progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4

Summary

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4 (MONDO:0014899) is a disease with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 2
• ClinVar variants: 24
• Phenotypes (HPO): 21

Clinical features

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0000590	Progressive external ophthalmoplegia	Frequent (30-79%)
HP:0001488	Bilateral ptosis	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0003325	Limb-girdle muscle weakness	Frequent (30-79%)
HP:0003390	Sensory axonal neuropathy	Frequent (30-79%)
HP:0003797	Limb-girdle muscle atrophy	Frequent (30-79%)
HP:0007340	Lower limb muscle weakness	Frequent (30-79%)
HP:0008615	Adult onset sensorineural hearing impairment	Frequent (30-79%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000726	Dementia	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001618	Dysphonia	Occasional (5-29%)
HP:0003326	Myalgia	Occasional (5-29%)
HP:0003394	Muscle spasm	Occasional (5-29%)
HP:0003558	Viral infection-induced rhabdomyolysis	Occasional (5-29%)
HP:0003749	Pelvic girdle muscle weakness	Occasional (5-29%)
HP:0025406	Asthenia	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4
Mondo ID	MONDO:0014899
OMIM	617070
Orphanet	329314
DOID	DOID:0111516
SNOMED CT	733599009
UMLS	C4310733
MedGen	934700
GARD	0017501
Is cancer (heuristic)	no

Also known as: adult-onset multiple mitochondrial DNA deletion syndrome due to DGUOK deficiency · adult-onset multiple mtDNA deletion syndrome due to DGUOK deficiency · PEOB4 · progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4 · progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive type 4

Data availability: 24 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › progressive external ophthalmoplegia › progressive external ophthalmoplegia with mitochondrial DNA deletions › progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4

Related subtypes (7): autosomal dominant progressive external ophthalmoplegia, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1, mitochondrial DNA deletion syndrome with progressive myopathy, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5, progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal recessive 6

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

24 retrieved; paginated sample, class counts are floors:

7 pathogenic, 7 pathogenic/likely pathogenic, 3 uncertain significance, 3 conflicting classifications of pathogenicity, 2 likely pathogenic, 1 benign/likely benign, 1 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
253066	NM_080916.3(DGUOK):c.130G>A (p.Glu44Lys)	DGUOK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
253068	NM_080916.3(DGUOK):c.186C>A (p.Tyr62Ter)	DGUOK	Pathogenic	no assertion criteria provided
2574219	NM_080916.3(DGUOK):c.592-4_592-3del	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
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
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
3382406	NM_080916.3(DGUOK):c.214_215del (p.Val72fs)	DGUOK	Likely pathogenic	criteria provided, single submitter
3586934	NM_080916.3(DGUOK):c.14_15del (p.Arg5fs)	LOC129934096	Likely pathogenic	criteria provided, single submitter
208752	NM_080916.3(DGUOK):c.211C>G (p.Pro71Ala)	DGUOK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214285	NM_080916.3(DGUOK):c.462T>A (p.Asn154Lys)	DGUOK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
253069	NM_080916.3(DGUOK):c.444-11C>G	DGUOK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1526089	NM_080916.3(DGUOK):c.789AGA[1] (p.Glu264del)	DGUOK	Uncertain significance	criteria provided, single submitter
2442201	NM_080916.3(DGUOK):c.14G>A (p.Arg5His)	DGUOK	Uncertain significance	criteria provided, single submitter
638350	NM_080916.3(DGUOK):c.155C>G (p.Ser52Cys)	DGUOK	Uncertain significance	criteria provided, single submitter
137082	NM_080916.3(DGUOK):c.509A>G (p.Gln170Arg)	DGUOK	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
137083	NM_080916.3(DGUOK):c.*13A>T	DGUOK	Benign	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.