Multiple mitochondrial dysfunctions syndrome 6

Summary

Multiple mitochondrial dysfunctions syndrome 6 (MONDO:0054785) is a disease caused by PMPCB (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PMPCB (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 28

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple mitochondrial dysfunctions syndrome 6
Mondo ID	MONDO:0054785
OMIM	617954
Orphanet	569290
DOID	DOID:0070332
UMLS	C4693741
MedGen	1643082
GARD	0018004
Is cancer (heuristic)	no

Also known as: MMDS6 · multiple mitochondrial dysfunctions syndrome 6 · multiple mitochondrial dysfunctions syndrome type 6 · PMPCB deficiency

Data availability: 28 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 › inherited lipoic acid biosynthesis defect › fatal multiple mitochondrial dysfunctions syndrome › multiple mitochondrial dysfunctions syndrome 6

Related subtypes (8): multiple mitochondrial dysfunctions syndrome 1, multiple mitochondrial dysfunctions syndrome 2, multiple mitochondrial dysfunctions syndrome 3, multiple mitochondrial dysfunctions syndrome 4, multiple mitochondrial dysfunctions syndrome 5, multiple mitochondrial dysfunctions syndrome 7, multiple mitochondrial dysfunctions syndrome 9b, multiple mitochondrial dysfunctions syndrome 10

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

28 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 5 likely pathogenic, 4 conflicting classifications of pathogenicity, 3 pathogenic, 1 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
523140	NM_004279.3(PMPCB):c.524G>A (p.Arg175His)	PMPCB	Pathogenic	criteria provided, single submitter
523141	NM_004279.3(PMPCB):c.530T>G (p.Val177Gly)	PMPCB	Pathogenic	no assertion criteria provided
523142	NM_004279.3(PMPCB):c.1265T>C (p.Ile422Thr)	PMPCB	Pathogenic	no assertion criteria provided
1341818	NM_004279.3(PMPCB):c.32C>A (p.Ser11Ter)	LOC129999056	Likely pathogenic	criteria provided, single submitter
1342344	NM_004279.3(PMPCB):c.606T>A (p.Tyr202Ter)	PMPCB	Likely pathogenic	criteria provided, single submitter
2500914	NM_004279.3(PMPCB):c.543_544del (p.Glu181fs)	PMPCB	Likely pathogenic	criteria provided, single submitter
2585259	NM_004279.3(PMPCB):c.1078dup (p.Thr360fs)	PMPCB	Likely pathogenic	criteria provided, single submitter
523138	NM_004279.3(PMPCB):c.523C>T (p.Arg175Cys)	PMPCB	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1030758	NM_004279.3(PMPCB):c.28T>G (p.Leu10Val)	LOC129999056	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1299086	NM_004279.3(PMPCB):c.1336A>G (p.Asn446Asp)	PMPCB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1342345	NM_004279.3(PMPCB):c.1462C>T (p.Arg488Cys)	PMPCB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
523139	NM_004279.3(PMPCB):c.601G>C (p.Ala201Pro)	PMPCB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031399	NM_004279.3(PMPCB):c.-3G>T	LOC129999056	Uncertain significance	criteria provided, single submitter
2689795	NM_004279.3(PMPCB):c.19C>G (p.Arg7Gly)	LOC129999056	Uncertain significance	criteria provided, single submitter
1030756	NM_004279.3(PMPCB):c.1087T>C (p.Trp363Arg)	PMPCB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030757	NM_004279.3(PMPCB):c.150A>C (p.Gln50His)	PMPCB	Uncertain significance	criteria provided, single submitter
1030759	NM_004279.3(PMPCB):c.470T>G (p.Leu157Arg)	PMPCB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1325591	NM_004279.3(PMPCB):c.661A>G (p.Ile221Val)	PMPCB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1806211	NM_004279.3(PMPCB):c.122G>A (p.Arg41Lys)	PMPCB	Uncertain significance	criteria provided, multiple submitters, no conflicts
2075245	NM_004279.3(PMPCB):c.355C>A (p.Leu119Met)	PMPCB	Uncertain significance	criteria provided, multiple submitters, no conflicts
2227950	NM_004279.3(PMPCB):c.136C>A (p.Gln46Lys)	PMPCB	Uncertain significance	criteria provided, multiple submitters, no conflicts
3341422	NM_004279.3(PMPCB):c.1195C>G (p.Arg399Gly)	PMPCB	Uncertain significance	criteria provided, single submitter
3377567	NM_004279.3(PMPCB):c.986G>A (p.Gly329Glu)	PMPCB	Uncertain significance	criteria provided, single submitter
3391358	NM_004279.3(PMPCB):c.1164_1165del (p.Cys389fs)	PMPCB	Uncertain significance	criteria provided, single submitter
4532049	NM_004279.3(PMPCB):c.1133T>A (p.Leu378Gln)	PMPCB	Uncertain significance	criteria provided, single submitter
4846896	NM_004279.3(PMPCB):c.736+6T>G	PMPCB	Uncertain significance	criteria provided, single submitter
1234421	NM_004279.3(PMPCB):c.737-3T>C	PMPCB	Benign	criteria provided, multiple submitters, no conflicts
1601646	NM_004279.3(PMPCB):c.935G>A (p.Cys312Tyr)	PMPCB	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
PMPCB	Strong	Autosomal recessive	multiple mitochondrial dysfunctions syndrome 6	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PMPCB	Orphanet:569290	Multiple mitochondrial dysfunctions syndrome type 6

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
PMPCB	HGNC:9119	ENSG00000105819	O75439	Mitochondrial-processing peptidase subunit beta	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PMPCB	Mitochondrial-processing peptidase subunit beta	Catalytic subunit of the essential mitochondrial processing protease (MPP), which cleaves the mitochondrial sequence off newly imported precursors proteins.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PMPCB	Protease	yes	3.4.24.64	Pept_M16_Zn_BS, Peptidase_M16_C, Metalloenz_LuxS/M16

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

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PMPCB	297	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PMPCB	4,266

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PMPCB	O75439	87.48

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Processing of SMDT1	1	634.4×	0.005	PMPCB
Mitochondrial calcium ion transport	1	543.8×	0.005	PMPCB
Protein localization	1	190.3×	0.007	PMPCB
Mitochondrial protein import	1	167.9×	0.007	PMPCB
Transport of small molecules	1	25.1×	0.040	PMPCB

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
obsolete protein processing involved in protein targeting to mitochondrion	1	2106.5×	0.001	PMPCB
mitochondrial calcium ion transmembrane transport	1	991.3×	0.002	PMPCB
protein processing	1	170.2×	0.006	PMPCB

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PMPCB	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PMPCB	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PMPCB	3.4.24.64	mitochondrial processing peptidase

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	1	PMPCB
E	Difficult family or no structure, no drug	0

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)
PMPCB	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.