mitochondrial DNA depletion syndrome 6 (hepatocerebral type)

Summary

mitochondrial DNA depletion syndrome 6 (hepatocerebral type) (MONDO:0009747) is a disease caused by MPV17 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MPV17 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 99

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		49	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial DNA depletion syndrome 6 (hepatocerebral type)
Mondo ID	MONDO:0009747
MeSH	C538344
OMIM	256810
Orphanet	255229
DOID	DOID:0080125
UMLS	C1850406
MedGen	338045
GARD	0003972
Is cancer (heuristic)	no

Also known as: mitochondrial DNA depletion syndrome 6 · mitochondrial DNA depletion syndrome 6 (hepatocerebral type) · MPV17-related hepatocerebral mitochondrial DNA depletion syndrome · MTDPS6 · Navajo neurohepatopathy · Navajo neuropathy · NN

Data availability: 99 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, hepatocerebral form › mitochondrial DNA depletion syndrome 6 (hepatocerebral type)

Related subtypes (4): mitochondrial DNA depletion syndrome 4a, mitochondrial DNA depletion syndrome 3 (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

99 retrieved; paginated sample, class counts are floors:

30 uncertain significance, 20 pathogenic/likely pathogenic, 17 conflicting classifications of pathogenicity, 14 pathogenic, 13 likely pathogenic, 3 benign, 1 benign/likely benign, 1 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
1420339	NM_002437.5(MPV17):c.391del (p.Ile132fs)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451738	NM_002437.5(MPV17):c.405C>A (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
16161	NM_002437.5(MPV17):c.498C>A (p.Asn166Lys)	MPV17	Pathogenic	no assertion criteria provided
16162	NM_002437.5(MPV17):c.148C>T (p.Arg50Trp)	MPV17	Pathogenic	criteria provided, multiple submitters, no conflicts
16163	NM_002437.5(MPV17):c.122_147del (p.Arg41fs)	MPV17	Pathogenic	no assertion criteria provided
16164	NM_002437.5(MPV17):c.359G>A (p.Trp120Ter)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16166	NC_000002.12:g.27309311_27310884delinsCAGG	MPV17	Pathogenic	no assertion criteria provided
214662	NM_002437.5(MPV17):c.135del (p.Glu45fs)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2203027	NM_002437.5(MPV17):c.461+1G>C	MPV17	Pathogenic	criteria provided, multiple submitters, no conflicts
2430184	NM_002437.5(MPV17):c.210C>A (p.Tyr70Ter)	MPV17	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
38347	NM_002437.5(MPV17):c.186+2T>C	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
38358	NM_002437.5(MPV17):c.509C>T (p.Ser170Phe)	MPV17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3902229	NM_002437.5(MPV17):c.112del (p.Val38fs)	MPV17	Pathogenic	criteria provided, single submitter
522374	NM_002437.5(MPV17):c.293del (p.Pro98fs)	MPV17	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
522377	NM_002437.4(MPV17):c.71-2_79delins4	MPV17	Pathogenic	criteria provided, single submitter
598353	NM_002437.5(MPV17):c.461+2T>C	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
635346	NM_002437.5(MPV17):c.414dup (p.Pro139fs)	MPV17	Pathogenic	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
MPV17	Definitive	Autosomal recessive	mitochondrial DNA depletion syndrome 6 (hepatocerebral type)	6

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	gencc,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.