Multiple mitochondrial dysfunctions syndrome 1

Summary

Multiple mitochondrial dysfunctions syndrome 1 (MONDO:0011582) is a disease caused by NFU1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NFU1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 123

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		21	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple mitochondrial dysfunctions syndrome 1
Mondo ID	MONDO:0011582
OMIM	605711
Orphanet	401869
DOID	DOID:0080133
UMLS	C3276432
MedGen	478062
GARD	0017661
Is cancer (heuristic)	no

Also known as: fatal multiple mitochondrial dysfunctions syndrome caused by mutation in NFU1 · Mmds · MMDS1 · multiple mitochondrial dysfunctions syndrome 1 · multiple mitochondrial dysfunctions syndrome type 1 · NFU1 deficiency · NFU1 fatal multiple mitochondrial dysfunctions syndrome

Data availability: 123 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 1

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

123 retrieved; paginated sample, class counts are floors:

47 uncertain significance, 43 likely benign, 9 benign, 8 conflicting classifications of pathogenicity, 6 pathogenic, 5 likely pathogenic, 3 pathogenic/likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3338689	NM_001002755.4(NFU1):c.62G>C (p.Arg21Pro)	LOC129934004	Pathogenic	no assertion criteria provided
1031688	NM_001002755.4(NFU1):c.545G>A (p.Arg182Gln)	NFU1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30700	NM_001002755.4(NFU1):c.622G>T (p.Gly208Cys)	NFU1	Pathogenic	criteria provided, multiple submitters, no conflicts
3338690	NFU1, 55.6-KB DEL, EX4-8DEL	NFU1	Pathogenic	no assertion criteria provided
3356228	NM_001002755.4(NFU1):c.62+89G>A	NFU1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3716398	NM_001002755.4(NFU1):c.264del (p.Thr90fs)	NFU1	Pathogenic	criteria provided, single submitter
3730503	NM_001002755.4(NFU1):c.507del (p.Val170fs)	NFU1	Pathogenic	criteria provided, single submitter
488563	NM_001002755.4(NFU1):c.545+5G>A	NFU1	Pathogenic	criteria provided, multiple submitters, no conflicts
488564	NM_001002755.4(NFU1):c.544C>T (p.Arg182Trp)	NFU1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1285476	NM_001002755.4(NFU1):c.565G>A (p.Gly189Arg)	NFU1	Likely pathogenic	criteria provided, single submitter
1285477	NM_001002755.4(NFU1):c.545G>T (p.Arg182Leu)	NFU1	Likely pathogenic	criteria provided, single submitter
214869	NM_001002755.4(NFU1):c.303-2A>T	NFU1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
647954	NC_000002.11:g.(?69627476)(69627690_?)dup	NFU1	Likely pathogenic	criteria provided, single submitter
804384	NM_001002755.4(NFU1):c.485-1G>C	NFU1	Likely pathogenic	criteria provided, single submitter
1412325	NM_001002755.4(NFU1):c.20G>T (p.Arg7Leu)	LOC129934004	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
336894	NM_001002755.4(NFU1):c.62+10G>A	LOC129934004	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1712751	NM_001002755.4(NFU1):c.302+3A>G	NFU1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
336887	NM_001002755.4(NFU1):c.702G>A (p.Glu234=)	NFU1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
336888	NM_001002755.4(NFU1):c.629G>T (p.Cys210Phe)	NFU1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
336892	NM_001002755.4(NFU1):c.167-13T>G	NFU1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
336893	NM_001002755.4(NFU1):c.166+8T>A	NFU1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
336898	NM_001002755.2(NFU1):c.-119G>A	NFU1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1342045	NM_001002755.4(NFU1):c.17G>A (p.Arg6Lys)	LOC129934004	Uncertain significance	criteria provided, multiple submitters, no conflicts
1521113	NM_001002755.4(NFU1):c.8C>G (p.Ala3Gly)	LOC129934004	Uncertain significance	criteria provided, single submitter
2177062	NM_001002755.4(NFU1):c.4G>A (p.Ala2Thr)	LOC129934004	Uncertain significance	criteria provided, single submitter
336895	NM_001002755.4(NFU1):c.-1G>A	LOC129934004	Uncertain significance	criteria provided, single submitter
3707049	NM_001002755.4(NFU1):c.40G>C (p.Val14Leu)	LOC129934004	Uncertain significance	criteria provided, single submitter
898174	NM_001002755.4(NFU1):c.12G>A (p.Thr4=)	LOC129934004	Uncertain significance	criteria provided, single submitter
899272	NM_001002755.4(NFU1):c.-7G>A	LOC129934004	Uncertain significance	criteria provided, single submitter
1027130	NM_001002755.4(NFU1):c.698C>T (p.Pro233Leu)	NFU1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
NFU1	Definitive	Autosomal recessive	multiple mitochondrial dysfunctions syndrome 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NFU1	Orphanet:401869	Multiple mitochondrial dysfunctions syndrome type 1

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
NFU1	HGNC:16287	ENSG00000169599	Q9UMS0	NFU1 iron-sulfur cluster scaffold homolog, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NFU1	NFU1 iron-sulfur cluster scaffold homolog, mitochondrial	Iron-sulfur cluster scaffold protein which can assemble [4Fe-4S] clusters and deliver them to target proteins.

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)
NFU1	Other/Unknown	no		NIF_FeS_clus_asmbl_NifU_C, Nfu/NifU_N, FSCA_dom_sf

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
biceps brachii	1
heart right ventricle	1
skeletal muscle tissue of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NFU1	291	ubiquitous	marker	heart right ventricle, biceps brachii, skeletal muscle tissue of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NFU1	1,832

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NFU1	Q9UMS0	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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 lipoylation	1	1038.2×	1e-03	NFU1

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
iron-sulfur cluster assembly	1	601.9×	0.003	NFU1
protein maturation	1	163.6×	0.006	NFU1

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
NFU1	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	NFU1

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)
NFU1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.