Combined oxidative phosphorylation defect type 13

Summary

Combined oxidative phosphorylation defect type 13 (MONDO:0013977) is a disease caused by PNPT1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PNPT1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 52
• Phenotypes (HPO): 33

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

33 HPO clinical features (Orphanet curated; top 33 by frequency):

HPO ID	Term	Frequency
HP:0002151	Increased circulating lactate concentration	Very frequent (80-99%)
HP:0200125	Mitochondrial respiratory chain defects	Very frequent (80-99%)
HP:0000407	Sensorineural hearing impairment	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0001266	Choreoathetosis	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0002421	Poor head control	Frequent (30-79%)
HP:0002451	Limb dystonia	Frequent (30-79%)
HP:0002490	Increased CSF lactate	Frequent (30-79%)
HP:0007069	Profound static encephalopathy	Frequent (30-79%)
HP:0008936	Axial hypotonia	Frequent (30-79%)
HP:0010994	Abnormal corpus striatum morphology	Frequent (30-79%)
HP:0012448	Delayed myelination	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Occasional (5-29%)
HP:0002134	Abnormality of the basal ganglia	Occasional (5-29%)
HP:0002310	Orofacial dyskinesia	Occasional (5-29%)
HP:0003273	Hip contracture	Occasional (5-29%)
HP:0003548	Subsarcolemmal accumulations of abnormally shaped mitochondria	Occasional (5-29%)
HP:0003554	Type 2 muscle fiber atrophy	Occasional (5-29%)
HP:0003803	Type 1 muscle fiber predominance	Occasional (5-29%)
HP:0006466	Ankle flexion contracture	Occasional (5-29%)
HP:0006895	Lower limb hypertonia	Occasional (5-29%)
HP:0011471	Gastrostomy tube feeding in infancy	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0040204	Elevated CSF neopterin level	Occasional (5-29%)
HP:0000496	Abnormality of eye movement	Occasional (5-29%)
HP:0000519	Developmental cataract	Occasional (5-29%)
HP:0000762	Decreased nerve conduction velocity	Occasional (5-29%)
HP:0000763	Sensory neuropathy	Occasional (5-29%)
HP:0001273	Abnormal corpus callosum morphology	Occasional (5-29%)
HP:0001344	Absent speech	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	combined oxidative phosphorylation defect type 13
Mondo ID	MONDO:0013977
OMIM	614932
Orphanet	319514
DOID	DOID:0111467
SNOMED CT	763110007
UMLS	C4706283
MedGen	1631854
GARD	0017454
Is cancer (heuristic)	no

Also known as: combined oxidative phosphorylation deficiency 13 · combined oxidative phosphorylation deficiency caused by mutation in PNPT1 · combined oxidative phosphorylation deficiency type 13 · COXPD13 · PNPT1 combined oxidative phosphorylation deficiency

Data availability: 52 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 › combined oxidative phosphorylation deficiency › combined oxidative phosphorylation defect type 13

Related subtypes (57): severe X-linked mitochondrial encephalomyopathy, hepatoencephalopathy due to combined oxidative phosphorylation defect type 1, combined oxidative phosphorylation defect type 2, fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3, combined oxidative phosphorylation defect type 4, hypotonia with lactic acidemia and hyperammonemia, combined oxidative phosphorylation defect type 7, combined oxidative phosphorylation defect type 8, combined oxidative phosphorylation defect type 9, mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency, combined oxidative phosphorylation defect type 11, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, combined oxidative phosphorylation defect type 14, combined oxidative phosphorylation defect type 15, infantile hypertrophic cardiomyopathy due to MRPL44 deficiency, combined oxidative phosphorylation defect type 17, growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndrome, combined oxidative phosphorylation deficiency 19, combined oxidative phosphorylation defect type 20, combined oxidative phosphorylation defect type 21, mitochondrial proton-transporting ATP synthase complex deficiency, combined oxidative phosphorylation defect type 23, combined oxidative phosphorylation defect type 24, combined oxidative phosphorylation defect type 25, combined oxidative phosphorylation defect type 26, combined oxidative phosphorylation defect type 27, combined oxidative phosphorylation deficiency 28, combined oxidative phosphorylation deficiency 29, combined oxidative phosphorylation defect type 30, lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome, combined oxidative phosphorylation deficiency 40, combined oxidative phosphorylation deficiency 41, combined oxidative phosphorylation deficiency 42, combined oxidative phosphorylation deficiency 43, combined oxidative phosphorylation deficiency 44, combined oxidative phosphorylation deficiency 52, combined oxidative phosphorylation deficiency 53, combined oxidative phosphorylation deficiency 54, combined oxidative phosphorylation deficiency 37, combined oxidative phosphorylation deficiency 38, combined oxidative phosphorylation deficiency 39, combined oxidative phosphorylation deficiency 45, combined oxidative phosphorylation deficiency 46, combined oxidative phosphorylation deficiency 47, combined oxidative phosphorylation deficiency 48, combined oxidative phosphorylation deficiency 51, combined oxidative phosphorylation deficiency 32, combined oxidative phosphorylation deficiency 33, combined oxidative phosphorylation deficiency 34, combined oxidative phosphorylation deficiency 35, combined oxidative phosphorylation deficiency 36, combined oxidative phosphorylation deficiency 55, combined oxidative phosphorylation deficiency 56, combined oxidative phosphorylation deficiency 57, combined oxidative phosphorylation deficiency 58, combined oxidative phosphorylation deficiency 59, combined oxidative phosphorylation deficiency 60

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

52 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 11 conflicting classifications of pathogenicity, 10 pathogenic, 6 benign, 5 likely pathogenic, 5 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1700630	NM_033109.5(PNPT1):c.1579_1580insGAT (p.Tyr527Ter)	PNPT1	Pathogenic	no assertion criteria provided
1805654	NM_033109.5(PNPT1):c.406C>T (p.Arg136Cys)	PNPT1	Pathogenic	criteria provided, single submitter
2036155	NM_033109.5(PNPT1):c.1223del (p.Lys407_Ser408insTer)	PNPT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2140524	NM_033109.5(PNPT1):c.394C>T (p.Arg132Ter)	PNPT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215010	NM_033109.5(PNPT1):c.1519G>T (p.Ala507Ser)	PNPT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218175	NM_033109.5(PNPT1):c.404-1G>A	PNPT1	Pathogenic	no assertion criteria provided
253224	NM_033109.5(PNPT1):c.1528G>C (p.Ala510Pro)	PNPT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
253225	NM_033109.5(PNPT1):c.760C>A (p.Gln254Lys)	PNPT1	Pathogenic	criteria provided, single submitter
39801	NM_033109.5(PNPT1):c.1160A>G (p.Gln387Arg)	PNPT1	Pathogenic	no assertion criteria provided
4813546	NM_033109.5(PNPT1):c.310C>T (p.Gln104Ter)	PNPT1	Pathogenic	criteria provided, single submitter
587375	NM_033109.5(PNPT1):c.407G>A (p.Arg136His)	PNPT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
587376	NM_033109.5(PNPT1):c.208T>C (p.Ser70Pro)	PNPT1	Pathogenic	no assertion criteria provided
587377	NM_033109.5(PNPT1):c.2137G>T (p.Asp713Tyr)	PNPT1	Pathogenic	no assertion criteria provided
587378	NM_033109.5(PNPT1):c.1495G>C (p.Gly499Arg)	PNPT1	Pathogenic	no assertion criteria provided
869396	NM_033109.5(PNPT1):c.1818T>G (p.Val606=)	PNPT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1031032	NM_033109.5(PNPT1):c.1906+1G>A	PNPT1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1805612	NM_033109.5(PNPT1):c.1400C>A (p.Pro467His)	PNPT1	Likely pathogenic	criteria provided, single submitter
3068270	NM_033109.5(PNPT1):c.1284+4A>C	PNPT1	Likely pathogenic	criteria provided, single submitter
39802	NM_033109.5(PNPT1):c.1424A>G (p.Glu475Gly)	PNPT1	Likely pathogenic	criteria provided, single submitter
801714	NM_033109.5(PNPT1):c.526G>A (p.Ala176Thr)	PNPT1	Likely pathogenic	criteria provided, single submitter
1342762	NM_033109.5(PNPT1):c.40C>T (p.Arg14Trp)	PNPT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
209184	NM_033109.5(PNPT1):c.1592C>G (p.Thr531Arg)	PNPT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
209185	NM_033109.5(PNPT1):c.1525G>A (p.Val509Ile)	PNPT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
215005	NM_033109.5(PNPT1):c.493C>T (p.Pro165Ser)	PNPT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
215008	NM_033109.5(PNPT1):c.688G>C (p.Glu230Gln)	PNPT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
215009	NM_033109.5(PNPT1):c.1453A>G (p.Met485Val)	PNPT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
427125	NM_033109.5(PNPT1):c.517G>A (p.Ala173Thr)	PNPT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
548987	NM_033109.5(PNPT1):c.1361C>G (p.Ala454Gly)	PNPT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
732314	NM_033109.5(PNPT1):c.412A>G (p.Ile138Val)	PNPT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
972897	NM_033109.5(PNPT1):c.1619A>G (p.Asn540Ser)	PNPT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 3 · 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
PNPT1	Definitive	Autosomal recessive	combined oxidative phosphorylation defect type 13	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PNPT1	Orphanet:101111	Spinocerebellar ataxia type 25
PNPT1	Orphanet:319514	Combined oxidative phosphorylation defect type 13
PNPT1	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

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
PNPT1	HGNC:23166	ENSG00000138035	Q8TCS8	Polyribonucleotide nucleotidyltransferase 1, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PNPT1	Polyribonucleotide nucleotidyltransferase 1, mitochondrial	RNA-binding protein implicated in numerous RNA metabolic processes.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

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
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PNPT1	Scaffold/PPI	no	2.7.7.8	ExoRNase_PH_dom1, S1_domain, KH_dom

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
left ventricle myocardium	1
secondary oocyte	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PNPT1	258	ubiquitous	marker	left ventricle myocardium, secondary oocyte, tibialis anterior

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PNPT1	3,741

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PNPT1	Q8TCS8	11

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
Mitochondrial RNA degradation	1	1631.4×	6e-04	PNPT1

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
RNA import into mitochondrion	1	16852.0×	6e-04	PNPT1
nuclear polyadenylation-dependent mRNA catabolic process	1	16852.0×	6e-04	PNPT1
mitochondrial RNA 5’-end processing	1	8426.0×	6e-04	PNPT1
mitochondrial mRNA catabolic process	1	5617.3×	6e-04	PNPT1
positive regulation of mitochondrial RNA catabolic process	1	5617.3×	6e-04	PNPT1
mitochondrial RNA 3’-end processing	1	5617.3×	6e-04	PNPT1
rRNA import into mitochondrion	1	5617.3×	6e-04	PNPT1
mitochondrial mRNA polyadenylation	1	4213.0×	6e-04	PNPT1
positive regulation of miRNA catabolic process	1	4213.0×	6e-04	PNPT1
mitochondrial RNA catabolic process	1	2808.7×	8e-04	PNPT1
regulation of cellular respiration	1	2808.7×	8e-04	PNPT1
regulation of cellular senescence	1	1404.3×	0.001	PNPT1
positive regulation of mRNA catabolic process	1	1203.7×	0.002	PNPT1
response to growth hormone	1	1123.5×	0.002	PNPT1
protein homotrimerization	1	991.3×	0.002	PNPT1
cellular response to interferon-beta	1	526.6×	0.003	PNPT1
response to cAMP	1	510.7×	0.003	PNPT1
liver regeneration	1	510.7×	0.003	PNPT1
mRNA catabolic process	1	495.6×	0.003	PNPT1
RNA catabolic process	1	455.5×	0.003	PNPT1
cellular response to oxidative stress	1	154.6×	0.007	PNPT1
mitochondrion organization	1	151.8×	0.007	PNPT1
protein homooligomerization	1	122.1×	0.009	PNPT1
mRNA processing	1	78.8×	0.013	PNPT1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PNPT1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PNPT1	2.7.7.8	polyribonucleotide nucleotidyltransferase

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PNPT1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PNPT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.