Progressive External Ophthalmoplegia, Autosomal Recessive 6 (PEOB6; RRM1): Research Report

Summary

• The disease and its gene. PEOB6 (MONDO:0957993; OMIM #620647) is an autosomal recessive mitochondrial DNA (mtDNA) maintenance disorder. It is caused by homozygous variants in RRM1 (hgnc:10451; OMIM *180410; 11p15.4). RRM1 is the catalytic subunit of ribonucleotide reductase (RNR), the enzyme that makes DNA building blocks (dNTPs) from scratch.
• The evidence base is one paper. It rests entirely on Shintaku et al., J Clin Invest 2022, PMID:35617047 (PMC9246377). The recessive disease covers 5 patients from 3 families, all homozygous for a change at arginine 381.
• The search found no later case reports or treatment studies (2023–2026).
• Dominant p.N427K is a separate disease. The same paper reports a heterozygous catalytic-site variant, p.N427K, in one British family. OMIM's gene-map row for RRM1 lists both AD and AR inheritance. That dominant family is not PEOB6 and should not be lumped into this entry.

Before any of this goes into the KB:

• Snippets. The fetch tools would not return abstracts word for word, so only short fragments from the PMID:35617047 abstract are quoted here. Use just fetch-reference PMID:35617047 and copy snippets from the cached text.
• Ontology IDs. Every HP, GO, CL, UBERON and NCIT ID below is a lead written from memory. Look each one up before binding it, as the repo's CURIE rule requires.

1. Disease information

What it is. Adult-onset (in one patient, childhood-onset) ptosis and progressive external ophthalmoplegia. It comes with variable myopathy, gut dysmotility and cachexia, neuropathy, and multiple mtDNA deletions in skeletal muscle.

Synonyms: PEOB6; progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 6.

Type of source. All information comes from individual patient case descriptions in one multicentre paper. There are no registry or EHR data.

Key abstract statements (PMID:35617047): - "5 probands from 4 families who presented with ptosis and ophthalmoplegia as well as other clinical manifestations and multiple mtDNA deletions in muscle" - "Our data reveal that primary RRM1 deficiency and, by extension, impaired de novo nucleotide synthesis are causes of MDDS."

2. Etiology

• Cause. Biallelic (homozygous) loss-of-function missense variants in RRM1. Both known recessive variants change arginine 381:
• c.1142G>A, p.R381H
• c.1141C>T, p.R381C
• The abstract describes them as "RRM1 loss-of-function variants … 2 homozygous recessive variants at p.R381."
• Risk factors.
• Parental consanguinity: the Saudi family 1 (probands 1a and 1b) is consanguineous.
• Recurrence of p.R381C in two apparently unrelated Northern European families (Dutch family 2; family 4).
• Environmental risk factors: none known.
• Protective factors and gene–environment interactions: none reported.
• Plausible but unproven modifier: factors that raise dNTP demand or block de novo synthesis. Hydroxyurea and gemcitabine directly inhibit RNR. This is an inference, not a documented interaction (see §5).

3. Phenotypes

The 5 recessive patients are 1a, 1b, proband 2, proband 2's brother, and proband 4. Clinical detail is from the JCI full text; proband 2's brother is described only as "similarly affected."

Quality of life. The main burdens are visual (diplopia, ptosis), mobility (proximal weakness, gait), and nutrition (cachexia in family 1). No validated quality-of-life instrument data exist.

4. Genetic and molecular information

Gene. RRM1, ribonucleotide reductase catalytic subunit M1. - IDs: hgnc:10451; NCBI Gene 6240; UniProt P23921; Ensembl ENSG00000167325; OMIM 180410; 11p15.4 (HGNC REST). - The protein is the large R1 subunit of class Ia RNR. It holds: - the catalytic site; - the allosteric specificity site (loop 2), which sets the dNTP balance; - the activity (ATP-cone) site. - It pairs with RRM2 (in S phase) or with RRM2B/p53R2 (outside S phase and in post-mitotic tissues).

Variants (transcript NM_001033; protein NP_001024.1):

• Where R381 sits. R381 lies near the specificity site, as "an extension of loop 1." It interacts with S260.
• Functional effect. Loss of function: RNR activity ([¹⁴C]CDP → dCDP) was reduced in patient fibroblasts, while RRM1 protein levels were normal. That means reduced catalytic function, not protein instability.
• Variant class: missense only. All variants are germline.
• Modifier genes: none known.
• Epigenetics and chromosomal abnormalities: none reported or relevant.

5. Environmental information

• No environmental, lifestyle or infectious causes are known.
• Inferred pharmacological concern: RNR inhibitors (hydroxyurea, gemcitabine, clofarabine, cladribine) act on RRM1. In theory they could worsen dNTP depletion in carriers or patients. This is not documented.

6. Mechanism and pathophysiology

Causal chain:

1. Lesion. Homozygous missense at RRM1 Arg381 (p.R381H or p.R381C) changes the local structure near loop 1, the specificity site and the dimer interface. This step is inferred from molecular dynamics simulations (computational evidence).
2. → Reduced RNR catalytic activity. Less ribonucleoside diphosphate (NDP) is turned into deoxyribonucleoside diphosphate (dNDP). This was shown in patient fibroblasts (in vitro).
3. → Abnormal nucleotide pools. NDPs are raised and mitochondrial dGTP and dTTP are lowered. Shown in fibroblasts: the pool changes were clearest in probands 2 and 3 and were not seen in 1a/1b.
4. → More ribonucleotides built into mtDNA, because the dNTP:rNTP ratio falls. Shown by alkaline hydrolysis and denaturing Southern blot.
5. → Impaired mtDNA replication in cells that depend on de novo dNTP synthesis. mtDNA depletion appears in proliferating fibroblasts, but not in quiescent ones, which rely on the salvage pathway. Expression of salvage-pathway genes was normal.
6. → Stalled replication and faulty repair in post-mitotic muscle produce multiple mtDNA deletions. This step is inferred by analogy with RRM2B, TK2 and POLG. Long-range PCR found no deletions in cultured fibroblasts; deletions were found only in muscle.
7. → Clonal build-up of deleted mtDNA gives mosaic respiratory chain deficiency: COX-negative and ragged-red fibers, and reduced activity of complex IV and complexes II+III.
8. → Energy failure in high-demand, long-lived cells, branching into three outcomes:
9. 8a. extraocular and levator muscles → ptosis and progressive external ophthalmoplegia;
10. 8b. limb skeletal muscle → proximal myopathy, atrophy, raised CK;
11. 8c. enteric smooth muscle or neurons, and peripheral nerve → GI dysmotility, cachexia, axonal neuropathy. This branch was seen only in family 1 (R381H) and is a mechanistic inference.

Mechanism categories:

• Molecular pathway: de novo dNTP synthesis (Reactome "Synthesis of dNTPs"; KEGG purine and pyrimidine metabolism).
• Suggested GO terms:
• GO:0009263 deoxyribonucleotide biosynthetic process (DECREASED);
• GO:0004748 ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor (DECREASED);
• GO:0000002 mitochondrial genome maintenance;
• GO:0006264 mitochondrial DNA replication;
• cellular component GO:0005971 ribonucleoside-diphosphate reductase complex; GO:0005829 cytosol; GO:0005739 mitochondrion (where the defect shows).
• Cell types (CL): skeletal muscle fiber (CL:0008002 or CL:0000188); extraocular muscle fibers; fibroblast (CL:0000057; the in vitro model); possibly enteric neurons or smooth muscle.
• Immune involvement: none.
• Tissue damage: respiratory chain failure, fiber necrosis and regeneration, atrophy.
• Omics, single-cell, CRISPR screens: none disease-specific. RRM1 is pan-essential in DepMap, which fits the total-knockout lethality below.
• Context from mouse (PMID:20724444, Ylikallio 2010). Overexpressing RNR subunits does not raise mtDNA copy number. Imbalanced dNTP pools from overexpressing two subunits caused progressive mtDNA depletion in muscle. This supports dNTP balance, not just quantity, as the critical variable.

7. Anatomical structures affected

• Primary:
• extraocular muscles (UBERON:0001601 extra-ocular muscle);
• levator palpebrae superioris / upper eyelid;
• skeletal muscle (UBERON:0001134 skeletal muscle tissue).
• Secondary:
• gastrointestinal tract (small intestine motility);
• peripheral nerves (UBERON:0001021 nerve);
• inner ear / cochlea (only in the dominant family).
• Subcellular: mitochondrion and mitochondrial nucleoid (GO:0042645).
• Laterality: bilateral, symmetric ptosis and ophthalmoplegia.

8. Temporal development

• Onset:
• usually adulthood (early 40s to 61);
• adolescence in family 1 (GI symptoms at 7, ophthalmoparesis at 17);
• proband 4 reported subjective weakness since childhood.
• Course: insidious, slowly progressive, and lifelong. Diplopia → ptosis → complete ophthalmoplegia → limb weakness and gait difficulty.
• Remission: none.
• Natural-history data: none.

9. Inheritance and population

• Inheritance: autosomal recessive (HP:0000007).
• Penetrance: apparently complete in homozygotes; no heterozygous carrier was affected.
• Expressivity: variable. R381H (family 1) gives an earlier, more multisystem, MNGIE-like picture. R381C gives late-onset ocular myopathy.
• Anticipation and germline mosaicism: none.
• Founder effect: possible for R381C in Northern Europeans (two families). Not formally tested.
• Consanguinity: present in family 1.
• Prevalence: unknown. Ultra-rare, with 5 patients reported (Orphanet-style class "<1/1,000,000"; measure type CASES_IN_LITERATURE). Carrier frequency of R381C is about 1 in 10,000.
• Sex: both affected (3 men, including the brother; 2 women).
• Geography: Saudi Arabia; the Netherlands; family 4 of unstated ancestry.

10. Diagnostics

Clinical and laboratory: - CK, which may be raised. - Lactate. - Muscle biopsy with COX/SDH histochemistry (COX-negative and ragged-red fibers). - Respiratory chain enzyme assays. - Long-range PCR or Southern blot of muscle mtDNA for multiple deletions: the hallmark. - qPCR for mtDNA copy number.

Electrophysiology: nerve conduction and EMG (axonal sensorimotor neuropathy, myopathic EMG).

Genetic testing: - Exome or genome sequencing, or a nuclear mtDNA-maintenance gene panel. - RRM1 is on PanelApp Australia's mitochondrial disease panel (#203). - Analyse a blood sample for nuclear genes. Muscle mtDNA analysis shows the deletions, but blood mtDNA testing will be normal.

Supporting functional assays (research): - RNR activity in fibroblasts; - dNTP pools; - mtDNA depletion in proliferating, but not quiescent, fibroblasts; - mtDNA ribonucleotide content.

Differential diagnosis (other nuclear causes of PEO with multiple mtDNA deletions):

Screening: no newborn or population screening. Carrier and cascade testing is possible within families.

11. Outcome and prognosis

• No survival data exist. Patients survive into their 30s–60s with progressive disability.
• Cachexia and GI dysmotility (family 1) are the probable life-limiting complications.
• Other complications: aspiration from dysphagia, falls, and exposure keratopathy from ptosis.
• No prognostic biomarkers are known.

12. Treatment

No disease-specific therapy has been reported. Management is supportive, following general guidance for primary mitochondrial myopathy.

• Experimental / theoretical: deoxynucleoside supplementation. dC/dT therapy is effective in TK2 deficiency (doxecitine/doxribtimine). It might bypass the de novo block through salvage enzymes, which stay intact in RRM1 patient cells. This is a hypothesis that has not been tested; the search found no trials or case reports.
• Clinical trials: none for RRM1 (ClinicalTrials.gov search for "RRM1 ophthalmoplegia" returns none).
• Pharmacogenomics: avoid RNR inhibitors where possible. This is inferred, not established.

13. Prevention

• Primary prevention: carrier testing in at-risk relatives, especially in the consanguineous family. Prenatal or preimplantation diagnosis once both variants in a family are known.
• Tertiary prevention:
• watch for dysphagia, nutrition, cardiac and respiratory status (generic mitochondrial surveillance);
• corneal protection after ptosis surgery.
• Vaccination, public health and environmental measures: not applicable.

14. Other species and natural disease

• OMIA: no naturally occurring RRM1 disease is known in animals.
• Orthologs:
• mouse Rrm1 (MGI:98180; NCBITaxon:10090);
• zebrafish rrm1 (ZFIN:ZDB-GENE-990415-247; NCBITaxon:7955);
• Drosophila RnrL;
• yeast RNR1 and RNR3 (NCBITaxon:4932).
• RRM1 is highly conserved: the class Ia R1 catalytic machinery is shared from E. coli NrdA to humans.
• Zoonotic relevance: none.

15. Model organisms

• Main gap: no knock-in mouse or zebrafish model carries R381H or R381C. A homozygous R381 knock-in, or patient iPSC-derived myotubes, would be the natural next model.
• Resources: MGI, IMPC, ZFIN, Cellosaurus (no patient lines deposited).

Knowledge gaps

1. Only 5 patients are known; the phenotype spectrum and natural history are undefined.
2. How depletion in proliferating cells leads to deletions in post-mitotic muscle has not been demonstrated (§6, step 6).
3. Why only family 1 has GI involvement (R381H versus R381C, or background) is unexplained.
4. Whether deoxynucleoside therapy rescues the defect, in fibroblasts or in patients, has not been tested.
5. The source of several MedGen/OMIM-listed features (intellectual disability, gastroparesis, loss of ambulation) is unclear; they may belong to the dominant family.

Sources

• Shintaku J, Pernice WM, Eyaid W, … Taylor RW, Hirano M. "RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis." J Clin Invest. 2022 Jul 1;132(13):e145660. PMID:35617047; PMC9246377. JCI · PubMed · PMC
• Ylikallio E, et al. "Ribonucleotide reductase is not limiting for mitochondrial DNA copy number in mice." Nucleic Acids Res. 2010;38(22). PMID:20724444.
• MedGen C5882731 / UID 1847098 (PEOB6)
• OMIM Clinical Synopsis #620647 (blocked by HTTP 403; content seen through search snippets only)
• OMIM *180410 RRM1
• HGNC REST: RRM1
• KEGG H01395
• PanelApp Australia, panel 203, RRM1
• GeneCards RRM1
• NIH GTR RRM1
• MGI Rrm1 · IMPC Rrm1 · Alliance
• ZFIN rrm1
• Specks J, et al. Mol Cell Biol 2015 (Rrm1-W688G knock-in; PMID not retrieved)

Reference Validation

Checked with linkml-reference-validator 0.4.0.

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

• MONDO:0957993 (2 mentions) - the report calls it "MONDO"; MONDO calls it progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal recessive 6
• NCBITaxon:4932 (1 mention) - the report calls it "yeast RNR1 and RNR3"; NCBITaxon calls it Saccharomyces cerevisiae

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

• GO:0000002 (obsolete mitochondrial genome maintenance) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

• GO:0042645 (1 mention) - the report calls it "Subcellular: mitochondrion and mitochondrial nucleoid"; GO calls it mitochondrial nucleoid**

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.