NDUFS4

Summary

NDUFS4 (NADH:ubiquinone oxidoreductase subunit S4, HGNC:7711) is a protein-coding gene on chromosome 5q11.2, encoding NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial (O43181). Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis.

This gene encodes an nuclear-encoded accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I, or NADH:ubiquinone oxidoreductase). Complex I removes electrons from NADH and passes them to the electron acceptor ubiquinone. Mutations in this gene can cause mitochondrial complex I deficiencies such as Leigh syndrome. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 4724 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Leigh syndrome (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 17
• Clinical variants (ClinVar): 209 total — 18 pathogenic, 21 likely-pathogenic
• Phenotypes (HPO): 79
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_002495

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7711
Approved symbol	NDUFS4
Name	NADH:ubiquinone oxidoreductase subunit S4
Location	5q11.2
Locus type	gene with protein product
Status	Approved
Aliases	AQDQ, CI-18
Ensembl gene	ENSG00000164258
Ensembl biotype	protein_coding
OMIM	602694
Entrez	4724

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 3 nonsense_mediated_decay, 1 retained_intron

ENST00000296684, ENST00000502423, ENST00000506765, ENST00000506974, ENST00000507026, ENST00000509443, ENST00000856911, ENST00000932904

RefSeq mRNA: 2 — MANE Select: NM_002495 NM_001318051, NM_002495

CCDS: CCDS3960

Canonical transcript exons

ENST00000296684 — 5 exons

Exon	Start	End
ENSE00003494905	53603452	53603530
ENSE00003496539	53683118	53683338
ENSE00003529584	53658551	53658624
ENSE00003651013	53646233	53646405
ENSE00003846937	53560639	53560760

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 98.97.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 95.7867 / max 1955.1988, expressed in 1823 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
56431	95.7867	1823

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	98.97	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.52	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.47	gold quality
muscle of leg	UBERON:0001383	98.40	gold quality
gastrocnemius	UBERON:0001388	98.31	gold quality
muscle organ	UBERON:0001630	98.21	gold quality
diaphragm	UBERON:0001103	98.20	gold quality
body of tongue	UBERON:0011876	98.16	gold quality
biceps brachii	UBERON:0001507	97.96	gold quality
heart left ventricle	UBERON:0002084	97.94	gold quality
cardiac ventricle	UBERON:0002082	97.90	gold quality
apex of heart	UBERON:0002098	97.88	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.83	gold quality
skeletal muscle tissue	UBERON:0001134	97.80	gold quality
ganglionic eminence	UBERON:0004023	97.76	gold quality
right atrium auricular region	UBERON:0006631	97.72	gold quality
rectum	UBERON:0001052	97.66	gold quality
heart	UBERON:0000948	97.64	gold quality
quadriceps femoris	UBERON:0001377	97.63	gold quality
popliteal artery	UBERON:0002250	97.60	gold quality
tibial artery	UBERON:0007610	97.60	gold quality
left ovary	UBERON:0002119	97.55	gold quality
adrenal tissue	UBERON:0018303	97.55	gold quality
vastus lateralis	UBERON:0001379	97.51	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.46	gold quality
heart right ventricle	UBERON:0002080	97.42	gold quality
cardiac atrium	UBERON:0002081	97.42	gold quality
islet of Langerhans	UBERON:0000006	97.41	gold quality
muscle tissue	UBERON:0002385	97.38	gold quality
ventricular zone	UBERON:0003053	97.38	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ENAD-17	no	1192.75
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

18 targeting NDUFS4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-4802-3P	99.72	70.13	1273
HSA-MIR-548M	99.70	68.87	1749
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-3171	99.49	69.06	776
HSA-MIR-20B-3P	99.29	67.05	784
HSA-MIR-12135	98.99	70.26	1814
HSA-MIR-942-3P	98.81	69.04	876
HSA-MIR-4266	98.53	67.29	1035
HSA-MIR-3137	97.26	66.78	761
HSA-MIR-4703-3P	96.68	68.61	545
HSA-MIR-6888-5P	95.89	63.78	831
HSA-MIR-6503-3P	93.87	66.39	348

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 22)

• REVIEW: Phosphorylation of the NDUFS4 protein, overall respiratory activity, and mutations sassociated with deficiency of complex I. (PMID:11860175)
• In patients with complex I deficiency, the increased whole-body oxygen consumption rate at rest reflects increased electron transport through the respiratory chain, driven by a decreased phosphorylation potential. (PMID:11940698)
• observations show the essential role of the 18-kDa subunit of respiratory complex I (NDUFS4) gene in the structure and function of complex I and give insight into pathogenic mechanism of NDUFS4 gene mutations in a severe defect of complex I (PMID:12944388)
• A nonsense mutation leading to the abrogation of mRNA decay was found in NDUFS4 gene of a Leigh syndrome patient. (PMID:15975579)
• mutations in the NDUFS1 and NDUFS4 genes of complex I cause dysfunction in cellular oxidative metabolism (PMID:16478720)
• NDUSF4 is required for the assembly and stabilization of a portion of complex I that contains a number of subunits. (PMID:17438127)
• impact of PKA mediated phosphorylation on the mitochondrial import of in vitro and in vivo synthesized NDUFS4 protein (PMID:18291624)
• regulation of alternative transcripts of the NDUFS4 gene of complex I of the respiratory chain (PMID:18555024)
• case Report: A novel mutation in NDUFS4 causes Leigh syndrome in an Ashkenazi Jewish family. (PMID:19107570)
• NDUFS4 presents a hotspot of mutations in the genetic apparatus of oxidative phosphorylation and the correct assembly of the subunit it encodes is essential for completion of the assembly of complex I. (PMID:19364667)
• Studies indicate that that the functional capacity of complex I depends on phosphorylation and import of subunit NDUFS4 protein. (PMID:21945319)
• In fibroblast cultures, protein kinase A-mediated phosphorylation of the NDUFS4 subunit of complex I rescues the activity of the oxidatively damaged complex. (PMID:22198267)
• Elevated expression of CO I and ND4 were associated with gastric tumorigenesis and tumor dedifferentiation (PMID:22407105)
• Mutations in the NDUFS4 gene and its subunits are associated with the mitochondrial complex I deficiency. (Review) (PMID:23378164)
• The c.462delA deletion led to a complete lack of NDUFS4 peptide in isolated mitochondria, and this deficiency caused an inefficient mitochondrial complex I assembly and Leigh syndrome symptoms. (PMID:24020637)
• The authors concluded that NDUFS4-related Leigh syndrome is invariably linked to an early onset severe phenotype that results in early death. (PMID:27079373)
• The clinical presentations of five individuals of Hutterite descent with Leigh disease are described herein. An identity-by-descent mapping and candidate gene approach was used to identify a novel homozygous c.393dupA frameshift mutation in the NADH dehydrogenase (ubiquinone) Fe-S protein 4 (NDUFS4) gene. (PMID:27671926)
• BAP31 interacts with mitochondria-localized proteins, including Tom40, to stimulate the translocation of NDUFS4, the component of complex I from the cytosol to the mitochondria. (PMID:31206022)
• NDUFS4 deletion triggers loss of NDUFA12 in Ndufs4(-/-) mice and Leigh syndrome patients: A stabilizing role for NDUFAF2. (PMID:32335026)
• Uniparental isodisomy as a cause of mitochondrial complex I respiratory chain disorder due to a novel splicing NDUFS4 mutation. (PMID:33093004)
• Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention. (PMID:34849584)
• Direct neuronal reprogramming of NDUFS4 patient cells identifies the unfolded protein response as a novel general reprogramming hurdle. (PMID:38266647)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndufs4	ENSDARG00000052840
mus_musculus	Ndufs4	ENSMUSG00000021764
rattus_norvegicus	Ndufs4	ENSRNOG00000011383
drosophila_melanogaster	ND-18	FBGN0031021
caenorhabditis_elegans	lpd-5	WBGENE00003061

Paralogs (1): WDR93 (ENSG00000140527)

Protein

Protein identifiers

NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial — O43181 (reviewed: O43181)

Alternative names: Complex I-18 kDa, Complex I-AQDQ, NADH-ubiquinone oxidoreductase 18 kDa subunit

All UniProt accessions (6): A0A0S2Z433, D6R916, D6REP1, D6RI09, H0Y9M8, O43181

UniProt curated annotations — full annotation on UniProt →

Function. Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone.

Subunit / interactions. Mammalian complex I is composed of 45 different subunits. This is a component of the iron-sulfur (IP) fragment of the enzyme. Interacts with BCAP31 and TOMM40; the interaction mediates its translocation to the mitochondria; the interaction with BCAP31 is direct.

Subcellular location. Mitochondrion inner membrane.

Disease relevance. Mitochondrial complex I deficiency, nuclear type 1 (MC1DN1) [MIM:252010] A form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the complex I NDUFS4 subunit family.

RefSeq proteins (2): NP_001304980, NP_002486* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006885	NADH_UbQ_FeS_4_mit-like	Family
IPR038532	NDUFS4-like_sf	Homologous_superfamily

Pfam: PF04800

UniProt features (25 total): strand 6, sequence variant 5, turn 4, helix 4, transit peptide 1, chain 1, sequence conflict 1, region of interest 1, modified residue 1, mutagenesis site 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
9I4I	ELECTRON MICROSCOPY	2.63
9TI4	ELECTRON MICROSCOPY	2.66
5XTB	ELECTRON MICROSCOPY	3.4
9CWT	ELECTRON MICROSCOPY	3.44
5XTD	ELECTRON MICROSCOPY	3.7
5XTH	ELECTRON MICROSCOPY	3.9
5XTI	ELECTRON MICROSCOPY	17.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43181-F1	84.47	0.70

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 173

Mutagenesis-validated functional residues (1):

Position	Phenotype
173	loss of phosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-611105	Respiratory electron transport
R-HSA-6799198	Complex I biogenesis
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism

MSigDB gene sets: 416 (showing top): MODULE_93, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_PHOSPHORYLATION, MODULE_151, MODULE_77, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, MORF_HDAC1, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, AAAYRNCTG_UNKNOWN, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, EFC_Q6, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_MONOATOMIC_CATION_TRANSPORT

GO Biological Process (10): regulation of protein phosphorylation (GO:0001932), mitochondrial electron transport, NADH to ubiquinone (GO:0006120), brain development (GO:0007420), aerobic respiration (GO:0009060), mitochondrial respiratory chain complex I assembly (GO:0032981), proton motive force-driven mitochondrial ATP synthesis (GO:0042776), response to cAMP (GO:0051591), reactive oxygen species metabolic process (GO:0072593), electron transport chain (GO:0022900), proton transmembrane transport (GO:1902600)

GO Molecular Function (2): NADH dehydrogenase (ubiquinone) activity (GO:0008137), protein binding (GO:0005515)

GO Cellular Component (6): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), perinuclear theca (GO:0033011), respiratory chain complex I (GO:0045271), sperm glycocalyx (GO:0120238), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Aerobic respiration and respiratory electron transport	1
Respiratory electron transport	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein phosphorylation	1
regulation of protein modification process	1
regulation of phosphorylation	1
aerobic electron transport chain	1
mitochondrial ATP synthesis coupled electron transport	1
central nervous system development	1
animal organ development	1
head development	1
cellular respiration	1
NADH dehydrogenase complex assembly	1
mitochondrial respiratory chain complex assembly	1
mitochondrion	1
oxidative phosphorylation	1
proton motive force-driven ATP synthesis	1
response to purine-containing compound	1
response to organophosphorus	1
response to oxygen-containing compound	1
metabolic process	1
generation of precursor metabolites and energy	1
monoatomic cation transmembrane transport	1
NADH dehydrogenase activity	1
electron transfer activity	1
proton transmembrane transporter activity	1
oxidoreduction-driven active transmembrane transporter activity	1
oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor	1
active monoatomic ion transmembrane transporter activity	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
cytoskeleton	1
perinuclear region of cytoplasm	1
NADH dehydrogenase complex	1
respiratory chain complex	1
transmembrane transporter complex	1
glycocalyx	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2542 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NDUFS4	NDUFS6	O75380	987
NDUFS4	NDUFS1	P28331	984
NDUFS4	NDUFV1	P49821	978
NDUFS4	NDUFV2	P19404	975
NDUFS4	NDUFS2	O75306	956
NDUFS4	NDUFS7	O75251	933
NDUFS4	NDUFS8	O00217	924
NDUFS4	NDUFS3	O75489	914
NDUFS4	NDUFA2	O43678	901
NDUFS4	NDUFA1	O15239	875
NDUFS4	NDUFV3	P56181	864
NDUFS4	NDUFAF2	Q8N183	863
NDUFS4	NDUFA12	Q9UI09	863
NDUFS4	NDUFS5	O43920	845
NDUFS4	NDUFAF5	Q5TEU4	814

IntAct

127 interactions, top by confidence:

A	B	Type	Score
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFA13	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFA9	NDUFS4	psi-mi:“MI:0914”(association)	0.640
ASPH	STXBP3	psi-mi:“MI:0914”(association)	0.640
ENPP6	SCAMP1	psi-mi:“MI:0914”(association)	0.640
NDUFS5	NDUFS8	psi-mi:“MI:0914”(association)	0.530
NDUFA9	NDUFS8	psi-mi:“MI:0914”(association)	0.530
GDPD5	GOLIM4	psi-mi:“MI:0914”(association)	0.530
NDUFA8	NDUFS8	psi-mi:“MI:0914”(association)	0.530
FUT1	GOLIM4	psi-mi:“MI:0914”(association)	0.530
GALNT6	NDUFS4	psi-mi:“MI:0914”(association)	0.530
YIPF3	TMEM120B	psi-mi:“MI:0914”(association)	0.530
SYP	APBB1	psi-mi:“MI:0914”(association)	0.530

BioGRID (278): NDUFS4 (Affinity Capture-MS), NDUFS4 (Affinity Capture-MS), NDUFS4 (Affinity Capture-MS), NDUFS4 (Affinity Capture-MS), ATP5C1 (Co-fractionation), NDUFS4 (Co-fractionation), NDUFS4 (Co-fractionation), NDUFS4 (Co-fractionation), NDUFS4 (Co-fractionation), NDUFS4 (Co-fractionation), NDUFS4 (Co-fractionation), NDUFS4 (Co-fractionation), NDUFS4 (Co-fractionation), NDUFS4 (Co-fractionation), NDUFS4 (Co-fractionation)

ESM2 similar proteins: A0JN61, A4FUH0, A5GFS8, B9N1F9, B9SQI7, E0CSI1, E1C6Q1, F1QH17, O22969, O35427, O43181, O76031, O88984, O95292, O95453, P11497, P50886, P52865, P69341, Q0II25, Q0J035, Q0MQH0, Q13085, Q13901, Q1RMS5, Q24K03, Q28559, Q28IL6, Q32PE4, Q3ZBL5, Q5R752, Q5RBU4, Q5RC51, Q5SWU9, Q5ZHS3, Q5ZID6, Q6P4W8, Q6PBL0, Q8L5Y9, Q99J36

Diamond homologs: A0A1D8PCD3, O43181, P0CB95, P0CB96, P25711, Q02375, Q0MQH0, Q0MQH1, Q5XIF3, Q66XS7, Q9CXZ1, Q8T1V6, Q9FJW4, Q9VWI0, P80268

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
NDUFS4	“form complex”	“NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I”	binding
TFEB	“up-regulates quantity by expression”	NDUFS4	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 107 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Complex I biogenesis	22	49.9×	2e-30
Respiratory electron transport	23	30.0×	2e-26
Aerobic respiration and respiratory electron transport	21	25.5×	1e-22
Mitochondrial protein degradation	7	10.9×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	18	69.4×	3e-27
proton motive force-driven mitochondrial ATP synthesis	21	59.5×	7e-30
aerobic respiration	21	56.0×	2e-29
mitochondrial respiratory chain complex I assembly	8	35.4×	8e-09

Disease & clinical

Clinical variants and AI predictions

ClinVar

209 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	21
Uncertain significance	53
Likely benign	70
Benign	25

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
2109527	NM_002495.4(NDUFS4):c.208G>T (p.Glu70Ter)	Pathogenic
2203649	NM_002495.4(NDUFS4):c.393dup (p.Glu132fs)	Pathogenic
2424473	NC_000005.9:g.(?52856493)(52856610_?)del	Pathogenic
2500769	NM_002495.4(NDUFS4):c.350+1G>T	Pathogenic
2711416	NM_002495.4(NDUFS4):c.360del (p.Leu121fs)	Pathogenic
2758562	NM_002495.4(NDUFS4):c.179dup (p.Asp60fs)	Pathogenic
2836340	NM_002495.4(NDUFS4):c.261_262delinsTT (p.Met87_Gln88delinsIleTer)	Pathogenic
2847065	NM_002495.4(NDUFS4):c.320G>A (p.Trp107Ter)	Pathogenic
2851671	NM_002495.4(NDUFS4):c.298G>T (p.Glu100Ter)	Pathogenic
3246502	NC_000005.9:g.(?52954361)(52954474_?)del	Pathogenic
40257	NM_002495.4(NDUFS4):c.462del (p.Lys154fs)	Pathogenic
4279223	GRCh37/hg19 5q11.2(chr5:52962908-52995777)x1	Pathogenic
488559	NM_002495.4(NDUFS4):c.178-2A>G	Pathogenic
488560	NM_002495.4(NDUFS4):c.470_471del (p.Lys156_Ser157insTer)	Pathogenic
496165	NM_002495.4(NDUFS4):c.99-1G>A	Pathogenic
6888	NM_002495.4(NDUFS4):c.291del (p.Lys96_Trp97insTer)	Pathogenic
6889	NM_002495.4(NDUFS4):c.316C>T (p.Arg106Ter)	Pathogenic
930177	NM_002495.4(NDUFS4):c.350+5G>A	Pathogenic
2429189	NM_002495.4(NDUFS4):c.504_511del (p.Arg169fs)	Likely pathogenic
2502291	NM_002495.4(NDUFS4):c.351-1G>C	Likely pathogenic
2671778	NM_002495.4(NDUFS4):c.351-2A>G	Likely pathogenic
2676990	NM_002495.4(NDUFS4):c.415G>T (p.Glu139Ter)	Likely pathogenic
2676992	NM_002495.4(NDUFS4):c.424+2T>A	Likely pathogenic
2676993	NM_002495.4(NDUFS4):c.235del (p.Ile79fs)	Likely pathogenic
2676994	NM_002495.4(NDUFS4):c.424G>T (p.Gly142Ter)	Likely pathogenic
2676996	NM_002495.4(NDUFS4):c.342G>A (p.Trp114Ter)	Likely pathogenic
2676997	NM_002495.4(NDUFS4):c.479dup (p.Tyr160Ter)	Likely pathogenic
2676998	NM_002495.4(NDUFS4):c.351-2A>C	Likely pathogenic
2676999	NM_002495.4(NDUFS4):c.136dup (p.Gln46fs)	Likely pathogenic
2708848	NM_002495.4(NDUFS4):c.350+1G>C	Likely pathogenic

SpliceAI

2005 predictions. Top by Δscore:

Variant	Effect	Δscore
5:53560759:AGGT:A	donor_loss	1.0000
5:53560761:GTAAT:G	donor_loss	1.0000
5:53603070:T:A	acceptor_gain	1.0000
5:53603527:ATTGG:A	donor_loss	1.0000
5:53603528:TTGG:T	donor_loss	1.0000
5:53603531:G:GC	donor_loss	1.0000
5:53603531:G:GG	donor_gain	1.0000
5:53603532:TAA:T	donor_loss	1.0000
5:53645987:G:GT	donor_gain	1.0000
5:53646228:T:TA	acceptor_gain	1.0000
5:53646229:GTA:G	acceptor_loss	1.0000
5:53646230:TA:T	acceptor_loss	1.0000
5:53646231:A:AG	acceptor_gain	1.0000
5:53646231:AG:A	acceptor_gain	1.0000
5:53646232:G:GG	acceptor_gain	1.0000
5:53646232:GG:G	acceptor_gain	1.0000
5:53646232:GGA:G	acceptor_gain	1.0000
5:53646232:GGAT:G	acceptor_gain	1.0000
5:53646401:TCAAC:T	donor_gain	1.0000
5:53646402:CAACG:C	donor_loss	1.0000
5:53646404:AC:A	donor_gain	1.0000
5:53646404:ACGTG:A	donor_loss	1.0000
5:53646406:G:A	donor_loss	1.0000
5:53646406:G:GG	donor_gain	1.0000
5:53646408:GAGT:G	donor_loss	1.0000
5:53646409:AGTA:A	donor_loss	1.0000
5:53560762:T:G	donor_loss	0.9900
5:53566659:GT:G	donor_gain	0.9900
5:53566660:T:TA	donor_gain	0.9900
5:53566661:A:AA	donor_gain	0.9900

AlphaMissense

1141 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:53683183:T:C	F164L	0.999
5:53683185:T:A	F164L	0.999
5:53683185:T:G	F164L	0.999
5:53646344:T:A	W97R	0.998
5:53646344:T:C	W97R	0.998
5:53646395:T:A	W114R	0.998
5:53646395:T:C	W114R	0.998
5:53683189:T:A	W166R	0.996
5:53683189:T:C	W166R	0.996
5:53646397:G:C	W114C	0.995
5:53646397:G:T	W114C	0.995
5:53683120:T:A	W143R	0.995
5:53683120:T:C	W143R	0.995
5:53683171:T:C	Y160H	0.995
5:53646280:A:C	R75S	0.994
5:53646280:A:T	R75S	0.994
5:53646376:G:C	W107C	0.994
5:53646376:G:T	W107C	0.994
5:53646382:T:A	N109K	0.994
5:53646382:T:G	N109K	0.994
5:53658582:T:C	F128L	0.994
5:53658584:C:A	F128L	0.994
5:53658584:C:G	F128L	0.994
5:53646401:T:C	S116P	0.993
5:53683206:A:C	R171S	0.993
5:53683206:A:T	R171S	0.993
5:53683184:T:C	F164S	0.992
5:53646291:T:A	I79N	0.991
5:53646291:T:C	I79T	0.991
5:53646346:G:C	W97C	0.991

dbSNP variants (sampled 300 via entrez): RS1000007941 (5:53663117 T>A,C), RS1000040269 (5:53642664 A>G), RS1000049521 (5:53606364 A>G), RS1000115369 (5:53635974 C>T), RS1000120576 (5:53566173 A>G), RS1000142611 (5:53678690 G>A), RS1000150961 (5:53595557 T>G), RS1000183688 (5:53678918 C>A,G), RS1000200191 (5:53628326 A>G), RS1000202639 (5:53564859 C>T), RS1000212200 (5:53622553 C>T), RS1000288877 (5:53588943 G>A,C), RS1000289229 (5:53649052 C>T), RS1000293659 (5:53598471 G>A,T), RS1000314344 (5:53628106 G>C)

Disease associations

OMIM: gene MIM:602694 | disease phenotypes: MIM:252010, MIM:256000

GenCC curated gene-disease

Disease	Classification	Inheritance
Leigh syndrome	Definitive	Autosomal recessive
mitochondrial complex I deficiency, nuclear type 1	Strong	Autosomal recessive
mitochondrial complex I deficiency, nuclear type	Moderate	Autosomal recessive
Leigh syndrome with leukodystrophy	Supportive	Autosomal recessive
mitochondrial complex I deficiency	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Leigh syndrome	Definitive	AR
mitochondrial disease	Definitive	AR

Mondo (6): mitochondrial complex I deficiency, nuclear type 1 (MONDO:0100224), Leigh syndrome (MONDO:0009723), mitochondrial complex I deficiency (MONDO:0100133), mitochondrial disease (MONDO:0044970), (MONDO:0009640), (MONDO:0016815)

Orphanet (3): Leigh syndrome (Orphanet:506), Isolated complex I deficiency (Orphanet:2609), Mitochondrial disease (Orphanet:68380)

HPO phenotypes

79 total (30 of 79 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000047	Hypospadias
HP:0000114	Proximal tubulopathy
HP:0000252	Microcephaly
HP:0000331	Short chin
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000543	Optic disc pallor
HP:0000582	Upslanted palpebral fissure
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000817	Reduced eye contact
HP:0000819	Diabetes mellitus
HP:0000961	Cyanosis
HP:0001138	Optic neuropathy
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001257	Spasticity
HP:0001259	Coma
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001272	Cerebellar atrophy
HP:0001298	Encephalopathy
HP:0001308	Tongue fasciculations
HP:0001324	Muscle weakness
HP:0001347	Hyperreflexia
HP:0001399	Hepatic failure
HP:0001427	Mitochondrial inheritance

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST002481_13	Acne (severe)	5.000000e-09
GCST003542_137	Night sleep phenotypes	1.000000e-06
GCST003996_37	Monobrow	2.000000e-17
GCST004283_25	Midgestational circulating levels of PCBs	8.000000e-08
GCST004562_122	Waist circumference adjusted for body mass index	5.000000e-08
GCST004562_185	Waist circumference adjusted for body mass index	1.000000e-08
GCST004563_235	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	1.000000e-07
GCST004563_99	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	3.000000e-07
GCST004564_27	Waist circumference adjusted for BMI in active individuals	1.000000e-06
GCST004564_28	Waist circumference adjusted for BMI in active individuals	2.000000e-06
GCST006931_1	Verbal memory	4.000000e-08
GCST006988_51	Blond vs. brown/black hair color	3.000000e-17
GCST011878_13	Mitochondrial heteroplasmy measurement	9.000000e-10
GCST012308_2	Schizophrenia	9.000000e-06
GCST012309_1	Schizophrenia	9.000000e-06
GCST012310_7	Schizophrenia x sex interaction	2.000000e-06
GCST012311_15	Schizophrenia x sex interaction	2.000000e-06

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0007906	synophrys measurement
EFO:0007042	polychlorinated biphenyls measurement
EFO:0007964	gestational serum measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0008002	physical activity measurement
EFO:0009591	verbal memory measurement
EFO:0003924	hair color
EFO:0600008	mitochondrial heteroplasmy measurement
EFO:0008343	sex interaction measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520
C537475	Mitochondrial complex I deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2363065 (PROTEIN COMPLEX)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

8 potent at pChembl≥5 of 18 total, top 8 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.06	IC50	870	nM	R-(+)-MARMIN-6’-UNDECANOATE
6.04	IC50	920	nM	R-(+)-MARMIN-6’-LINOLEATE
5.63	IC50	2350	nM	R-(+)-MARMIN-6’-LINOLEATE
5.51	IC50	3080	nM	R-(+)-MARMIN-6’-OCTANOATE
5.43	IC50	3670	nM	R-(+)-MARMIN-6’-UNDECANOATE
5.43	IC50	3710	nM	R-(+)-MARMIN-6’-OCTANOATE
5.31	IC50	4900	nM	(+)-9’-ISOVALEROXYLARICIRESINOL
5.04	IC50	9100	nM	(+)-9’-ISOVALEROXYLARICIRESINOL

PubChem BioAssay actives

8 with measured affinity, of 28 total; 4 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
[(E,3R)-2-hydroxy-2,6-dimethyl-8-(2-oxochromen-7-yl)oxyoct-6-en-3-yl] undecanoate	739270: Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1% O2-induced HIF1 activation incubated for 30 mins prior to 1% O2-challenge measured after 16 hrs by luciferase reporter assay	ic50	0.8700	uM
[(E,3R)-2-hydroxy-2,6-dimethyl-8-(2-oxochromen-7-yl)oxyoct-6-en-3-yl] (9Z,12Z)-octadeca-9,12-dienoate	739270: Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1% O2-induced HIF1 activation incubated for 30 mins prior to 1% O2-challenge measured after 16 hrs by luciferase reporter assay	ic50	0.9200	uM
[(E,3R)-2-hydroxy-2,6-dimethyl-8-(2-oxochromen-7-yl)oxyoct-6-en-3-yl] octanoate	739270: Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1% O2-induced HIF1 activation incubated for 30 mins prior to 1% O2-challenge measured after 16 hrs by luciferase reporter assay	ic50	3.0800	uM
[(2S,3R,4R)-2-(4-hydroxy-3-methoxyphenyl)-4-[(4-hydroxy-3-methoxyphenyl)methyl]oxolan-3-yl]methyl 3-methylbutanoate	739269: Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1,10-phenanthroline-induced HIF1 activation incubated for 30 mins prior to 1,10-phenanthroline-challenge measured after 16 hrs by luciferase reporter assay	ic50	4.9000	uM

CTD chemical–gene interactions

49 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Rotenone	decreases expression, decreases reaction, increases expression	3
bisphenol A	affects cotreatment, decreases methylation, affects expression, increases abundance	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
PQQ Cofactor	decreases expression, decreases reaction, increases response to substance	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
ginger extract	affects cotreatment, affects expression, increases abundance	1
dicrotophos	decreases expression	1
deoxynivalenol	decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
perfluorooctanoic acid	decreases expression	1
3-methyladenine	affects cotreatment, decreases expression, decreases reaction	1
tris(chloroethyl)phosphate	increases abundance, decreases expression	1
1-nitropyrene	affects cotreatment, decreases reaction, decreases expression	1
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, decreases expression	1
chloropicrin	affects expression	1
corosolic acid	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1
bisphenol S	decreases methylation	1
bisphenol AF	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	affects cotreatment, decreases expression	1
Ethanol	affects cotreatment, decreases expression, increases abundance	1
Arsenic	affects cotreatment, increases abundance, increases expression, decreases expression	1
Vehicle Emissions	decreases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Doxorubicin	decreases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2353025	Binding	Inhibition of mitochondrial ETC complex 1 in human T47D cells assessed as inhibition of 1% O2-induced HIF1 activation at 30 uM incubated for 30 mins prior to 1% O2-challenge measured after 16 hrs by luciferase reporter assay	Semisynthetic studies identify mitochondria poisons from botanical dietary supplements–geranyloxycoumarins from Aegle marmelos. — Bioorg Med Chem

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 finite cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_EQ46	7898	Finite cell line	Male
CVCL_TA20	HAP1 NDUFS4 (-) 1	Cancer cell line	Male
CVCL_TA21	HAP1 NDUFS4 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

112 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT01721733	PHASE2	COMPLETED	Safety and Efficacy Study of EPI-743 in Children With Leigh Syndrome
NCT02352896	PHASE2	COMPLETED	Long-Term Safety and Efficacy Evaluation of EPI-743 in Children With Leigh Syndrome
NCT03747328	PHASE2	WITHDRAWN	ABI-009 (Nab-sirolimus) in Patients With Genetically-confirmed Leigh or Leigh-like Syndrome
NCT06843811	PHASE2	ENROLLING_BY_INVITATION	Sirolimus for Leigh Syndrome
NCT06990984	PHASE2	NOT_YET_RECRUITING	A Dose-ranging Study of TTI-0102 in Adults and Children With Leigh Syndrome Spectrum (LSS)
NCT02398201	PHASE2	COMPLETED	A Study of Bezafibrate in Mitochondrial Myopathy
NCT02473445	PHASE2	TERMINATED	A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT02805790	PHASE2	COMPLETED	Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT02976038	PHASE2	TERMINATED	Open-Label Extension Trial to Characterize the Long-term Safety and Tolerability of Elamipretide in Subjects With Genetically Confirmed Primary Mitochondrial Myopathy (PMM)
NCT03177798	PHASE2	COMPLETED	Mitochondria and Chronic Kidney Disease
NCT03866954	PHASE2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT05650229	PHASE2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT05972954	PHASE2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
NCT06017869	PHASE2	RECRUITING	Evaluate the Safety and Therapeutic Effects of a Single Intravenous Infusion (IV) of Autologous CD34+ Cells Enriched With Allogenic Placenta-derived Mitochondria in Patients With a Diagnosis of Pearson Syndrome (PS)
NCT07514338	PHASE2	NOT_YET_RECRUITING	Open Label Extension to Assess Long Term Safety and Efficacy of KL1333 in Patients With Primary Mitochondrial Disease
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT00060515	PHASE1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	PHASE1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT05241262	PHASE1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels
NCT05569122	PHASE1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	PHASE1	RECRUITING	Validation of Nanosensor Oxygen Measurement
NCT07258667	PHASE1	NOT_YET_RECRUITING	Pilot Study of the Efficacy of Nicotinamide (Vitamin B3) in Leber’s Hereditary Optic Neuropathy
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01780168	Not specified	RECRUITING	The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Metabolism
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT03137355	Not specified	RECRUITING	The International Registry for Leigh Syndrome