Multiple mitochondrial dysfunctions syndrome 2

Summary

Multiple mitochondrial dysfunctions syndrome 2 (MONDO:0013675) is a disease caused by BOLA3 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: BOLA3 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 30

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple mitochondrial dysfunctions syndrome 2
Mondo ID	MONDO:0013675
OMIM	614299
Orphanet	401874
DOID	DOID:0080134
UMLS	C3280378
MedGen	482008
GARD	0017662
Is cancer (heuristic)	no

Also known as: BOLA3 deficiency · BOLA3 fatal multiple mitochondrial dysfunctions syndrome · fatal multiple mitochondrial dysfunctions syndrome caused by mutation in BOLA3 · MMDS2 · multiple mitochondrial dysfunctions syndrome 2 · multiple mitochondrial dysfunctions syndrome type 2

Data availability: 30 ClinVar variants · 5 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 2

Related subtypes (8): multiple mitochondrial dysfunctions syndrome 1, multiple mitochondrial dysfunctions syndrome 3, multiple mitochondrial dysfunctions syndrome 4, multiple mitochondrial dysfunctions syndrome 5, multiple mitochondrial dysfunctions syndrome 6, 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

30 retrieved; paginated sample, class counts are floors:

18 uncertain significance, 4 conflicting classifications of pathogenicity, 3 likely pathogenic, 2 pathogenic/likely pathogenic, 2 pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1189446	NM_212552.3(BOLA3):c.176G>A (p.Cys59Tyr)	BOLA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224514	NM_212552.3(BOLA3):c.136C>T (p.Arg46Ter)	BOLA3	Pathogenic	criteria provided, multiple submitters, no conflicts
31020	NM_212552.3(BOLA3):c.123dup (p.Glu42fs)	BOLA3	Pathogenic	no assertion criteria provided
816938	NM_212552.3(BOLA3):c.220_222del (p.Glu74del)	BOLA3	Pathogenic/Likely pathogenic	no assertion criteria provided
2577215	NM_212552.3(BOLA3):c.259-1G>C	BOLA3	Likely pathogenic	criteria provided, single submitter
4072006	NM_212552.3(BOLA3):c.251T>C (p.Val84Ala)	BOLA3	Likely pathogenic	criteria provided, single submitter
816698	NM_212552.3(BOLA3):c.200T>A (p.Ile67Asn)	BOLA3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
214170	NM_212552.3(BOLA3):c.319C>T (p.Arg107Cys)	BOLA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337058	NM_212552.3(BOLA3):c.137G>A (p.Arg46Gln)	BOLA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
390067	NM_212552.3(BOLA3):c.258+9A>C	BOLA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895392	NM_212552.3(BOLA3):c.19G>A (p.Ala7Thr)	BOLA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029540	NM_212552.3(BOLA3):c.131T>G (p.Phe44Cys)	BOLA3	Uncertain significance	criteria provided, single submitter
1029541	NM_212552.3(BOLA3):c.317A>G (p.Lys106Arg)	BOLA3	Uncertain significance	criteria provided, single submitter
1029542	NM_212552.3(BOLA3):c.76T>C (p.Phe26Leu)	BOLA3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1163413	NM_212552.3(BOLA3):c.296G>A (p.Arg99Gln)	BOLA3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1679842	NM_212552.3(BOLA3):c.253A>G (p.Asn85Asp)	BOLA3	Uncertain significance	criteria provided, single submitter
1878638	NM_212552.3(BOLA3):c.170G>A (p.Gly57Glu)	BOLA3	Uncertain significance	criteria provided, single submitter
2439540	NM_212552.3(BOLA3):c.308_309del (p.Ser103fs)	BOLA3	Uncertain significance	criteria provided, single submitter
2439541	NM_212552.3(BOLA3):c.82A>C (p.Thr28Pro)	BOLA3	Uncertain significance	criteria provided, single submitter
2585013	NM_212552.3(BOLA3):c.295C>T (p.Arg99Trp)	BOLA3	Uncertain significance	criteria provided, single submitter
337054	NM_212552.3(BOLA3):c.*190G>A	BOLA3	Uncertain significance	criteria provided, single submitter
337055	NM_212552.3(BOLA3):c.*31T>C	BOLA3	Uncertain significance	criteria provided, single submitter
337056	NM_212552.3(BOLA3):c.256C>G (p.Gln86Glu)	BOLA3	Uncertain significance	criteria provided, multiple submitters, no conflicts
337057	NM_212552.3(BOLA3):c.181G>A (p.Ala61Thr)	BOLA3	Uncertain significance	criteria provided, single submitter
337059	NM_212552.3(BOLA3):c.-8G>A	BOLA3	Uncertain significance	criteria provided, single submitter
337060	NM_212552.3(BOLA3):c.-35C>T	BOLA3	Uncertain significance	criteria provided, single submitter
3898034	NM_212552.3(BOLA3):c.258G>C (p.Gln86His)	BOLA3	Uncertain significance	criteria provided, single submitter
895391	NM_212552.3(BOLA3):c.21C>T (p.Ala7=)	BOLA3	Uncertain significance	criteria provided, single submitter
898379	NM_212552.3(BOLA3):c.*134T>C	TET3	Uncertain significance	criteria provided, single submitter
214169	NM_212552.3(BOLA3):c.45G>T (p.Gly15=)	BOLA3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
BOLA3	Strong	Autosomal recessive	multiple mitochondrial dysfunctions syndrome 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BOLA3	Orphanet:401874	Multiple mitochondrial dysfunctions syndrome type 2
TET3	Orphanet:684216	Intellectual disability-facial dysmorphism-joint hypermobility-hearing loss syndrome

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
BOLA3	HGNC:24415	ENSG00000163170	Q53S33	BolA-like protein 3	gencc,clinvar
TET3	HGNC:28313	ENSG00000187605	O43151	Methylcytosine dioxygenase TET3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BOLA3	BolA-like protein 3	Acts as a mitochondrial iron-sulfur (Fe-S) cluster assembly factor that facilitates (Fe-S) cluster insertion into a subset of mitochondrial proteins.
TET3	Methylcytosine dioxygenase TET3	Dioxygenase that catalyzes the conversion of the modified genomic base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and plays a key role in epigenetic chromatin reprogramming in the zygote following fertilization.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BOLA3	Other/Unknown	no		BolA, BolA-like_sf, Mt_Fe-S_assembly_factor
TET3	Transcription factor	no		Znf_CXXC, 2OGFeDO_JBP1/TET_oxygenase_dom, TET1/2/3

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 muscle of right atrium	1
left ventricle myocardium	1
myocardium	1
oocyte	1
secondary oocyte	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BOLA3	256	ubiquitous	marker	left ventricle myocardium, cardiac muscle of right atrium, myocardium
TET3	259	ubiquitous	marker	oocyte, secondary oocyte, type B pancreatic cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TET3	1,430
BOLA3	1,291

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TET3	O43151	2
BOLA3	Q53S33	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 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
TET1,2,3 and TDG demethylate DNA	1	2855.0×	0.002	TET3
Maternal to zygotic transition (MZT)	1	713.8×	0.004	TET3
Chromatin modifications during the maternal to zygotic transition (MZT)	1	163.1×	0.012	TET3
Epigenetic regulation of gene expression	1	71.4×	0.021	TET3
Gene expression (Transcription)	1	17.8×	0.067	TET3
Developmental Biology	1	14.5×	0.069	TET3

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
response to lipoic acid	1	4213.0×	0.003	BOLA3
epigenetic programing of male pronucleus	1	2106.5×	0.003	TET3
protein lipoylation	1	1203.7×	0.004	BOLA3
positive regulation of gene expression via chromosomal CpG island demethylation	1	601.9×	0.005	TET3
adaptive thermogenesis	1	526.6×	0.005	BOLA3
iron-sulfur cluster assembly	1	300.9×	0.007	BOLA3
cell redox homeostasis	1	172.0×	0.010	BOLA3
energy homeostasis	1	135.9×	0.010	BOLA3
glucose metabolic process	1	127.7×	0.010	BOLA3
intracellular iron ion homeostasis	1	122.1×	0.010	BOLA3
protein O-linked glycosylation	1	112.3×	0.010	TET3
protein maturation	1	81.8×	0.013	BOLA3
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	TET3

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · 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).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
TET3	VADADUSTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TET3	2	4
BOLA3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VADADUSTAT	4	TET3
PANOBINOSTAT	4	TET3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TET3	8	Binding:8

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

2 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)
VADADUSTAT	4	TET3
PANOBINOSTAT	4	TET3

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TET3
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	BOLA3

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)
BOLA3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.