DHTKD1

Chr 10ADAR

dehydrogenase E1 and transketolase domain containing 1

Also known as: AAKAD, AMOXAD, CMT2Q, E1a, OADC-E1, OADH-E1

The protein functions as the 2-oxoadipate dehydrogenase component of the mitochondrial 2-oxoadipate dehydrogenase complex, catalyzing the rate-limiting decarboxylation of 2-oxoadipate in the final degradation pathway of lysine, hydroxylysine, and tryptophan. Mutations cause either alpha-aminoadipic and alpha-ketoadipic aciduria (a metabolic disorder) or Charcot-Marie-Tooth disease type 2Q (an axonal peripheral neuropathy), with both autosomal dominant and autosomal recessive inheritance patterns reported. The gene shows relatively low constraint against loss-of-function variants, which may explain the variable clinical presentations and inheritance patterns.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismAD/ARLOEUF 1.252 OMIM phenotypes
Clinical SummaryDHTKD1
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Gene-Disease Validity (ClinGen)
2-aminoadipic 2-oxoadipic aciduria · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint
1.25LOEUF
pLI 0.000
Z-score 0.16
OE 0.97 (0.771.25)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
-0.12Z-score
OE missense 1.01 (0.941.09)
539 obs / 531.5 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.97 (0.771.25)
00.351.4
Missense OE1.01 (0.941.09)
00.61.4
Synonymous OE1.10
01.21.6
LoF obs/exp: 46 / 47.2Missense obs/exp: 539 / 531.5Syn Z: -1.16
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongDHTKD1-related 2-aminoadipic and 2-oxoadipic aciduriaLOFAR

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

DN
0.5280th %ile
GOF
0.4974th %ile
LOF
0.4430th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

LOFNotably, DHTKD1 Arg834* resulted in haploinsufficiency in the affected family members through nonsense-mediated decay (NMD).PMID:29669943

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

DHTKD1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
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