progressive external ophthalmoplegia with mitochondrial DNA deletions

Summary

progressive external ophthalmoplegia with mitochondrial DNA deletions (MONDO:0000090) is a disease (an umbrella term covering 8 Mondo subtypes) with 2 cohort genes.

At a glance

• Umbrella term: 8 Mondo subtypes
• Cohort genes: 2
• ClinVar variants: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	progressive external ophthalmoplegia with mitochondrial DNA deletions
Mondo ID	MONDO:0000090
OMIM	157640
GARD	0022709
Is cancer (heuristic)	no

Also known as: progressive external ophthalmoplegia with mtDNA deletions

Data availability: 1 ClinVar variant · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 8 Mondo subtypes.

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

Related subtypes (2): Kearns-Sayre syndrome, autosomal recessive progressive external ophthalmoplegia

Subtypes (8): 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 4, 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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
640935	NM_002693.3(POLG):c.3255dup (p.Ser1086fs)	POLG	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 9 · 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
RRM1	Moderate	Autosomal recessive	progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal recessive 6	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RRM1	Orphanet:254886	Autosomal recessive progressive external ophthalmoplegia
POLG	Orphanet:254881	Spinocerebellar ataxia with epilepsy
POLG	Orphanet:254886	Autosomal recessive progressive external ophthalmoplegia
POLG	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
POLG	Orphanet:298	Mitochondrial neurogastrointestinal encephalomyopathy
POLG	Orphanet:402082	Progressive myoclonic epilepsy type 5
POLG	Orphanet:70595	Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome
POLG	Orphanet:726	Alpers-Huttenlocher syndrome
POLG	Orphanet:94125	Recessive mitochondrial ataxia syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RRM1	HGNC:10451	ENSG00000167325	P23921	Ribonucleoside-diphosphate reductase large subunit	gencc
POLG	HGNC:9179	ENSG00000140521	P54098	DNA polymerase subunit gamma-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RRM1	Ribonucleoside-diphosphate reductase large subunit	Provides the precursors necessary for DNA synthesis.
POLG	DNA polymerase subunit gamma-1	Catalytic subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA).

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RRM1	Enzyme (other)	yes	1.17.4.1	RNR_lg_C, ATP-cone_dom, RNR_R1-su_N
POLG	Other/Unknown	no		DNA-dir_DNA_pol_A_palm_dom, DNA-dir_DNA_pol_A_mt, RNaseH-like_sf

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
cervix squamous epithelium	1
ganglionic eminence	1
ventricular zone	1
granulocyte	1
small intestine Peyer’s patch	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RRM1	296	ubiquitous	marker	ventricular zone, ganglionic eminence, cervix squamous epithelium
POLG	295	ubiquitous	marker	granulocyte, small intestine Peyer’s patch, tibial nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RRM1	4,985
POLG	3,400

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLG	P54098	36
RRM1	P23921	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Strand-asynchronous mitochondrial DNA replication	1	571.0×	0.004	POLG
Interconversion of nucleotide di- and triphosphates	1	178.4×	0.006	RRM1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrial DNA replication	2	1532.0×	8e-06	RRM1, POLG
pyrimidine nucleobase metabolic process	1	4213.0×	0.001	RRM1
ribonucleoside diphosphate metabolic process	1	2808.7×	0.001	RRM1
deoxyribonucleotide biosynthetic process	1	2808.7×	0.001	RRM1
2’-deoxyribonucleotide biosynthetic process	1	2808.7×	0.001	RRM1
DNA replication proofreading	1	2808.7×	0.001	POLG
positive regulation of G0 to G1 transition	1	1685.2×	0.002	RRM1
cell proliferation in forebrain	1	648.1×	0.003	RRM1
base-excision repair, gap-filling	1	561.7×	0.003	POLG
DNA metabolic process	1	526.6×	0.003	POLG
protein heterotetramerization	1	526.6×	0.003	RRM1
DNA synthesis involved in DNA repair	1	468.1×	0.004	RRM1
positive regulation of G2/M transition of mitotic cell cycle	1	300.9×	0.005	RRM1
DNA-templated DNA replication	1	280.9×	0.005	POLG
base-excision repair	1	234.1×	0.006	POLG
response to ionizing radiation	1	205.5×	0.006	RRM1
positive regulation of G1/S transition of mitotic cell cycle	1	200.6×	0.006	RRM1
retina development in camera-type eye	1	127.7×	0.009	RRM1
male gonad development	1	78.0×	0.013	RRM1
DNA repair	1	31.9×	0.031	RRM1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
POLG	ADEFOVIR DIPIVOXIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RRM1	1	3
POLG	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ADEFOVIR DIPIVOXIL	4	POLG
TRIAPINE	3	RRM1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
RRM1	83	Binding:80, Functional:3
POLG	33	Binding:30, ADMET:2, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RRM1	1.17.4.1	ribonucleoside-diphosphate reductase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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.

Compound	Max phase	Cohort target (bioactivity)
ADEFOVIR DIPIVOXIL	4	POLG
TRIAPINE	3	RRM1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	POLG
B	Phased (≥1) drug, not yet approved	1	RRM1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.