mitochondrial DNA depletion syndrome 3 (hepatocerebral type)

Summary

mitochondrial DNA depletion syndrome 3 (hepatocerebral type) (MONDO:0009636) is a disease caused by DGUOK (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DGUOK (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 66

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial DNA depletion syndrome 3 (hepatocerebral type)
Mondo ID	MONDO:0009636
OMIM	251880
Orphanet	279934
DOID	DOID:0080121
GARD	0013644
Is cancer (heuristic)	no

Also known as: DGUOK mitochondrial DNA depletion syndrome · mitochondrial DNA depletion syndrome 3 · mitochondrial DNA depletion syndrome 3 (hepatocerebral type) · mitochondrial DNA depletion syndrome caused by mutation in DGUOK · mitochondrial DNA depletion syndrome type 3 · MTDPS3

Data availability: 66 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of purine or pyrimidine metabolism › inborn disorder of purine metabolism › mitochondrial DNA depletion syndrome 3 (hepatocerebral type)

Related subtypes (15): severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency, adenylosuccinate lyase deficiency, familial juvenile hyperuricemic nephropathy type 1, phosphoribosylpyrophosphate synthetase superactivity, Charcot-Marie-Tooth disease X-linked recessive 5, AICA-ribosiduria, adenosine monophosphate deaminase deficiency, purine nucleoside phosphorylase deficiency, adenine phosphoribosyltransferase deficiency, developmental and epileptic encephalopathy, 35, hypoxanthine-guanine phosphoribosyltransferase deficiency, hereditary xanthinuria, X-linked intellectual disability-limb spasticity-retinal dystrophy-diabetes insipidus syndrome, hemolytic anemia due to erythrocyte adenosine deaminase overproduction, PAICS deficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

66 retrieved; paginated sample, class counts are floors:

15 uncertain significance, 13 pathogenic, 13 conflicting classifications of pathogenicity, 10 pathogenic/likely pathogenic, 9 likely pathogenic, 3 benign, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1322207	NM_080916.3(DGUOK):c.235C>T (p.Gln79Ter)	DGUOK	Pathogenic	criteria provided, multiple submitters, no conflicts
1324223	NM_080916.3(DGUOK):c.3G>A (p.Met1Ile)	DGUOK	Pathogenic	criteria provided, multiple submitters, no conflicts
1403676	NM_080916.3(DGUOK):c.444-62C>A	DGUOK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
214286	NM_080916.3(DGUOK):c.591G>A (p.Gln197=)	DGUOK	Pathogenic	criteria provided, multiple submitters, no conflicts
214288	NM_080916.3(DGUOK):c.605_606del (p.Arg202fs)	DGUOK	Pathogenic	criteria provided, multiple submitters, no conflicts
2572386	NM_080916.3(DGUOK):c.173_176del (p.Leu58fs)	DGUOK	Pathogenic	criteria provided, single submitter
2574219	NM_080916.3(DGUOK):c.592-4_592-3del	DGUOK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
286174	NM_080916.3(DGUOK):c.353G>A (p.Arg118His)	DGUOK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3381837	NM_080916.3(DGUOK):c.505_508del (p.Tyr169fs)	DGUOK	Pathogenic	criteria provided, single submitter
3895753	NM_080916.3(DGUOK):c.493G>A (p.Glu165Lys)	DGUOK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449312	NM_080916.3(DGUOK):c.195G>A (p.Trp65Ter)	DGUOK	Pathogenic	criteria provided, multiple submitters, no conflicts
488490	NM_080916.3(DGUOK):c.155C>T (p.Ser52Phe)	DGUOK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
488491	NM_080916.3(DGUOK):c.749T>C (p.Leu250Ser)	DGUOK	Pathogenic	criteria provided, multiple submitters, no conflicts
595262	NM_080916.3(DGUOK):c.494A>T (p.Glu165Val)	DGUOK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8153	NM_080916.3(DGUOK):c.255del (p.Ala86fs)	DGUOK	Pathogenic	criteria provided, single submitter
8154	NM_080916.3(DGUOK):c.313C>T (p.Arg105Ter)	DGUOK	Pathogenic	criteria provided, single submitter
8156	NM_080916.3(DGUOK):c.609_610del (p.Tyr204fs)	DGUOK	Pathogenic	criteria provided, single submitter
8157	NM_080916.3(DGUOK):c.425G>A (p.Arg142Lys)	DGUOK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8158	NM_080916.3(DGUOK):c.679G>A (p.Glu227Lys)	DGUOK	Pathogenic	criteria provided, multiple submitters, no conflicts
871763	NM_080916.3(DGUOK):c.707+3_707+6del	DGUOK	Pathogenic	criteria provided, multiple submitters, no conflicts
8155	NM_080916.3(DGUOK):c.763_766dup (p.Phe256Ter)	DGUOK-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8159	NM_080916.3(DGUOK):c.763G>T (p.Asp255Tyr)	DGUOK-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
253062	NM_080916.3(DGUOK):c.137A>G (p.Asn46Ser)	LOC129934096	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
135652	NM_080916.3(DGUOK):c.287T>C (p.Leu96Pro)	DGUOK	Likely pathogenic	no assertion criteria provided
2681151	NM_080916.3(DGUOK):c.384_385dup (p.Lys129fs)	DGUOK	Likely pathogenic	no assertion criteria provided
3235886	NM_080916.3(DGUOK):c.255+3_255+6del	DGUOK	Likely pathogenic	criteria provided, single submitter
3382406	NM_080916.3(DGUOK):c.214_215del (p.Val72fs)	DGUOK	Likely pathogenic	criteria provided, single submitter
3767193	NM_080916.3(DGUOK):c.11del (p.Gly4fs)	DGUOK	Likely pathogenic	criteria provided, single submitter
801725	NM_080916.3(DGUOK):c.707+2T>G	DGUOK	Likely pathogenic	criteria provided, single submitter
253063	NM_080916.3(DGUOK):c.797T>G (p.Leu266Arg)	DGUOK-AS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
DGUOK	Definitive	Autosomal recessive	mitochondrial DNA depletion syndrome 3 (hepatocerebral type)	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DGUOK	Orphanet:279934	Mitochondrial DNA depletion syndrome, hepatocerebral form due to DGUOK deficiency
DGUOK	Orphanet:329314	Adult-onset multiple mitochondrial DNA deletion syndrome due to DGUOK deficiency

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DGUOK	HGNC:2858	ENSG00000114956	Q16854	Deoxyguanosine kinase, mitochondrial	gencc,clinvar
DGUOK-AS1	HGNC:43441	ENSG00000237883		DGUOK antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DGUOK	Deoxyguanosine kinase, mitochondrial	Phosphorylates deoxyguanosine and deoxyadenosine in the mitochondrial matrix, with the highest efficiency for deoxyguanosine.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DGUOK	Kinase	yes	2.7.1.113	DCK/DGK, P-loop_NTPase, DNK_dom
DGUOK-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adenohypophysis	1
olfactory segment of nasal mucosa	1
pituitary gland	1
male germ line stem cell (sensu Vertebrata) in testis	1
mucosa of transverse colon	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DGUOK	297	ubiquitous	marker	adenohypophysis, olfactory segment of nasal mucosa, pituitary gland
DGUOK-AS1	133	broad	marker	primordial germ cell in gonad, mucosa of transverse colon, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DGUOK	201
DGUOK-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DGUOK	Q16854	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Purine salvage	1	878.5×	0.001	DGUOK

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
guanosine metabolic process	1	16852.0×	1e-04	DGUOK
dGTP metabolic process	1	16852.0×	1e-04	DGUOK
purine deoxyribonucleoside metabolic process	1	16852.0×	1e-04	DGUOK
dAMP salvage	1	5617.3×	3e-04	DGUOK
mitochondrial ATP synthesis coupled electron transport	1	1872.4×	6e-04	DGUOK
negative regulation of neuron projection development	1	237.3×	0.004	DGUOK

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DGUOK	0	0
DGUOK-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DGUOK	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DGUOK	2.7.1.113	deoxyguanosine kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	DGUOK
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DGUOK-AS1

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
DGUOK	1	—
DGUOK-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.