mitochondrial DNA depletion syndrome 15 (hepatocerebral type)

Summary

mitochondrial DNA depletion syndrome 15 (hepatocerebral type) (MONDO:0014943) is a disease caused by TFAM (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: TFAM (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 14

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial DNA depletion syndrome 15 (hepatocerebral type)
Mondo ID	MONDO:0014943
OMIM	617156
DOID	DOID:0080337
UMLS	C4310690
MedGen	934657
GARD	0025037
Is cancer (heuristic)	no

Also known as: mitochondrial DNA depletion syndrome 15 (hepatocerebral type) · mitochondrial DNA depletion syndrome caused by mutation in TFAM · MTDPS15 · TFAM mitochondrial DNA depletion syndrome

Data availability: 14 ClinVar variants · 3 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 15 (hepatocerebral type)

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 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, mitochondrial DNA depletion syndrome, hepatocerebral form, AFG3L2-related optic atrophy and/or spastic ataxia spectrum, mitochondrial dna depletion syndrome 21, mitochondrial dna depletion syndrome 14A (encephalomyopathic type)

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

14 retrieved; paginated sample, class counts are floors:

5 conflicting classifications of pathogenicity, 4 uncertain significance, 2 likely pathogenic, 2 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
381523	NM_002437.5(MPV17):c.191C>G (p.Pro64Arg)	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
221285	NM_003201.3(TFAM):c.533C>T (p.Pro178Leu)	TFAM	Likely pathogenic	criteria provided, single submitter
2585248	NM_003201.3(TFAM):c.441del (p.Glu148fs)	TFAM	Likely pathogenic	criteria provided, single submitter
335526	NM_002437.5(MPV17):c.373C>T (p.Arg125Trp)	MPV17	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
335527	NM_002437.5(MPV17):c.164T>C (p.Val55Ala)	MPV17	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
497955	NM_002437.5(MPV17):c.31C>T (p.Leu11=)	MPV17	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
706697	NM_002437.5(MPV17):c.390C>G (p.Ala130=)	MPV17	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2043897	NM_003201.3(TFAM):c.291+9A>G	TFAM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214661	NM_002437.5(MPV17):c.20A>G (p.Tyr7Cys)	MPV17	Uncertain significance	criteria provided, multiple submitters, no conflicts
214663	NM_002437.5(MPV17):c.196G>T (p.Val66Leu)	MPV17	Uncertain significance	criteria provided, single submitter
990646	NM_002437.5(MPV17):c.74C>A (p.Ser25Tyr)	MPV17	Uncertain significance	no assertion criteria provided
2437048	NM_003201.3(TFAM):c.313G>A (p.Ala105Thr)	TFAM	Uncertain significance	criteria provided, single submitter
749029	NM_002437.5(MPV17):c.249G>A (p.Val83=)	MPV17	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
TFAM	Strong	Autosomal recessive	mitochondrial DNA depletion syndrome 15 (hepatocerebral type)	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MPV17	Orphanet:255229	Navajo neurohepatopathy

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
TFAM	HGNC:11741	ENSG00000108064	Q00059	Transcription factor A, mitochondrial	gencc,clinvar
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)
TFAM	Transcription factor A, mitochondrial	Binds to the mitochondrial light strand promoter and functions in mitochondrial transcription regulation.
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: 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)
TFAM	Other/Unknown	no		HMG_box_dom, HMG_box_dom_sf, HMGB
MPV17	Other/Unknown	no		Mpv17_PMP22

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
left testis	1
right testis	1
secondary oocyte	1
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
TFAM	284	ubiquitous	marker	right testis, left testis, secondary oocyte
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
TFAM	4,690
MPV17	1,251

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TFAM	Q00059	16

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MPV17	P39210	90.23

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Mitochondrial transcription initiation	1	1903.3×	0.004	TFAM
Transcription from mitochondrial promoters	1	1427.5×	0.004	TFAM
Transcriptional activation of mitochondrial biogenesis	1	102.0×	0.020	TFAM
Protein localization	1	95.2×	0.020	MPV17
Peroxisomal protein import	1	86.5×	0.020	MPV17
Mitochondrial biogenesis	1	84.0×	0.020	TFAM
Mitochondrial protein degradation	1	57.1×	0.025	TFAM
Organelle biogenesis and maintenance	1	33.0×	0.038	TFAM
Gene expression (Transcription)	1	8.9×	0.121	TFAM
Metabolism of proteins	1	6.2×	0.155	TFAM

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
regulation of mitochondrial DNA metabolic process	1	4213.0×	0.002	MPV17
transcription initiation at mitochondrial promoter	1	2106.5×	0.002	TFAM
mitochondrial respiratory chain complex assembly	1	1404.3×	0.002	TFAM
mitochondrial transcription	1	1203.7×	0.002	TFAM
glomerular basement membrane development	1	766.0×	0.002	MPV17
inner ear development	1	187.2×	0.007	MPV17
response to nutrient	1	147.8×	0.008	TFAM
response to hypoxia	1	47.9×	0.021	TFAM

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

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
TFAM	0	0
MPV17	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TFAM	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

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	2	TFAM, MPV17

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TFAM	1	—
MPV17	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.