Multiple mitochondrial dysfunctions syndrome 3

Summary

Multiple mitochondrial dysfunctions syndrome 3 (MONDO:0014132) is a disease caused by IBA57 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: IBA57 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 228

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple mitochondrial dysfunctions syndrome 3
Mondo ID	MONDO:0014132
OMIM	615330
Orphanet	363424
DOID	DOID:0080135
UMLS	C3809165
MedGen	815495
GARD	0017555
Is cancer (heuristic)	no

Also known as: fatal multiple mitochondrial dysfunctions syndrome caused by mutation in IBA57 · IBA57 deficiency · IBA57 fatal multiple mitochondrial dysfunctions syndrome · MMDS3 · multiple mitochondrial dysfunctions syndrome 3 · multiple mitochondrial dysfunctions syndrome type 3

Data availability: 228 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

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 3

Related subtypes (8): multiple mitochondrial dysfunctions syndrome 1, multiple mitochondrial dysfunctions syndrome 2, 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

228 retrieved; paginated sample, class counts are floors:

87 uncertain significance, 86 likely benign, 23 pathogenic, 9 likely pathogenic, 8 conflicting classifications of pathogenicity, 5 pathogenic/likely pathogenic, 5 benign, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3247647	NC_000001.10:g.(?228194830)(228566496_?)del	ARF1	Pathogenic	criteria provided, single submitter
1064623	NM_001010867.4(IBA57):c.262dup (p.Ala88fs)	IBA57	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073739	NM_001010867.4(IBA57):c.265_286dup (p.Tyr96fs)	IBA57	Pathogenic	criteria provided, single submitter
1202371	NM_001010867.4(IBA57):c.307C>T (p.Gln103Ter)	IBA57	Pathogenic	criteria provided, multiple submitters, no conflicts
1323088	NM_001010867.4(IBA57):c.346C>T (p.Gln116Ter)	IBA57	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1396845	NM_001010867.4(IBA57):c.335T>A (p.Leu112Ter)	IBA57	Pathogenic	criteria provided, single submitter
1409036	NM_001010867.4(IBA57):c.316del (p.Thr106fs)	IBA57	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1806117	NM_001010867.4(IBA57):c.292del (p.His98fs)	IBA57	Pathogenic	criteria provided, single submitter
1968141	NM_001010867.4(IBA57):c.193_203dup (p.Phe69fs)	IBA57	Pathogenic	criteria provided, single submitter
1997279	NM_001010867.4(IBA57):c.74_75del (p.Ala25fs)	IBA57	Pathogenic	criteria provided, single submitter
203449	NM_001010867.4(IBA57):c.678A>G (p.Gln226=)	IBA57	Pathogenic	criteria provided, multiple submitters, no conflicts
2062660	NM_001010867.4(IBA57):c.454G>T (p.Glu152Ter)	IBA57	Pathogenic	criteria provided, single submitter
2187516	NM_001010867.4(IBA57):c.143G>A (p.Trp48Ter)	IBA57	Pathogenic	criteria provided, single submitter
2674639	NM_001010867.4(IBA57):c.569_579del (p.Arg190fs)	IBA57	Pathogenic	criteria provided, single submitter
2933389	NM_001010867.4(IBA57):c.284_285insT (p.Tyr96fs)	IBA57	Pathogenic	criteria provided, single submitter
3761618	NM_001010867.4(IBA57):c.339C>G (p.Tyr113Ter)	IBA57	Pathogenic	criteria provided, single submitter
545645	NM_001010867.4(IBA57):c.436C>T (p.Arg146Trp)	IBA57	Pathogenic/Likely pathogenic	no assertion criteria provided
545646	NM_001010867.4(IBA57):c.586T>G (p.Trp196Gly)	IBA57	Pathogenic	no assertion criteria provided
545647	NM_001010867.4(IBA57):c.686C>T (p.Pro229Leu)	IBA57	Pathogenic	no assertion criteria provided
545648	NM_001010867.4(IBA57):c.706C>T (p.Pro236Ser)	IBA57	Pathogenic	no assertion criteria provided
545649	NM_001010867.4(IBA57):c.286T>C (p.Tyr96His)	IBA57	Pathogenic	criteria provided, multiple submitters, no conflicts
545650	NM_001010867.4(IBA57):c.316A>G (p.Thr106Ala)	IBA57	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
545651	NM_001010867.4(IBA57):c.697C>T (p.Arg233Ter)	IBA57	Pathogenic	criteria provided, single submitter
545653	NM_001010867.4(IBA57):c.940C>T (p.Gln314Ter)	IBA57	Pathogenic	no assertion criteria provided
545654	NM_001010867.4(IBA57):c.150C>A (p.Cys50Ter)	IBA57	Pathogenic	no assertion criteria provided
56829	NM_001010867.4(IBA57):c.941A>C (p.Gln314Pro)	IBA57	Pathogenic	no assertion criteria provided
660906	NM_001010867.4(IBA57):c.384dup (p.Asp129Ter)	IBA57	Pathogenic	criteria provided, single submitter
972915	NM_001010867.4(IBA57):c.589_590del (p.Arg197fs)	IBA57	Pathogenic	criteria provided, single submitter
433547	NM_001010867.3(IBA57):c.[167G>A];[826C>T]		Likely pathogenic	no assertion criteria provided
1067695	NM_001010867.4(IBA57):c.341+1G>T	IBA57	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · 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
IBA57	Strong	Autosomal recessive	multiple mitochondrial dysfunctions syndrome 3	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IBA57	Orphanet:363424	Multiple mitochondrial dysfunctions syndrome type 3
IBA57	Orphanet:468661	Autosomal recessive spastic paraplegia type 74
ARF1	Orphanet:98892	Periventricular nodular heterotopia

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
IBA57	HGNC:27302	ENSG00000181873	Q5T440	Iron-sulfur cluster assembly factor IBA57, mitochondrial	gencc,clinvar
ARF1	HGNC:652	ENSG00000143761	P84077	ADP-ribosylation factor 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IBA57	Iron-sulfur cluster assembly factor IBA57, mitochondrial	Mitochondrial protein involved in the maturation of mitochondrial [4Fe-4S]-proteins in the late stage of the iron-sulfur cluster assembly pathway.
ARF1	ADP-ribosylation factor 1	Small GTPase involved in protein trafficking between different compartments.

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)
IBA57	Other/Unknown	no		YgfZ/CAF17_C, TrmE/GcvT-like, YgfZ/GcvT
ARF1	Other/Unknown	no		Small_GTP-bd, Small_GTPase_ARF/SAR, Small_GTPase_ARF

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
pancreatic ductal cell	1
superficial temporal artery	1
adult organism	1
ileal mucosa	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IBA57	232	ubiquitous	yes	pancreatic ductal cell, superficial temporal artery, gastrocnemius
ARF1	295	ubiquitous	marker	adult organism, ileal mucosa, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IBA57	1,214
ARF1	485

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ARF1	P84077	40
IBA57	Q5T440	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 39. 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
Glycosphingolipid transport	1	1427.5×	0.012	ARF1
Nef Mediated CD4 Down-regulation	1	1268.9×	0.012	ARF1
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	1	634.4×	0.012	ARF1
The role of Nef in HIV-1 replication and disease pathogenesis	1	634.4×	0.012	ARF1
Synthesis of PIPs at the Golgi membrane	1	634.4×	0.012	ARF1
Interleukin-12 family signaling	1	475.8×	0.012	ARF1
Interleukin-12 signaling	1	407.9×	0.012	ARF1
PI Metabolism	1	356.9×	0.012	ARF1
Host Interactions of HIV factors	1	335.9×	0.012	ARF1
Lysosome Vesicle Biogenesis	1	326.3×	0.012	ARF1
Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation	1	300.5×	0.012	ARF1
Intra-Golgi traffic	1	259.6×	0.012	ARF1
trans-Golgi Network Vesicle Budding	1	253.8×	0.012	ARF1
Synthesis of PIPs at the plasma membrane	1	211.5×	0.012	ARF1
Phospholipid metabolism	1	200.3×	0.012	ARF1
Golgi Associated Vesicle Biogenesis	1	200.3×	0.012	ARF1
ER to Golgi Anterograde Transport	1	132.8×	0.016	ARF1
Golgi-to-ER retrograde transport	1	132.8×	0.016	ARF1
HIV Infection	1	119.0×	0.016	ARF1
COPI-dependent Golgi-to-ER retrograde traffic	1	110.9×	0.016	ARF1
COPI-mediated anterograde transport	1	109.8×	0.016	ARF1
Intra-Golgi and retrograde Golgi-to-ER traffic	1	104.8×	0.016	ARF1
Transport to the Golgi and subsequent modification	1	102.9×	0.016	ARF1
MHC class II antigen presentation	1	89.2×	0.018	ARF1
Signaling by Interleukins	1	64.2×	0.024	ARF1
Asparagine N-linked glycosylation	1	60.1×	0.025	ARF1
Cytokine Signaling in Immune system	1	40.8×	0.035	ARF1
Membrane Trafficking	1	37.1×	0.038	ARF1
Vesicle-mediated transport	1	34.8×	0.039	ARF1
Metabolism of lipids	1	31.6×	0.041	ARF1

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
mitotic cleavage furrow ingression	1	8426.0×	0.001	ARF1
dendritic spine organization	1	2106.5×	0.003	ARF1
regulation of receptor internalization	1	1203.7×	0.003	ARF1
regulation of Arp2/3 complex-mediated actin nucleation	1	526.6×	0.004	ARF1
intracellular copper ion homeostasis	1	468.1×	0.004	ARF1
long-term synaptic depression	1	443.5×	0.004	ARF1
heme biosynthetic process	1	300.9×	0.005	IBA57
iron-sulfur cluster assembly	1	300.9×	0.005	IBA57
cellular response to virus	1	100.3×	0.012	ARF1
vesicle-mediated transport	1	48.1×	0.023	ARF1
intracellular protein transport	1	32.4×	0.031	ARF1

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
IBA57	0	0
ARF1	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
ARF1	4	Binding:4

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	IBA57, ARF1

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)
IBA57	0	—
ARF1	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.