mitochondrial DNA depletion syndrome, hepatocerebral form

Summary

mitochondrial DNA depletion syndrome, hepatocerebral form (MONDO:0100512) is a disease (an umbrella term covering 5 Mondo subtypes) with 1 cohort gene.

At a glance

• Umbrella term: 5 Mondo subtypes
• Cohort genes: 1
• ClinVar variants: 46

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial DNA depletion syndrome, hepatocerebral form
Mondo ID	MONDO:0100512
MeSH	C580039
Orphanet	254871
ICD-11	1285620325
UMLS	C3711385
MedGen	777993
GARD	0020769
Is cancer (heuristic)	no

Also known as: deoxyguanosine kinase deficiency · mtDNA depletion syndrome, hepatocerebral form

Data availability: 46 ClinVar variants.

Disease family

An umbrella term covering 5 Mondo subtypes.

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, hepatocerebral form

Related subtypes (20): Sengers syndrome, mitochondrial DNA depletion syndrome 1, mitochondrial DNA depletion syndrome, myopathic form, mitochondrial DNA depletion syndrome 4b, mitochondrial DNA depletion syndrome 11, mitochondrial DNA deletion syndrome with progressive myopathy, mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive, mitochondrial DNA depletion syndrome 14B (cardioencephalomyopathic type), mitochondrial DNA depletion syndrome 15 (hepatocerebral type), mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant, mitochondrial DNA depletion syndrome, encephalomyopathic form, mitochondrial dna depletion syndrome 16B (neuroophthalmic type), mitochondrial DNA depletion syndrome 20 (mngie type), mitochondrial DNA depletion syndrome 16 (hepatic type), mitochondrial DNA depletion syndrome 17, mitochondrial DNA depletion syndrome 18, mitochondrial DNA depletion syndrome 19, AFG3L2-related optic atrophy and/or spastic ataxia spectrum, mitochondrial dna depletion syndrome 21, mitochondrial dna depletion syndrome 14A (encephalomyopathic type)

Subtypes (5): mitochondrial DNA depletion syndrome 4a, mitochondrial DNA depletion syndrome 3 (hepatocerebral type), mitochondrial DNA depletion syndrome 6 (hepatocerebral type), mitochondrial DNA depletion syndrome 7 (hepatocerebral type), mitochondrial DNA depletion syndrome, hepatocerebrorenal form

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

46 retrieved; paginated sample, class counts are floors:

15 uncertain significance, 14 pathogenic/likely pathogenic, 6 likely pathogenic, 5 conflicting classifications of pathogenicity, 4 pathogenic, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065949	NM_002437.5(MPV17):c.428T>G (p.Leu143Ter)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339934	NM_002437.5(MPV17):c.405C>G (p.Tyr135Ter)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16160	NM_002437.5(MPV17):c.149G>A (p.Arg50Gln)	MPV17	Pathogenic	criteria provided, multiple submitters, no conflicts
16162	NM_002437.5(MPV17):c.148C>T (p.Arg50Trp)	MPV17	Pathogenic	criteria provided, multiple submitters, no conflicts
214664	NM_002437.5(MPV17):c.370C>T (p.Gln124Ter)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2203028	NM_002437.4(MPV17):c.284delG	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2743813	NM_002437.5(MPV17):c.70+1G>A	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
290443	NM_002437.5(MPV17):c.280-1dup	MPV17	Pathogenic	criteria provided, multiple submitters, no conflicts
381523	NM_002437.5(MPV17):c.191C>G (p.Pro64Arg)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
38348	NM_002437.5(MPV17):c.206G>A (p.Trp69Ter)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
38352	NM_002437.5(MPV17):c.260AGA[1] (p.Lys88del)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
38355	NM_002437.5(MPV17):c.293C>T (p.Pro98Leu)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
38356	NM_002437.5(MPV17):c.451dup (p.Leu151fs)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
522375	NM_002437.5(MPV17):c.376-2A>C	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
522376	NM_002437.5(MPV17):c.376-1G>A	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
626263	NM_002437.5(MPV17):c.122G>A (p.Arg41Gln)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
808716	NM_002437.5(MPV17):c.185del (p.Val62fs)	MPV17	Pathogenic	criteria provided, multiple submitters, no conflicts
939232	NM_002437.5(MPV17):c.179del (p.Gly60fs)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1469178	NM_002437.5(MPV17):c.375+2T>C	MPV17	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2676674	NM_002437.5(MPV17):c.462-2A>C	MPV17	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3239744	NM_002437.5(MPV17):c.459C>G (p.Tyr153Ter)	MPV17	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4057910	NM_002437.5(MPV17):c.414G>A (p.Trp138Ter)	MPV17	Likely pathogenic	criteria provided, single submitter
4815048	NM_002437.5(MPV17):c.133del (p.Glu45fs)	MPV17	Likely pathogenic	criteria provided, single submitter
4815049	NM_002437.5(MPV17):c.473del (p.Val158fs)	MPV17	Likely pathogenic	criteria provided, single submitter
2433791	NM_002437.5(MPV17):c.1A>G (p.Met1Val)	LOC129933372	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214660	NM_002437.5(MPV17):c.121C>T (p.Arg41Trp)	MPV17	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
38350	NM_002437.5(MPV17):c.234_242del (p.Gly79_Thr81del)	MPV17	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
38353	NM_002437.5(MPV17):c.268TTG[1] (p.Leu91del)	MPV17	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
593343	NM_002437.5(MPV17):c.376-9T>G	MPV17	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4057912	NM_002437.5(MPV17):c.23A>C (p.Gln8Pro)	LOC129933372	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MPV17	Orphanet:255229	Navajo neurohepatopathy

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
MPV17	HGNC:7224	ENSG00000115204	P39210	Mitochondrial inner membrane protein Mpv17	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MPV17	Mitochondrial inner membrane protein Mpv17	Non-selective channel that modulates the membrane potential under normal conditions and oxidative stress, and is involved in mitochondrial homeostasis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MPV17	Other/Unknown	no		Mpv17_PMP22

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 adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MPV17	283	ubiquitous	marker	right adrenal gland, right adrenal gland cortex, left adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MPV17	1,251

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MPV17	P39210	90.23

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
Protein localization	1	190.3×	0.006	MPV17
Peroxisomal protein import	1	173.0×	0.006	MPV17

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
regulation of mitochondrial DNA metabolic process	1	8426.0×	4e-04	MPV17
glomerular basement membrane development	1	1532.0×	1e-03	MPV17
inner ear development	1	374.5×	0.003	MPV17

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
MPV17	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	MPV17

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)
MPV17	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.