DHTKD1

Summary

DHTKD1 (dehydrogenase E1 and transketolase domain containing 1, HGNC:23537) is a protein-coding gene on chromosome 10p14, encoding 2-oxoadipate dehydrogenase complex component E1 (Q96HY7). 2-oxoadipate dehydrogenase (E1a) component of the 2-oxoadipate dehydrogenase complex (OADHC).

This gene encodes a component of a mitochondrial 2-oxoglutarate-dehydrogenase-complex-like protein involved in the degradation pathways of several amino acids, including lysine. Mutations in this gene are associated with 2-aminoadipic 2-oxoadipic aciduria and Charcot-Marie-Tooth Disease Type 2Q.

Source: NCBI Gene 55526 — RefSeq curated summary.

At a glance

• Gene–disease (curated): 2-aminoadipic 2-oxoadipic aciduria (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 1,083 total — 39 pathogenic, 25 likely-pathogenic
• Phenotypes (HPO): 23
• MANE Select transcript: NM_018706

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23537
Approved symbol	DHTKD1
Name	dehydrogenase E1 and transketolase domain containing 1
Location	10p14
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1630, MGC3090, DKFZP762M115, CMT2Q, OADC-E1, OADH-E1, E1a
Ensembl gene	ENSG00000181192
Ensembl biotype	protein_coding
OMIM	614984
Entrez	55526

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 26 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000263035, ENST00000415935, ENST00000437298, ENST00000448829, ENST00000465617, ENST00000479283, ENST00000889952, ENST00000889953, ENST00000889954, ENST00000889955, ENST00000889956, ENST00000889957, ENST00000889958, ENST00000889959, ENST00000889960, ENST00000889961, ENST00000889962, ENST00000940761, ENST00000940762, ENST00000951892, ENST00000951893, ENST00000951894, ENST00000951895, ENST00000951896, ENST00000951897, ENST00000951898, ENST00000951899, ENST00000951900

RefSeq mRNA: 1 — MANE Select: NM_018706 NM_018706

CCDS: CCDS7087

Canonical transcript exons

ENST00000263035 — 17 exons

Exon	Start	End
ENSE00000550261	12097684	12097996
ENSE00000690693	12084540	12084751
ENSE00000690695	12081472	12081627
ENSE00000915145	12088986	12089255
ENSE00000915146	12091513	12091684
ENSE00000915147	12112900	12113064
ENSE00000985263	12117673	12117755
ENSE00000985264	12118749	12118918
ENSE00000985265	12120182	12120267
ENSE00000999711	12101042	12101181
ENSE00000999712	12100178	12100262
ENSE00000999713	12106246	12106396
ENSE00001166575	12068954	12069187
ENSE00001288744	12120787	12123221
ENSE00003520107	12087535	12087729
ENSE00003598319	12094073	12094271
ENSE00003661518	12107909	12108015

Expression profiles

Bgee: expression breadth ubiquitous, 270 present calls, max score 94.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.5211 / max 202.1707, expressed in 1777 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
103904	8.1028	1637
103903	4.7391	1669
103902	0.6793	405

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
liver	UBERON:0002107	94.30	gold quality
right lobe of liver	UBERON:0001114	94.06	gold quality
secondary oocyte	CL:0000655	92.55	gold quality
parotid gland	UBERON:0001831	92.37	gold quality
ventricular zone	UBERON:0003053	91.97	gold quality
renal medulla	UBERON:0000362	90.76	gold quality
ganglionic eminence	UBERON:0004023	88.84	gold quality
nephron tubule	UBERON:0001231	88.47	gold quality
adult mammalian kidney	UBERON:0000082	88.17	gold quality
kidney	UBERON:0002113	87.43	gold quality
oocyte	CL:0000023	87.21	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.37	gold quality
kidney epithelium	UBERON:0004819	86.30	gold quality
embryo	UBERON:0000922	86.07	gold quality
biceps brachii	UBERON:0001507	85.21	gold quality
gastrocnemius	UBERON:0001388	85.03	gold quality
muscle of leg	UBERON:0001383	84.98	gold quality
palpebral conjunctiva	UBERON:0001812	84.83	gold quality
corpus callosum	UBERON:0002336	84.63	gold quality
adult organism	UBERON:0007023	84.40	gold quality
adrenal tissue	UBERON:0018303	84.14	gold quality
cortical plate	UBERON:0005343	83.50	gold quality
body of pancreas	UBERON:0001150	83.40	gold quality
cortex of kidney	UBERON:0001225	83.36	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	83.18	gold quality
tonsil	UBERON:0002372	83.14	gold quality
stromal cell of endometrium	CL:0002255	83.01	gold quality
hindlimb stylopod muscle	UBERON:0004252	82.98	gold quality
blood	UBERON:0000178	82.91	gold quality
caput epididymis	UBERON:0004358	82.88	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.32

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

78 targeting DHTKD1, 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-7110-3P	100.00	73.18	2486
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057

Literature-anchored findings (GeneRIF, showing 10)

• DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria. (PMID:23141293)
• A nonsense mutation in DHTKD1 causes Charcot-Marie-Tooth disease type 2 in a large Chinese pedigree. (PMID:23141294)
• DHTKD1 contributes to mitochondrial biogenesis and function maintenance. (PMID:24076469)
• DHTKD1 encodes the E1 subunit of the alpha-ketoadipic acid dehydrogenase complex (PMID:25860818)
• Synthetic analogues of 2-oxo acids discriminate metabolic contribution of the 2-oxoglutarate and 2-oxoadipate dehydrogenases in mammalian cells and tissues. (PMID:32024885)
• DHTKD1 and OGDH display substrate overlap in cultured cells and form a hybrid 2-oxo acid dehydrogenase complex in vivo. (PMID:32160276)
• Structure-function analyses of the G729R 2-oxoadipate dehydrogenase genetic variant associated with a disorder of l-lysine metabolism. (PMID:32303640)
• Inhibition and Crystal Structure of the Human DHTKD1-Thiamin Diphosphate Complex. (PMID:32633484)
• Knock-Out of DHTKD1 Alters Mitochondrial Respiration and Function, and May Represent a Novel Pathway in Cardiometabolic Disease Risk. (PMID:34484123)
• Heterozygous DHTKD1 Variants in Two European Cohorts of Amyotrophic Lateral Sclerosis Patients. (PMID:35052424)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dhtkd1	ENSDARG00000016415
mus_musculus	Dhtkd1	ENSMUSG00000025815
rattus_norvegicus	Dhtkd1	ENSRNOG00000023587
drosophila_melanogaster	CG1544	FBGN0039827
caenorhabditis_elegans		WBGENE00014098

Paralogs (2): OGDH (ENSG00000105953), OGDHL (ENSG00000197444)

Protein

Protein identifiers

2-oxoadipate dehydrogenase complex component E1 — Q96HY7 (reviewed: Q96HY7)

Alternative names: 2-oxoadipate dehydrogenase, mitochondrial, Alpha-ketoadipate dehydrogenase, Dehydrogenase E1 and transketolase domain-containing protein 1, Probable 2-oxoglutarate dehydrogenase E1 component DHKTD1, mitochondrial

All UniProt accessions (4): C9JWN1, Q96HY7, H7C149, H7C1J3

UniProt curated annotations — full annotation on UniProt →

Function. 2-oxoadipate dehydrogenase (E1a) component of the 2-oxoadipate dehydrogenase complex (OADHC). Participates in the first step, rate limiting for the overall conversion of 2-oxoadipate (alpha-ketoadipate) to glutaryl-CoA and CO(2) catalyzed by the whole OADHC. Catalyzes the irreversible decarboxylation of 2-oxoadipate via the thiamine diphosphate (ThDP) cofactor and subsequent transfer of the decarboxylated acyl intermediate on an oxidized dihydrolipoyl group that is covalently amidated to the E2 enzyme (dihydrolipoyllysine-residue succinyltransferase or DLST). Can catalyze the decarboxylation of 2-oxoglutarate in vitro, but at a much lower rate than 2-oxoadipate. Responsible for the last step of L-lysine, L-hydroxylysine and L-tryptophan catabolism with the common product being 2-oxoadipate.

Subunit / interactions. The 2-oxoadipate dehydrogenase complex is composed of OADH (2-oxoadipate dehydrogenase; E1a), DLST (dihydrolipoamide succinyltransferase; E2) and DLD (dihydrolipoamide dehydrogenase; E3). E1a functional unit is a dimer. Interacts with DLST.

Subcellular location. Mitochondrion.

Disease relevance. Charcot-Marie-Tooth disease, axonal, type 2Q (CMT2Q) [MIM:615025] An axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. The disease is caused by variants affecting the gene represented in this entry. Alpha-aminoadipic and alpha-ketoadipic aciduria (AAKAD) [MIM:204750] An autosomal recessive metabolic disorder characterized by increased levels of 2-oxoadipate and 2-hydroxyadipate in the urine, and elevated 2-aminoadipate in the plasma. Patients can have mild to severe intellectual disability, muscular hypotonia, developmental delay, ataxia, and epilepsy. Most cases are asymptomatic. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Amino-acid degradation.

Miscellaneous. The mitochondrial 2-oxoglutarate and 2-oxoadipate dehydrogenase complexes (OGDHC and OADHC, respectively) share their E2 (DLST) and E3 (dihydrolipoyl dehydrogenase or DLD) components, but the E1 component is specific to each complex (E1o and E1a, respectively).

Similarity. Belongs to the alpha-ketoglutarate dehydrogenase family.

RefSeq proteins (1): NP_061176* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001017	DH_E1	Domain
IPR005475	Transketolase-like_Pyr-bd	Domain
IPR011603	2oxoglutarate_DH_E1	Family
IPR029061	THDP-binding	Homologous_superfamily
IPR031717	ODO-1/KGD_C	Domain
IPR042179	KGD_C_sf	Homologous_superfamily

Pfam: PF00676, PF02779, PF16870

Enzyme classification (BRENDA):

• EC 1.2.1.105 — 2-oxoglutarate dehydrogenase system (BRENDA: 28 organisms, 44 substrates, 119 inhibitors, 83 Km, 16 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
2-OXOGLUTARATE	0.0025–10.1	50
COA	0.0032–0.075	11
NAD+	0.0249–0.3	11
2-OXOVALERATE	0.0063–0.0163	5
2-OXOADIPATE	0.107–0.52	2

Catalyzed reactions (Rhea), 1 shown:

• N(6)-[(R)-lipoyl]-L-lysyl-[protein] + 2-oxoadipate + H(+) = N(6)-[(R)-S(8)-glutaryldihydrolipoyl]-L-lysyl-[protein] + CO2 (RHEA:69576)

UniProt features (97 total): helix 41, strand 28, sequence variant 13, turn 8, modified residue 4, transit peptide 1, chain 1, region of interest 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
5RW1	X-RAY DIFFRACTION	1.52
5RVY	X-RAY DIFFRACTION	1.61
5RVW	X-RAY DIFFRACTION	1.61
5RVX	X-RAY DIFFRACTION	1.66
5RW0	X-RAY DIFFRACTION	1.67
6SY1	X-RAY DIFFRACTION	1.87
5RVZ	X-RAY DIFFRACTION	1.98
6U3J	X-RAY DIFFRACTION	2.25

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96HY7-F1	95.19	0.92

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 (4): 183, 188, 800, 818

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9858328	OADH complex synthesizes glutaryl-CoA from 2-OA

MSigDB gene sets: 192 (showing top): GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GOBP_NUCLEOSIDE_TRIPHOSPHATE_METABOLIC_PROCESS, CAIRO_HEPATOBLASTOMA_DN, GOBP_CARBOHYDRATE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_CATABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS

GO Biological Process (3): hematopoietic progenitor cell differentiation (GO:0002244), generation of precursor metabolites and energy (GO:0006091), glycolytic process (GO:0006096)

GO Molecular Function (6): thiamine pyrophosphate binding (GO:0030976), 2-oxoadipate dehydrogenase activity (GO:0160166), oxoglutarate dehydrogenase (succinyl-transferring) activity (GO:0004591), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the aldehyde or oxo group of donors, disulfide as acceptor (GO:0016624)

GO Cellular Component (3): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), oxoadipate dehydrogenase complex (GO:0160167)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Lysine catabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
oxidoreductase activity, acting on the aldehyde or oxo group of donors, disulfide as acceptor	2
hemopoiesis	1
cell differentiation	1
metabolic process	1
phosphoglycerate kinase activity	1
phosphoglycerate mutase activity	1
phosphopyruvate hydratase activity	1
pyruvate kinase activity	1
pyruvate metabolic process	1
generation of precursor metabolites and energy	1
aerobic respiration	1
carbohydrate catabolic process	1
pyridine nucleotide catabolic process	1
glyceraldehyde-3-phosphate dehydrogenase [NAD(P)+] (phosphorylating) activity	1
ADP catabolic process	1
ATP metabolic process	1
nicotinamide nucleotide metabolic process	1
vitamin binding	1
anion binding	1
cation binding	1
quaternary ammonium group binding	1
heterocyclic compound binding	1
sulfur compound binding	1
binding	1
catalytic activity	1
oxidoreductase activity, acting on the aldehyde or oxo group of donors	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
alpha-ketoacid dehydrogenase complex	1
transferase complex	1

Protein interactions and networks

STRING

1990 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DHTKD1	DLST	P36957	981
DHTKD1	DLD	P09622	759
DHTKD1	IGHMBP2	P38935	555
DHTKD1	GDAP1	Q8TB36	552
DHTKD1	CS	O75390	547
DHTKD1	ACO2	Q99798	545
DHTKD1	IDH3G	P51553	541
DHTKD1	SH3TC2	Q8TF17	506
DHTKD1	NAGLU	P54802	491
DHTKD1	FGD4	Q96M96	485
DHTKD1	GCDH	Q92947	484
DHTKD1	CMPK1	P30085	481
DHTKD1	IDH3B	O43837	478
DHTKD1	SURF1	Q15526	475
DHTKD1	PDK3	Q15120	474

IntAct

30 interactions, top by confidence:

A	B	Type	Score
BMAL2	CLOCK	psi-mi:“MI:0914”(association)	0.670
BMAL1	DHTKD1	psi-mi:“MI:0915”(physical association)	0.560
IPO11	BSG	psi-mi:“MI:0914”(association)	0.560
PGLYRP3	DHTKD1	psi-mi:“MI:0915”(physical association)	0.560
BMAL2	CLOCK	psi-mi:“MI:0914”(association)	0.550
GATC	NME4	psi-mi:“MI:0914”(association)	0.530
MORN5	BCAT1	psi-mi:“MI:0914”(association)	0.530
RIMKLA	ZNG1C	psi-mi:“MI:0914”(association)	0.530
DHTKD1	UNC45B	psi-mi:“MI:0915”(physical association)	0.400
CEP170P1	PCYT1A	psi-mi:“MI:0914”(association)	0.350
Immt	GOSR1	psi-mi:“MI:0914”(association)	0.350
ICAM1	RTL8C	psi-mi:“MI:0914”(association)	0.350
YBEY	NUDT19	psi-mi:“MI:0914”(association)	0.350
PGLYRP3	MICA	psi-mi:“MI:0914”(association)	0.350
DENR	ATG13	psi-mi:“MI:0914”(association)	0.350
FAHD1	CLUH	psi-mi:“MI:0914”(association)	0.350
CEP135	MCRIP1	psi-mi:“MI:0914”(association)	0.350
CEP135	WWP2	psi-mi:“MI:0914”(association)	0.350
CEP135	WDR91	psi-mi:“MI:0914”(association)	0.350
DGKG	SMCHD1	psi-mi:“MI:0914”(association)	0.350
SLC22A11	CNOT1	psi-mi:“MI:0914”(association)	0.350
	VWA8	psi-mi:“MI:2364”(proximity)	0.270
HSPD1	VWA8	psi-mi:“MI:2364”(proximity)	0.270
MGST3	VWA8	psi-mi:“MI:2364”(proximity)	0.270
PDK1	VWA8	psi-mi:“MI:2364”(proximity)	0.270
TRMT61B	VWA8	psi-mi:“MI:2364”(proximity)	0.270
IMMP2L	MRPL45	psi-mi:“MI:2364”(proximity)	0.270
BMAL1	DHTKD1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (79): DHTKD1 (Affinity Capture-MS), DHTKD1 (Affinity Capture-MS), DHTKD1 (Affinity Capture-MS), DHTKD1 (Affinity Capture-MS), DHTKD1 (Co-fractionation), DHTKD1 (Affinity Capture-MS), DHTKD1 (Affinity Capture-MS), DHTKD1 (Affinity Capture-MS), DHTKD1 (Affinity Capture-MS), DHTKD1 (Affinity Capture-MS), DHTKD1 (Affinity Capture-MS), DHTKD1 (Affinity Capture-MS), DHTKD1 (Affinity Capture-MS), DHTKD1 (Affinity Capture-MS), DHTKD1 (Affinity Capture-MS)

ESM2 similar proteins: A0A7J6EK66, A0A803PDZ0, A1L0T0, A2ATU0, A2XFI3, A2Y5L9, A2YQ76, A6QQT9, A7YWE4, O22567, O61856, O78328, O82647, P20906, P28516, P33287, P39994, P51845, P51846, P51850, P51851, P66947, P9WG38, P9WG39, Q0D3D2, Q0DHF6, Q0JMH0, Q10MW3, Q38854, Q3JAD1, Q3MHH6, Q3U4I7, Q4KLP0, Q5RAP5, Q68FT3, Q6DDK5, Q6JQN1, Q6NV04, Q6YU51, Q8BU33

Diamond homologs: A0PVU7, A0R2B1, A1KI36, A1TDK2, A1UK81, A2ATU0, A3Q3N5, A5ISU5, A5U1U6, A5VSQ0, A6U1N4, A6WXF0, A7GMD4, A7X295, A7Z5J9, A8FE66, A9M8Q9, A9VJX9, B0CIS7, B2S877, B7HH19, B7I0H2, B7IM94, B7JEU9, B9IU58, C0RFG8, C1ELG5, C3LAU3, C3P487, C4L3W2, C5D802, D3ZQD3, O61199, O74378, P0AFG3, P0AFG4, P0AFG5, P20707, P20967, P23129

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1083 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	39
Likely pathogenic	25
Uncertain significance	571
Likely benign	326
Benign	66

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1421380	NM_018706.7(DHTKD1):c.186dup (p.Tyr63fs)	Pathogenic
1445495	NM_018706.7(DHTKD1):c.2559C>G (p.Tyr853Ter)	Pathogenic
1455780	NM_018706.7(DHTKD1):c.2461_2462del (p.Glu821fs)	Pathogenic
1936267	NM_018706.7(DHTKD1):c.199_203del (p.His66_Gly67insTer)	Pathogenic
1941313	NM_018706.7(DHTKD1):c.1565G>A (p.Trp522Ter)	Pathogenic
1982990	NM_018706.7(DHTKD1):c.487C>T (p.Arg163Ter)	Pathogenic
2006686	NM_018706.7(DHTKD1):c.1879C>T (p.Gln627Ter)	Pathogenic
2030322	NM_018706.7(DHTKD1):c.1544del (p.Pro515fs)	Pathogenic
2044577	NM_018706.7(DHTKD1):c.2347del (p.Ala783fs)	Pathogenic
2083045	NM_018706.7(DHTKD1):c.669del (p.His223fs)	Pathogenic
2127547	NM_018706.7(DHTKD1):c.2401A>T (p.Lys801Ter)	Pathogenic
2230330	NM_018706.7(DHTKD1):c.2583G>A (p.Trp861Ter)	Pathogenic
2426487	NC_000010.10:g.(?12143021)(12143200_?)del	Pathogenic
2426489	NC_000010.10:g.(?12111033)(12148415_?)del	Pathogenic
2426491	NC_000010.10:g.(?12130965)(12133703_?)del	Pathogenic
2506034	NM_018706.7(DHTKD1):c.2235T>G (p.Tyr745Ter)	Pathogenic
2707238	NM_018706.7(DHTKD1):c.1967del (p.Lys656fs)	Pathogenic
2718150	NM_018706.7(DHTKD1):c.1806_1809del (p.Ser602fs)	Pathogenic
2725954	NM_018706.7(DHTKD1):c.1669C>T (p.Gln557Ter)	Pathogenic
2726845	NM_018706.7(DHTKD1):c.967dup (p.Asp323fs)	Pathogenic
2747798	NM_018706.7(DHTKD1):c.331del (p.Glu111fs)	Pathogenic
2881928	NM_018706.7(DHTKD1):c.1452C>G (p.Tyr484Ter)	Pathogenic
2909924	NM_018706.7(DHTKD1):c.736C>T (p.Arg246Ter)	Pathogenic
2987860	NM_018706.7(DHTKD1):c.703C>T (p.Gln235Ter)	Pathogenic
3244847	NC_000010.10:g.(?12111033)(12162887_?)del	Pathogenic
3244848	NC_000010.10:g.(?12149888)(12150034_?)del	Pathogenic
3244850	NC_000010.10:g.(?12154879)(12155083_?)del	Pathogenic
3244851	NC_000010.10:g.(?12159652)(12159774_?)del	Pathogenic
3244853	NC_000010.10:g.(?12148225)(12162887_?)del	Pathogenic
3337726	NM_018706.7(DHTKD1):c.2282_2295del (p.Leu761fs)	Pathogenic

SpliceAI

2357 predictions. Top by Δscore:

Variant	Effect	Δscore
10:12069141:G:GT	donor_gain	1.0000
10:12069166:G:GT	donor_gain	1.0000
10:12081470:A:AG	acceptor_gain	1.0000
10:12081471:G:GG	acceptor_gain	1.0000
10:12084534:TCACA:T	acceptor_loss	1.0000
10:12084535:CACAG:C	acceptor_loss	1.0000
10:12084536:ACAGG:A	acceptor_loss	1.0000
10:12084537:CA:C	acceptor_loss	1.0000
10:12084538:A:AG	acceptor_gain	1.0000
10:12084538:AG:A	acceptor_gain	1.0000
10:12084538:AGG:A	acceptor_loss	1.0000
10:12084539:G:GG	acceptor_gain	1.0000
10:12084539:GG:G	acceptor_gain	1.0000
10:12084539:GGA:G	acceptor_gain	1.0000
10:12084539:GGATT:G	acceptor_gain	1.0000
10:12084747:CTCAG:C	donor_loss	1.0000
10:12084748:TCAGG:T	donor_loss	1.0000
10:12084749:CAG:C	donor_loss	1.0000
10:12084750:AG:A	donor_loss	1.0000
10:12084751:GG:G	donor_loss	1.0000
10:12084753:T:G	donor_loss	1.0000
10:12087534:GGA:G	acceptor_gain	1.0000
10:12088968:T:TA	acceptor_gain	1.0000
10:12088981:A:AG	acceptor_gain	1.0000
10:12094068:TTCA:T	acceptor_loss	1.0000
10:12094071:A:AG	acceptor_gain	1.0000
10:12094071:A:C	acceptor_loss	1.0000
10:12094071:AG:A	acceptor_gain	1.0000
10:12094072:G:GG	acceptor_gain	1.0000
10:12094072:GG:G	acceptor_gain	1.0000

AlphaMissense

6042 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:12094205:G:T	R431M	1.000
10:12094205:G:C	R431T	0.999
10:12087683:G:C	R224T	0.998
10:12087683:G:T	R224I	0.998
10:12091675:A:C	S384R	0.998
10:12091677:T:A	S384R	0.998
10:12091677:T:G	S384R	0.998
10:12094206:G:C	R431S	0.998
10:12094206:G:T	R431S	0.998
10:12106255:A:C	S636R	0.998
10:12106257:C:A	S636R	0.998
10:12106257:C:G	S636R	0.998
10:12106300:A:C	S651R	0.998
10:12106302:C:A	S651R	0.998
10:12106302:C:G	S651R	0.998
10:12106330:T:A	W661R	0.998
10:12106330:T:C	W661R	0.998
10:12106342:T:C	F665L	0.998
10:12106344:T:A	F665L	0.998
10:12106344:T:G	F665L	0.998
10:12087601:A:C	S197R	0.997
10:12087603:C:A	S197R	0.997
10:12087603:C:G	S197R	0.997
10:12087679:C:G	H223D	0.997
10:12087684:A:C	R224S	0.997
10:12087684:A:T	R224S	0.997
10:12089126:T:A	N286K	0.997
10:12089126:T:G	N286K	0.997
10:12089164:G:A	G299D	0.997
10:12091600:A:C	S359R	0.997

dbSNP variants (sampled 300 via entrez): RS1000039375 (10:12073637 T>C), RS1000044188 (10:12116681 G>A), RS1000102079 (10:12078183 G>T), RS1000104997 (10:12073334 A>G,T), RS1000198117 (10:12121455 A>G), RS1000282509 (10:12082888 G>C), RS1000380985 (10:12067854 G>A), RS1000394680 (10:12082611 T>C), RS1000421339 (10:12121193 C>G), RS1000497164 (10:12098913 G>A,C), RS1000584979 (10:12093477 C>G), RS1000668810 (10:12116446 A>G), RS1000775579 (10:12087105 G>T), RS1000785559 (10:12087301 G>A), RS1000858904 (10:12088064 G>A)

Disease associations

OMIM: gene MIM:614984 | disease phenotypes: MIM:204750, MIM:245130, MIM:615025, MIM:609260, MIM:617836

GenCC curated gene-disease

Disease	Classification	Inheritance
2-aminoadipic 2-oxoadipic aciduria	Strong	Autosomal recessive
Charcot-Marie-Tooth disease axonal type 2Q	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
2-aminoadipic 2-oxoadipic aciduria	Definitive	AR

Mondo (7): 2-aminoadipic 2-oxoadipic aciduria (MONDO:0008774), Charcot-Marie-Tooth disease axonal type 2Q (MONDO:0014012), nephrotic syndrome (MONDO:0005377), peripheral neuropathy (MONDO:0005244), Charcot-Marie-Tooth disease type 2A2 (MONDO:0012231), inborn disorder of lysine and hydroxylysine metabolism (MONDO:0017351), developmental delay and seizures with or without movement abnormalities (MONDO:0044326)

Orphanet (4): 2-aminoadipic 2-oxoadipic aciduria (Orphanet:79154), Autosomal dominant Charcot-Marie-Tooth disease type 2Q (Orphanet:329258), Autosomal dominant Charcot-Marie-Tooth disease type 2A2 (Orphanet:99947), Disorder of lysine and hydroxylysine metabolism (Orphanet:289832)

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000717	Autism
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001288	Gait disturbance
HP:0001761	Pes cavus
HP:0003202	Skeletal muscle atrophy
HP:0003474	Somatic sensory dysfunction
HP:0003621	Juvenile onset
HP:0006886	Impaired distal vibration sensation
HP:0007018	Attention deficit hyperactivity disorder
HP:0009053	Distal lower limb muscle weakness
HP:0011342	Mild global developmental delay
HP:0011462	Young adult onset
HP:0034465	2-hydroxyadipic aciduria
HP:0410309	Alpha-aminoadipic aciduria
HP:6000278	Elevated circulating 2-aminoadipic acid concentration

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009733_160	Urinary metabolite levels in chronic kidney disease	4.000000e-21

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005116	urinary metabolite measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D009404	Nephrotic Syndrome	C12.050.351.968.419.630.643; C12.200.777.419.630.643; C12.950.419.630.643
C563757	Charcot-Marie-Tooth Disease, Axonal, Type 2A2 (supp.)
C565453	Ketoadipicaciduria (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, affects cotreatment, increases expression, decreases expression, increases abundance	7
trichostatin A	affects cotreatment, increases expression	3
Aflatoxin B1	affects expression, decreases expression	3
Acetaminophen	decreases expression, increases expression	2
Valproic Acid	affects expression, increases expression	2
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
lead acetate	affects cotreatment, increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	increases expression, affects cotreatment	1
dinophysistoxin 1	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
NSC 689534	affects binding, decreases expression	1
bisphenol AF	increases expression	1
Arsenic Trioxide	increases expression	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	decreases expression	1
Carbamazepine	affects expression	1
Copper	affects binding, decreases expression	1
Coumestrol	increases expression, affects cotreatment	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Doxorubicin	increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Plant Oils	decreases expression	1
Smoke	decreases expression	1

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B5JW	HAP1 DHTKD1 (-) 2	Cancer cell line	Male
CVCL_B5JX	HAP1 DHTKD1 (-) 3	Cancer cell line	Male
CVCL_B5JY	HAP1 DHTKD1 (-) 4	Cancer cell line	Male
CVCL_B5JZ	HAP1 DHTKD1 (-) 5	Cancer cell line	Male
CVCL_B5K0	HAP1 DHTKD1 (-) 6	Cancer cell line	Male
CVCL_XN28	HAP1 DHTKD1 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00308321	PHASE4	UNKNOWN	Long Term Tapering or Standard Steroids for Nephrotic Syndrome
NCT01021540	PHASE4	COMPLETED	Prospective Study Evaluating the Effect of Repository Corticotropin in the Treatment of Various Nephrotic Syndromes
NCT01028287	PHASE4	COMPLETED	Adrenocorticotropic Hormone (ACTH) Treatment of Nephrotic Range Proteinuria in Diabetic Nephropathy (NRDN)
NCT01162005	PHASE4	COMPLETED	Therapeutic Effect of Tacrolimus on Primary Nephrotic Syndrome in Children
NCT01895894	PHASE4	COMPLETED	Mycophenolate Mofetil in Pediatric Steroid Dependent Nephrotic Syndrome
NCT02238418	PHASE4	COMPLETED	Efficacy of Usual Vitamin D Supplementation and Its Impact on Children and Adolescents Calciuria.
NCT02382575	PHASE4	UNKNOWN	Efficacy and Safety of Rituximab to That of Calcineurin Inhibitors in Children With Steroid Resistant Nephrotic Syndrome
NCT02427880	PHASE4	COMPLETED	Role of Acetazolamide and Hydrochlorothiazide Followed by Furosemide in Treating Nephrotic Edema
NCT03210688	PHASE4	COMPLETED	Active Vitamin D And Reduced Dose Prednisolone for Treatment in Minimal Change Nephropathy
NCT03347357	PHASE4	COMPLETED	Pharmacokinetics of Tacrolimus in Children
NCT05696977	PHASE4	UNKNOWN	Effect of Obesity on Cyclosporine Blood Trough Level in Nephrotic Syndrome Patients
NCT05966818	PHASE4	UNKNOWN	Effect of Dapagliflozin in Non-Diabetic Patients With Nephrotic Syndrome.
NCT06026787	PHASE4	COMPLETED	Clinical Value of Adding Dapagliflozin in Patients With Nephrotic Syndrome
NCT00380965	PHASE4	COMPLETED	Evaluation of the Efficacy of Cesamet™ for the Treatment of Pain in Patients With Chemotherapy-Induced Neuropathy
NCT00487981	PHASE4	TERMINATED	Spinal Cord Stimulation for Painful Diabetic Neuropathy
NCT00904202	PHASE4	COMPLETED	A Study Of Lidocaine Patch 5% Alone, Gabapentin Alone, And Lidocaine Patch 5% And Gabapentin In Combination For The Relief Of Pain In Patients With Diverse Peripheral Neuropathic Pain Conditions
NCT01192113	PHASE4	COMPLETED	Safety and Efficacy of Mecobalamin Injection in Peripheral Neuropathies Patients (Study JGAZSY091109)
NCT01373983	PHASE4	COMPLETED	Intrathecal Bolus Doses of Ziconotide
NCT01458015	PHASE4	TERMINATED	Tapentadol Versus Oxycodone - a Mechanism-based Treatment Approach in Neuropathic Pain
NCT02074267	PHASE4	COMPLETED	Clinical Study for Assessment of the Efficacy of Gabapentin (Carbatin and Neurontin) in Patients With Neuropathy Pain
NCT02372149	PHASE4	UNKNOWN	IVIg for Demyelination in Diabetes Mellitus
NCT02670161	PHASE4	ENROLLING_BY_INVITATION	Quality Improvement and Practice Based Research in Neurology Using the EMR
NCT07022938	PHASE4	COMPLETED	Nutritional Supplement for Treating Chemotherapy Induced Neuropathy
NCT07025005	PHASE4	RECRUITING	Fenofibrate Role in the Prophylaxis From Peripheral Neuropathy Induced by Bortezomib, Lenalidomide and Dexamethasone (VRd) Protocol in the Treatment of Patients With Multiple Myeloma (MM)
NCT00354731	PHASE3	COMPLETED	Efficacy of Pentoxifylline on Primary Nephrotic Syndrome
NCT00615667	PHASE3	COMPLETED	Prospective, Multicenter Study of the Efficacy and Tolerance of Tacrolimus on Refractory Nephrotic Syndrome (RNS)
NCT00981838	PHASE3	COMPLETED	Rituximab in Multirelapsing Minimal Change Disease (MCD) or Focal Segmental Glomerulosclerosis (FSGS)
NCT01197040	PHASE3	COMPLETED	Evaluation of Low Dose Corticosteroids Efficiency, Associated With Myfortic ® in the Treatment of Nephrotic Syndrome
NCT01309477	PHASE3	COMPLETED	The Efficacy and Tolerance of Tacrolimus Sustained-release Capsules on Refractory Nephrotic Syndrome (RNS)
NCT02132195	PHASE3	COMPLETED	Adrenocorticotropic Hormone (ACTH) for Frequently Relapsing and Steroid Dependent Nephrotic Syndrome
NCT02257697	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mizoribine in the Treatment of Refractory Nephrotic Syndrome
NCT02438982	PHASE3	COMPLETED	Efficacy and Safety of Rituximab to That of Calcineurin Inhibitors in Children With Steroid Dependent Nephrotic Syndrome
NCT03141970	PHASE3	COMPLETED	Prednisolone Trial in Children Younger Than 4 Years
NCT03501459	PHASE3	UNKNOWN	Lymphocyte Markers As Predictors Of Responsiveness To Rituximab Among Patients With Idiopathic Nephrotic Syndrome
NCT05079789	PHASE3	TERMINATED	Amiloride in Nephrotic Syndrome
NCT05716880	PHASE3	RECRUITING	Ketoanalogues for Muscle Mass Loss in Nephrotic Syndrome
NCT06635720	PHASE3	ACTIVE_NOT_RECRUITING	REduced-dose Steroid PrOtocol for Childhood Nephrotic SyndromE (RESPONSE)
NCT00058071	PHASE3	COMPLETED	Amifostine in Treating Peripheral Neuropathy in Patients Who Have Received Chemotherapy for Cancer
NCT00125268	PHASE3	TERMINATED	Near Infrared Light for the Treatment of Painful Peripheral Neuropathy
NCT00195013	PHASE3	COMPLETED	Randomized Placebo-Controlled Trial of Glutamine for Breast Cancer Patients With Peripheral Neuropathy