Progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal recessive 6

Summary

Progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal recessive 6 (MONDO:0957993) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal recessive 6
Mondo ID	MONDO:0957993
OMIM	620647
UMLS	C5882731
MedGen	1847098
GARD	0026904
Is cancer (heuristic)	no

Data availability: 2 ClinVar variants · 3 GenCC gene-disease records.

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 6

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 4, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5

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

2 retrieved; paginated sample, class counts are floors:

1 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2664486	NM_001033.5(RRM1):c.1141C>T (p.Arg381Cys)	RRM1	Pathogenic	no assertion criteria provided
2444243	NM_001033.5(RRM1):c.1142G>A (p.Arg381His)	RRM1	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RRM1	HGNC:10451	ENSG00000167325	P23921	Ribonucleoside-diphosphate reductase large subunit	gencc,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.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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	12.0×	0.083

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

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cervix squamous epithelium	1
ganglionic eminence	1
ventricular zone	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RRM1	4,985

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RRM1	P23921	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 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
Interconversion of nucleotide di- and triphosphates	1	356.9×	0.003	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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
pyrimidine nucleobase metabolic process	1	8426.0×	7e-04	RRM1
ribonucleoside diphosphate metabolic process	1	5617.3×	7e-04	RRM1
deoxyribonucleotide biosynthetic process	1	5617.3×	7e-04	RRM1
2’-deoxyribonucleotide biosynthetic process	1	5617.3×	7e-04	RRM1
positive regulation of G0 to G1 transition	1	3370.4×	9e-04	RRM1
mitochondrial DNA replication	1	1532.0×	0.002	RRM1
cell proliferation in forebrain	1	1296.3×	0.002	RRM1
protein heterotetramerization	1	1053.2×	0.002	RRM1
DNA synthesis involved in DNA repair	1	936.2×	0.002	RRM1
positive regulation of G2/M transition of mitotic cell cycle	1	601.9×	0.002	RRM1
response to ionizing radiation	1	411.0×	0.003	RRM1
positive regulation of G1/S transition of mitotic cell cycle	1	401.2×	0.003	RRM1
retina development in camera-type eye	1	255.3×	0.005	RRM1
male gonad development	1	156.0×	0.007	RRM1
DNA repair	1	63.8×	0.016	RRM1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RRM1	1	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
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

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RRM1	1.17.4.1	ribonucleoside-diphosphate reductase

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

1 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)
TRIAPINE	3	RRM1

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	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.