Mitochondrial pyruvate carrier deficiency

Summary

Mitochondrial pyruvate carrier deficiency (MONDO:0013877) is a disease caused by MPC1 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MPC1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 8

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial pyruvate carrier deficiency
Mondo ID	MONDO:0013877
OMIM	614741
Orphanet	447784
DOID	DOID:0080363
UMLS	C3553607
MedGen	766521
GARD	0017771
Is cancer (heuristic)	no

Also known as: mitochondrial pyruvate carrier deficiency · MPYCD

Data availability: 8 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

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 pyruvate carrier deficiency

Related subtypes (13): oxoglutaricaciduria, multiple acyl-CoA dehydrogenase deficiency, inborn mitochondrial myopathy, HSD10 mitochondrial disease, histiocytoid cardiomyopathy, hypotonia-cystinuria syndrome, fumaric aciduria, 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, mitochondrial oxidative phosphorylation disorder, mitochondrial membrane transport disorder, inherited lipoic acid biosynthesis defect, pyruvate dehydrogenase deficiency, OPA1-related optic atrophy with or without extraocular features

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

8 retrieved; paginated sample, class counts are floors:

4 likely pathogenic, 2 uncertain significance, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
35561	NM_016098.4(MPC1):c.289C>T (p.Arg97Trp)	MPC1	Pathogenic	criteria provided, single submitter
35562	NM_016098.4(MPC1):c.236T>A (p.Leu79His)	MPC1	Pathogenic	no assertion criteria provided
1236162	NM_016098.4(MPC1):c.208G>A (p.Ala70Thr)	MPC1	Likely pathogenic	criteria provided, single submitter
1236163	NM_016098.4(MPC1):c.290G>A (p.Arg97Gln)	MPC1	Likely pathogenic	criteria provided, single submitter
1299296	NM_016098.4(MPC1):c.109C>T (p.Pro37Ser)	MPC1	Likely pathogenic	criteria provided, single submitter
488547	NM_016098.4(MPC1):c.214A>G (p.Lys72Glu)	MPC1	Likely pathogenic	criteria provided, single submitter
1029576	NM_016098.4(MPC1):c.220C>A (p.Gln74Lys)	MPC1	Uncertain significance	criteria provided, single submitter
2627541	NM_016098.4(MPC1):c.274C>G (p.Leu92Val)	MPC1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
MPC1	Strong	Autosomal recessive	mitochondrial pyruvate carrier deficiency	4
MPC2	Moderate	Autosomal recessive	mitochondrial pyruvate carrier deficiency	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MPC1	Orphanet:447784	Mitochondrial pyruvate carrier deficiency

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
MPC1	HGNC:21606	ENSG00000060762	Q9Y5U8	Mitochondrial pyruvate carrier 1	gencc,clinvar
MPC2	HGNC:24515	ENSG00000143158	O95563	Mitochondrial pyruvate carrier 2	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MPC1	Mitochondrial pyruvate carrier 1	Mediates the uptake of pyruvate into mitochondria to maintain the balance between glycolysis and oxidative phosphorylation.
MPC2	Mitochondrial pyruvate carrier 2	Mediates the uptake of pyruvate into mitochondria to maintain the balance between glycolysis and oxidative phosphorylation.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MPC1	Other/Unknown	no		MPC
MPC2	Other/Unknown	no		MPC

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
cardiac ventricle	1
heart left ventricle	1
heart right ventricle	1
adult organism	1
male germ cell	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MPC1	288	ubiquitous	marker	heart right ventricle, cardiac ventricle, heart left ventricle
MPC2	298	ubiquitous	marker	sperm, adult organism, male germ cell

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MPC2	1,315
MPC1	633

Intra-cohort edges

A	B	Sources
MPC1	MPC2	biogrid_interaction, intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MPC2	O95563	17
MPC1	Q9Y5U8	13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Pyruvate metabolism	2	407.9×	2e-05	MPC1, MPC2
Aerobic respiration and respiratory electron transport	2	88.5×	2e-04	MPC1, MPC2
Metabolism	2	11.6×	0.007	MPC1, MPC2

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
pyruvate import into mitochondria	2	5617.3×	6e-08	MPC1, MPC2
pyruvate decarboxylation to acetyl-CoA	1	1053.2×	0.001	MPC2
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1	187.2×	0.005	MPC2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MPC2	1	2
MPC1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MITOGLITAZONE	2	MPC2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MPC2	1	Binding:1

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

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)
MITOGLITAZONE	2	MPC2

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	MPC2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MPC1

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)
MPC1	0	MPC2

Clinical trials & evidence

Clinical trials

Clinical trials: 0.