORF_RRM1, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_NEGATIVE_REGULATION_OF_PEPTIDE_SECRETION, GOBP_HORMONE_TRANSPORT

GO Biological Process (12): fatty acid beta-oxidation (GO:0006635), spermatogenesis (GO:0007283), response to xenobiotic stimulus (GO:0009410), response to activity (GO:0014823), cell differentiation (GO:0030154), response to insulin (GO:0032868), negative regulation of insulin secretion (GO:0046676), regulation of insulin secretion (GO:0050796), positive regulation of cold-induced thermogenesis (GO:0120162), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631), response to hormone (GO:0009725)

GO Molecular Function (6): (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity (GO:0003857), transferase activity (GO:0016740), identical protein binding (GO:0042802), NAD+ binding (GO:0070403), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor (GO:0016616)

GO Cellular Component (4): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
mitochondrial fatty acid beta-oxidation of saturated fatty acids	5
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to chemical	2
insulin secretion	2
catalytic activity	2
cellular anatomical structure	2
fatty acid catabolic process	1
fatty acid ligase activity	1
fatty acid oxidation	1
developmental process involved in reproduction	1
male gamete generation	1
response to stimulus	1
cellular developmental process	1
response to peptide hormone	1
negative regulation of protein secretion	1
regulation of insulin secretion	1
negative regulation of peptide hormone secretion	1
regulation of protein secretion	1
regulation of peptide hormone secretion	1
positive regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
primary metabolic process	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
response to endogenous stimulus	1
oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	1
protein binding	1
anion binding	1
NAD binding	1
oxidoreductase activity, acting on CH-OH group of donors	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

2208 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HADH	ECHS1	P30084	964
HADH	HADHB	P55084	953
HADH	HSD17B10	Q99714	841
HADH	ECH1	Q13011	833
HADH	ASL	P04424	821
HADH	HSD17B4	P51659	807
HADH	ACADL	P28330	754
HADH	ACADVL	P49748	734
HADH	CS	O75390	716
HADH	ACADM	P11310	713
HADH	ACADS	P16219	709
HADH	CROT	Q9UKG9	706
HADH	ACAA2	P42765	677
HADH	ACAA1	P09110	645
HADH	MDH2	P40926	640

IntAct

36 interactions, top by confidence:

A	B	Type	Score
HADH	HADH	psi-mi:“MI:0407”(direct interaction)	0.440
	HADH	psi-mi:“MI:0407”(direct interaction)	0.440
	AGPS	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
HADH	E7	psi-mi:“MI:0915”(physical association)	0.370
HADH	ADH1A	psi-mi:“MI:0915”(physical association)	0.370
HADH	STAT1	psi-mi:“MI:0915”(physical association)	0.370
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
RAD1	PRMT5	psi-mi:“MI:0914”(association)	0.350
NEK7	SUPT5H	psi-mi:“MI:0914”(association)	0.350
UBA5	PGK1	psi-mi:“MI:0914”(association)	0.350
RTN4	ESYT2	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
	SYNCRIP	psi-mi:“MI:0914”(association)	0.350
DDX28	UBA6	psi-mi:“MI:0914”(association)	0.350
DNAJC30	UBA6	psi-mi:“MI:0914”(association)	0.350
	HNRNPR	psi-mi:“MI:0914”(association)	0.350
MRPL49	UBA6	psi-mi:“MI:0914”(association)	0.350
NPPB	ACOT7	psi-mi:“MI:0914”(association)	0.350
OAS1	UBA6	psi-mi:“MI:0914”(association)	0.350
OSBPL11	DNM1L	psi-mi:“MI:0914”(association)	0.350
PEX7	UBA6	psi-mi:“MI:0914”(association)	0.350

BioGRID (142): HADH (Affinity Capture-RNA), HADH (Affinity Capture-RNA), CLIC3 (Co-fractionation), CLIC4 (Co-fractionation), ETFA (Co-fractionation), ETFB (Co-fractionation), FKBP2 (Co-fractionation), HADH (Co-fractionation), MMAB (Co-fractionation), PITPNA (Co-fractionation), PSMA1 (Co-fractionation), PSMA2 (Co-fractionation), PSMB8 (Co-fractionation), RSU1 (Co-fractionation), SF1 (Co-fractionation)

ESM2 similar proteins: C4LYI2, O07513, O07817, O66536, O76463, O84390, O89106, O94586, P00348, P0A5B6, P0ACE7, P0ACE8, P0ACE9, P26724, P32083, P36186, P36187, P42855, P42856, P44956, P47143, P47378, P49773, P49774, P49776, P49789, P53795, P62958, P62959, P64382, P64383, P70349, P73481, P75504, P80912, P9WML2, P9WML3, Q04344, Q16836, Q1KZG4

Diamond homologs: A0KR50, A1RDW6, A1S1I8, A3CYJ4, A4TR27, A4Y1B6, A4YI89, A5W6H0, A5WH99, A6V382, A7FDF2, A8GYG0, A9R754, B0TLB9, B0VLX4, B1JP63, B2I2J9, B2K0Z6, B5EZW0, B7UYR6, B8CH91, F1LU71, O32178, O34893, P00348, P14604, P34439, P83589, P94549, Q02PH8, Q08A39, Q0AVM1, Q0HPB7, Q0I0T3, Q13825, Q16836, Q1C2C4, Q1CN99, Q1Q8J9, Q2TBT3

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
HADH	“down-regulates quantity”	(S)-3-hydroxylauroyl-CoA	“chemical modification”
HADH	“down-regulates quantity”	NAD(1-)	“chemical modification”
HADH	“up-regulates quantity”	3-oxolauroyl-CoA	“chemical modification”
HADH	“up-regulates quantity”	NADH(2-)	“chemical modification”
HADH	“down-regulates quantity”	(S)-3-hydroxydecanoyl-CoA	“chemical modification”
HADH	“up-regulates quantity”	3-oxodecanoyl-CoA	“chemical modification”
HADH	“down-regulates quantity”	(S)-3-hydroxyoctanoyl-CoA	“chemical modification”
HADH	“up-regulates quantity”	3-oxooctanoyl-CoA	“chemical modification”
HADH	“down-regulates quantity”	(S)-3-hydroxyhexanoyl-CoA	“chemical modification”
HADH	“up-regulates quantity”	3-oxohexanoyl-CoA	“chemical modification”
HADH	“down-regulates quantity”	(S)-3-hydroxybutanoyl-CoA	“chemical modification”
HADH	“up-regulates quantity”	acetoacetyl-CoA(4-)	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	14
Uncertain significance	86
Likely benign	166
Benign	24

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
2675961	NM_005327.7(HADH):c.419+1G>A	Pathogenic
2726575	NM_005327.7(HADH):c.516del (p.Phe172fs)	Pathogenic
2758232	NM_005327.7(HADH):c.304_307dup (p.Ser103fs)	Pathogenic
2796951	NM_005327.7(HADH):c.493C>T (p.Arg165Ter)	Pathogenic
2809363	NM_005327.7(HADH):c.664_668del (p.Leu222fs)	Pathogenic
2826330	NM_005327.7(HADH):c.369del (p.Asn123_Leu124insTer)	Pathogenic
2836479	NM_005327.7(HADH):c.64del (p.Ala22fs)	Pathogenic
3246655	NC_000004.11:g.(?108911089)(108955513_?)del	Pathogenic
3246656	NC_000004.11:g.(?108911089)(108911240_?)del	Pathogenic
3645395	NM_005327.7(HADH):c.776_779del (p.Phe259fs)	Pathogenic
3674169	NM_005327.7(HADH):c.859del (p.His287fs)	Pathogenic
3678133	NM_005327.7(HADH):c.854del (p.Pro285fs)	Pathogenic
39483	NC_000004.12:g.107986495_107992009del	Pathogenic
39484	NM_005327.7(HADH):c.636+471G>T	Pathogenic
4056485	Single allele	Pathogenic
8020	NM_005327.7(HADH):c.773C>T (p.Pro258Leu)	Pathogenic
8021	NM_005327.7(HADH):c.547-3_549del	Pathogenic
1685343	NM_005327.7(HADH):c.636+2_636+3insCT	Likely pathogenic
1805045	NM_005327.7(HADH):c.434C>A (p.Ala145Asp)	Likely pathogenic
2446434	NM_005327.7(HADH):c.166_169del (p.Val56fs)	Likely pathogenic
2675956	NM_005327.7(HADH):c.262-2A>G	Likely pathogenic
2675957	NM_005327.7(HADH):c.424dup (p.Thr142fs)	Likely pathogenic
2675958	NM_005327.7(HADH):c.130C>T (p.Gln44Ter)	Likely pathogenic
2675959	NM_005327.7(HADH):c.419+1G>C	Likely pathogenic
2675960	NM_005327.7(HADH):c.709+2T>C	Likely pathogenic
2707419	NM_005327.7(HADH):c.636+2T>C	Likely pathogenic
2874131	NM_005327.7(HADH):c.261+2T>A	Likely pathogenic
3241723	NM_005327.7(HADH):c.710-1G>A	Likely pathogenic
3241724	NM_005327.7(HADH):c.271G>T (p.Glu91Ter)	Likely pathogenic
3589733	NM_005327.7(HADH):c.132+1G>A	Likely pathogenic

SpliceAI

1725 predictions. Top by Δscore:

Variant	Effect	Δscore
4:107990062:CAGGT:C	donor_loss	1.0000
4:107990064:GGTGA:G	donor_loss	1.0000
4:107990066:T:G	donor_loss	1.0000
4:108009754:TCTA:T	acceptor_loss	1.0000
4:108009755:CTAG:C	acceptor_loss	1.0000
4:108009756:TA:T	acceptor_loss	1.0000
4:108009757:A:AG	acceptor_gain	1.0000
4:108009757:AG:A	acceptor_gain	1.0000
4:108009757:AGGTT:A	acceptor_gain	1.0000
4:108009758:G:GG	acceptor_gain	1.0000
4:108009758:GG:G	acceptor_gain	1.0000
4:108009758:GGTT:G	acceptor_gain	1.0000
4:108009758:GGTTG:G	acceptor_gain	1.0000
4:108009852:A:T	donor_gain	1.0000
4:108009883:TTAAG:T	donor_loss	1.0000
4:108009884:TAAGG:T	donor_loss	1.0000
4:108009885:AAGGT:A	donor_loss	1.0000
4:108009886:AGG:A	donor_loss	1.0000
4:108009887:GGTAA:G	donor_loss	1.0000
4:108009888:GTA:G	donor_loss	1.0000
4:108009889:T:A	donor_loss	1.0000
4:108014421:ACT:A	acceptor_gain	1.0000
4:108014423:T:A	acceptor_gain	1.0000
4:108014426:ATTAG:A	acceptor_gain	1.0000
4:108014427:T:G	acceptor_gain	1.0000
4:108014584:GC:G	donor_gain	1.0000
4:108014584:GCTGA:G	donor_gain	1.0000
4:108014585:C:G	donor_gain	1.0000
4:108014585:CTGA:C	donor_gain	1.0000
4:108014587:GA:G	donor_gain	1.0000

AlphaMissense

2075 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:108019556:A:C	S146R	0.999
4:108019558:C:A	S146R	0.999
4:108019558:C:G	S146R	0.999
4:108019628:C:G	H170D	0.999
4:108033248:T:C	L261P	0.999
4:108014534:A:T	E122V	0.998
4:108014549:A:T	K127I	0.998
4:108019634:T:C	F172L	0.998
4:108019636:C:A	F172L	0.998
4:108019636:C:G	F172L	0.998
4:108027700:T:C	F217L	0.998
4:108027702:T:A	F217L	0.998
4:108027702:T:G	F217L	0.998
4:108027713:G:C	R221P	0.998
4:108033263:G:A	G266E	0.998
4:108034320:G:A	G303D	0.998
4:108014550:A:C	K127N	0.997
4:108014550:A:T	K127N	0.997
4:108019561:C:A	N147K	0.997
4:108019561:C:G	N147K	0.997
4:108023560:C:G	C211W	0.997
4:108027688:G:C	D213H	0.997
4:108027711:C:A	N220K	0.997
4:108027711:C:G	N220K	0.997
4:107990027:T:A	V32D	0.996
4:107990033:G:A	G34D	0.996
4:108014524:G:C	A119P	0.996
4:108019566:C:A	S149Y	0.996
4:108019626:T:C	L169P	0.996
4:108019630:T:A	H170Q	0.996

dbSNP variants (sampled 300 via entrez): RS1000029245 (4:108020923 A>T), RS1000064751 (4:108030854 C>G), RS1000071774 (4:108015125 T>G), RS1000130912 (4:108018724 A>G), RS1000447592 (4:108011996 A>G), RS1000464495 (4:108020069 T>A), RS1000578549 (4:108019800 C>T), RS1000670839 (4:108013358 C>T), RS1000735612 (4:108012186 C>T), RS1000781599 (4:107988638 T>C), RS1000812477 (4:108006420 C>G,T), RS1000829468 (4:108001329 G>T), RS1000830046 (4:108007255 C>T), RS1000882786 (4:108006181 AGT>A), RS10008909 (4:108008631 T>C,G)

Disease associations

OMIM: gene MIM:601609 | disease phenotypes: MIM:256450, MIM:231530, MIM:609975

GenCC curated gene-disease

Disease	Classification	Inheritance
hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency	Definitive	Autosomal recessive
3-hydroxyacyl-CoA dehydrogenase deficiency	Definitive	Autosomal recessive
hyperinsulinemic hypoglycemia, familial, 4	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
obsolete hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency	Definitive	AR

Mondo (7): hyperinsulinemic hypoglycemia (MONDO:0005803), 3-hydroxyacyl-CoA dehydrogenase deficiency (MONDO:0017715), hyperinsulinemic hypoglycemia, familial, 4 (MONDO:0012382), monogenic diabetes (MONDO:0015967), familial hyperinsulinism (MONDO:0017182), hyperinsulinemic hypoglycemia, familial, 1 (MONDO:0009734), (MONDO:0009278)

Orphanet (7): 3-hydroxyacyl-CoA dehydrogenase deficiency (Orphanet:309127), Hyperinsulinemic hypoglycaemia (Orphanet:443095), Hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency (Orphanet:71212), Rare genetic diabetes mellitus (Orphanet:183625), Familial hyperinsulinism (Orphanet:276525), Autosomal dominant hyperinsulinism due to SUR1 deficiency (Orphanet:276575), Diazoxide-resistant focal hyperinsulinism due to SUR1 deficiency (Orphanet:276598)

HPO phenotypes

45 total (30 of 45 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000580	Pigmentary retinopathy
HP:0000825	Hyperinsulinemic hypoglycemia
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001270	Motor delay
HP:0001289	Confusion
HP:0001290	Generalized hypotonia
HP:0001319	Neonatal hypotonia
HP:0001325	Hypoglycemic coma
HP:0001397	Hepatic steatosis
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001511	Intrauterine growth retardation
HP:0001639	Hypertrophic cardiomyopathy
HP:0001644	Dilated cardiomyopathy
HP:0001657	Prolonged QT interval
HP:0001985	Hypoketotic hypoglycemia
HP:0001987	Hyperammonemia
HP:0001998	Neonatal hypoglycemia
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002173	Hypoglycemic seizures
HP:0002605	Hepatic necrosis
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0002913	Myoglobinuria
HP:0003128	Lactic acidosis
HP:0003215	Dicarboxylic aciduria
HP:0003234	Decreased circulating carnitine concentration

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002337_109	Amyotrophic lateral sclerosis (sporadic)	3.000000e-06

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C535310	3-Hydroxyacyl-CoA Dehydrogenase Deficiency (supp.)
C566493	Hyperinsulinemic Hypoglycemia, Familial, 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067363 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.20	Kd	6.252	nM	CHEMBL3752910
8.20	ED50	6.252	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149971: Binding affinity to human HADH incubated for 45 mins by Kinobead based pull down assay	kd	0.0063	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression, affects expression	5
Estradiol	affects cotreatment, increases expression, increases oxidation	4
Valproic Acid	affects expression, affects cotreatment, increases expression	4
Cyclosporine	decreases expression, increases expression	4
sodium arsenite	affects binding, increases reaction, decreases expression, affects cotreatment, increases abundance	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	2
Dexamethasone	affects cotreatment, increases expression	2
Doxorubicin	decreases expression, affects response to substance	2
Tetrachlorodibenzodioxin	increases expression	2
Aflatoxin B1	affects expression, decreases expression	2
Genistein	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression	1
2,4,6-tribromophenol	increases expression	1
triphenyl phosphate	affects expression	1
uranyl acetate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
decabromobiphenyl ether	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	increases expression	1
tetrabromobisphenol A	increases expression	1
periodate-oxidized adenosine	affects expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
corosolic acid	decreases expression	1
K 7174	decreases expression	1
GW 4064	affects cotreatment, decreases expression	1
GW 7647	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5653013	Binding	Binding affinity to human HADH incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A5IP	HEK293 HADH-/-	Transformed cell line	Female
CVCL_E1YR	HAP1 HADH (-) 1	Cancer cell line	Male
CVCL_E1YS	HAP1 HADH (-) 2	Cancer cell line	Male
CVCL_E1YT	HAP1 HADH (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01070758	PHASE4	COMPLETED	Lanreotide Autogel Treatment of Patients With Congenital Hyperinsulinism of Infancy
NCT03042416	PHASE3	COMPLETED	18F-DOPA PET Imaging: an Evaluation of Biodistribution and Safety
NCT03777176	PHASE3	COMPLETED	A Two-Period Open-label Trial Evaluating Efficacy and Safety of Dasiglucagon in Children With Congenital Hyperinsulinism
NCT03941236	PHASE3	ACTIVE_NOT_RECRUITING	Extension Trial Evaluating the Long-term Safety and Efficacy of Dasiglucagon in Children With Congenital Hyperinsulinism
NCT04706910	PHASE3	RECRUITING	18F-DOPA II - PET Imaging Optimization
NCT06208215	PHASE3	ACTIVE_NOT_RECRUITING	RZ358 Treatment for Congenital Hyperinsulinism
NCT03770637	PHASE2	COMPLETED	Glucagon Ready to Use (RTU) in Subjects With Hyperinsulinemic Hypoglycemia After Bariatric Surgery
NCT03984370	PHASE2	COMPLETED	Dasiglucagon in the Treatment of Postprandial Hypoglycaemia After Roux-en-Y Gastric Bypass
NCT04652479	PHASE2	COMPLETED	Avexitide Safety and Efficacy to Treat Acquired Hyperinsulinemic Hypoglycemia
NCT04836273	PHASE2	COMPLETED	Treatment of Post-bariatric Hypoglycaemia
NCT06976658	PHASE2	RECRUITING	Glucokinase Activator in Monogenic Diabetes
NCT00674440	PHASE2	COMPLETED	Utility of [F-18] fluoroDOPA for Neonatal Hyperinsulinism
NCT00987168	PHASE2	COMPLETED	Sandostatine® LP and Hyperinsulinism
NCT01468454	PHASE2	COMPLETED	Phase II Safety and Efficacy Study of 18FDOPA PET-CT in Children With Hyperinsulinemic Hypoglycemia
NCT02604485	PHASE2	COMPLETED	A Single-Dose Open-Label Study of XOMA 358 in Subjects With Congenital Hyperinsulinism
NCT02937558	PHASE2	COMPLETED	CSI-Glucagon for Prevention of Hypoglycemia in Children With Congenital Hyperinsulinism
NCT03053284	PHASE2	WITHDRAWN	Pasireotide in Hyperinsulinemic Hypoglycemia
NCT04205604	PHASE2	RECRUITING	18FluoroLDOPA PET Imaging for the Detection and Localization of Focal Congenital Hyperinsulinism
NCT04538989	PHASE2	COMPLETED	An Open-Label Multiple Dose Study of RZ358 in Patients With Congenital Hyperinsulinism
NCT04732416	PHASE2	ACTIVE_NOT_RECRUITING	HM15136 (Efpegerglucagon) Treatment for 8 Weeks in Subjects Aged ≥2 Years With Congenital Hyperinsulinism (CHI)
NCT02685852	PHASE1	COMPLETED	Evaluating Exenatide for the Treatment of Postprandial Hyperinsulinemic Hypoglycemia
NCT02996812	PHASE1	COMPLETED	Evaluation of Single Ascending Doses of Subcutaneous Exendin 9-39 in Patients With Post-Bariatric Hypoglycemia
NCT03103009	PHASE1	COMPLETED	Treatment Plan for an Individual Patient With Pasireotide for Hyperinsulinemic Hypoglycemia
NCT01795144	PHASE1	COMPLETED	Incretin Regulation of Insulin Secretion in Monogenic Diabetes
NCT02021604	PHASE1	RECRUITING	Fluorodopa F 18 in Congenital Hyperinsulinism and Insulinoma
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT01933490	Not specified	COMPLETED	Post-Gastric Bypass Hypoglycemia
NCT03930368	Not specified	UNKNOWN	Application of Raw Corn Starch on Patients With Insulinoma
NCT05597475	Not specified	UNKNOWN	GLP1R-imaging in Post-RYGB Hypoglycemia
NCT04409795	PHASE2/PHASE3	COMPLETED	Oral Hypoglycemic Therapy for Monogenic Variant Carriers of the Joslin Medalist Study
NCT03988764	Not specified	RECRUITING	Monogenic Diabetes Misdiagnosed as Type 1
NCT05586594	Not specified	NOT_YET_RECRUITING	Identifying Maturity-onset Diabetes of the Young in Emirati Patients
NCT06478121	Not specified	RECRUITING	Understanding Beta Cell Disorders Through the Study of Rare Genotypes (ENDURE)
NCT06746610	Not specified	RECRUITING	Screening and Molecular Diagnosis-based Individualized Precision Management of Monogenic Diabetes
NCT07492004	Not specified	RECRUITING	China Monogenic Diabetes Registry
NCT07564518	Not specified	NOT_YET_RECRUITING	Application of FreeStyle Libre 2 for Evaluating Glycemic Variability Characteristics in Patients With Extreme Glucose Metabolism Phenotypes
NCT04172441	PHASE2/PHASE3	COMPLETED	Trial Evaluating Efficacy and Safety of Dasiglucagon in Children With Congenital Hyperinsulinism
NCT00571324	PHASE1/PHASE2	COMPLETED	Effect of Exendin-(9-39) on Glycemic Control in Subjects With Congenital Hyperinsulinism
NCT00835328	PHASE1/PHASE2	TERMINATED	Effect of Exendin (9-39) on Glucose Requirements to Maintain Euglycemia
NCT00897676	PHASE1/PHASE2	COMPLETED	Effect of Exendin-(9-39) on Fasting Adaptation and Protein Sensitivity