mitochondrial DNA depletion syndrome 8a

Summary

mitochondrial DNA depletion syndrome 8a (MONDO:0012792) is a disease caused by RRM2B (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RRM2B (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 157

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial DNA depletion syndrome 8a
Mondo ID	MONDO:0012792
OMIM	612075
Orphanet	255235
DOID	DOID:0070331, DOID:0080127
SNOMED CT	765100000
UMLS	C2749861
MedGen	412815
GARD	0013200
Is cancer (heuristic)	no

Also known as: encephalomyopathic type with renal tubulopathy · mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy) · mitochondrial DNA depletion syndrome caused by mutation in RRM2B · mitochondrial DNA depletion syndrome type 8a · mtDNA depletion syndrome, encephalomyopathic form with renal tubulopathy · MTDPS8A · RRM2B mitochondrial DNA depletion syndrome · RRM2B-related mitochondrial DNA depletion syndrome

Data availability: 157 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › mitochondrial DNA depletion syndrome › mitochondrial DNA depletion syndrome, encephalomyopathic form › mitochondrial DNA depletion syndrome 8a

Related subtypes (3): mitochondrial DNA depletion syndrome 9, mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria, mitochondrial DNA depletion syndrome 13

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

157 retrieved; paginated sample, class counts are floors:

69 uncertain significance, 24 benign, 22 conflicting classifications of pathogenicity, 15 likely pathogenic, 12 benign/likely benign, 7 pathogenic, 6 pathogenic/likely pathogenic, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
132103	NM_015713.5(RRM2B):c.48G>A (p.Glu16=)	LOC130000896	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
132104	NM_015713.5(RRM2B):c.121C>T (p.Arg41Trp)	RRM2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
132122	NM_015713.5(RRM2B):c.671T>G (p.Ile224Ser)	RRM2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215091	NM_015713.5(RRM2B):c.520C>T (p.Arg174Ter)	RRM2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4845340	NM_015713.5(RRM2B):c.414_415del (p.Tyr138_Ser139delinsTer)	RRM2B	Pathogenic	criteria provided, single submitter
5386	NM_015713.5(RRM2B):c.850C>T (p.Gln284Ter)	RRM2B	Pathogenic	no assertion criteria provided
5387	NM_015713.5(RRM2B):c.322-2A>G	RRM2B	Pathogenic	criteria provided, multiple submitters, no conflicts
5388	NM_015713.5(RRM2B):c.580G>A (p.Glu194Lys)	RRM2B	Pathogenic	no assertion criteria provided
5390	NM_015713.5(RRM2B):c.707G>T (p.Cys236Phe)	RRM2B	Pathogenic	no assertion criteria provided
5391	NM_015713.5(RRM2B):c.979C>T (p.Arg327Ter)	RRM2B	Pathogenic	criteria provided, multiple submitters, no conflicts
5392	NM_015713.5(RRM2B):c.686G>T (p.Gly229Val)	RRM2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
817116	NM_015713.5(RRM2B):c.109_110del (p.Lys37fs)	RRM2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
830053	NM_015713.5(RRM2B):c.527_528insG (p.Ile176fs)	RRM2B	Pathogenic	criteria provided, single submitter
3595034	NM_015713.5(RRM2B):c.40C>T (p.Gln14Ter)	LOC130000896	Likely pathogenic	criteria provided, single submitter
1030272	NM_015713.5(RRM2B):c.48+268_48+269delinsAA	RRM2B	Likely pathogenic	criteria provided, single submitter
132112	NM_015713.5(RRM2B):c.328C>T (p.Arg110Cys)	RRM2B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
132123	NM_015713.5(RRM2B):c.846G>C (p.Met282Ile)	RRM2B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1524868	NM_015713.5(RRM2B):c.455+1G>A	RRM2B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
216993	NM_015713.5(RRM2B):c.635_636insAAG (p.Gly212_Leu213insSer)	RRM2B	Likely pathogenic	criteria provided, single submitter
3062047	NM_015713.5(RRM2B):c.472G>A (p.Ala158Thr)	RRM2B	Likely pathogenic	criteria provided, single submitter
3064800	NM_015713.5(RRM2B):c.94G>T (p.Glu32Ter)	RRM2B	Likely pathogenic	criteria provided, single submitter
3068322	NM_015713.5(RRM2B):c.49-2A>G	RRM2B	Likely pathogenic	criteria provided, single submitter
3250467	NM_015713.5(RRM2B):c.540del (p.Lys180fs)	RRM2B	Likely pathogenic	criteria provided, single submitter
3362612	NM_015713.5(RRM2B):c.184del (p.Ser62fs)	RRM2B	Likely pathogenic	criteria provided, single submitter
3595032	NM_015713.5(RRM2B):c.168T>A (p.Tyr56Ter)	RRM2B	Likely pathogenic	criteria provided, single submitter
3767177	NM_015713.5(RRM2B):c.1027A>G (p.Asn343Asp)	RRM2B	Likely pathogenic	criteria provided, single submitter
3767231	NM_015713.5(RRM2B):c.969_972del (p.Phe323fs)	RRM2B	Likely pathogenic	criteria provided, single submitter
830054	NM_015713.5(RRM2B):c.128T>A (p.Val43Asp)	RRM2B	Likely pathogenic	criteria provided, single submitter
430458	NM_015713.5(RRM2B):c.1A>G (p.Met1Val)	LOC130000896	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1163492	NM_015713.5(RRM2B):c.119G>A (p.Arg40His)	RRM2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 5 · 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
RRM2B	Definitive	Autosomal recessive	mitochondrial DNA depletion syndrome 8a	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RRM2B	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
RRM2B	Orphanet:255235	Mitochondrial DNA depletion syndrome, encephalomyopathic form with renal tubulopathy
RRM2B	Orphanet:298	Mitochondrial neurogastrointestinal encephalomyopathy
RRM2B	Orphanet:329336	Adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy
RRM2B	Orphanet:480	Kearns-Sayre syndrome

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
RRM2B	HGNC:17296	ENSG00000048392	Q7LG56	Ribonucleoside-diphosphate reductase subunit M2 B	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RRM2B	Ribonucleoside-diphosphate reductase subunit M2 B	Plays a pivotal role in cell survival by repairing damaged DNA in a p53/TP53-dependent manner.

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)
RRM2B	Enzyme (other)	yes	1.17.4.1	RNR_small_fam, Ferritin-like_SF, RNR-like

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
deltoid	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RRM2B	254	ubiquitous	marker	secondary oocyte, oocyte, deltoid

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RRM2B	2,432

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RRM2B	Q7LG56	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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×	0.006	RRM2B
TP53 Regulates Metabolic Genes	1	129.8×	0.008	RRM2B

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
deoxyribonucleoside triphosphate metabolic process	1	16852.0×	6e-04	RRM2B
ribonucleoside diphosphate metabolic process	1	5617.3×	6e-04	RRM2B
deoxyribonucleotide biosynthetic process	1	5617.3×	6e-04	RRM2B
2’-deoxyribonucleotide biosynthetic process	1	5617.3×	6e-04	RRM2B
positive regulation of G0 to G1 transition	1	3370.4×	8e-04	RRM2B
negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator	1	2407.4×	1e-03	RRM2B
response to amine	1	1872.4×	0.001	RRM2B
mitochondrial DNA replication	1	1532.0×	0.001	RRM2B
renal system process	1	1123.5×	0.001	RRM2B
DNA synthesis involved in DNA repair	1	936.2×	0.001	RRM2B
positive regulation of G2/M transition of mitotic cell cycle	1	601.9×	0.002	RRM2B
kidney development	1	140.4×	0.008	RRM2B
response to oxidative stress	1	130.6×	0.008	RRM2B
DNA repair	1	63.8×	0.016	RRM2B

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
RRM2B	1	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TRIAPINE	3	RRM2B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
RRM2B	47	Binding:44, Functional:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RRM2B	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	RRM2B

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	RRM2B
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.