NDUFB11

Summary

NDUFB11 (NADH:ubiquinone oxidoreductase subunit B11, HGNC:20372) is a protein-coding gene on chromosome Xp11.3, encoding NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mitochondrial (Q9NX14). Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis. It is a selective cancer dependency (DepMap: 26.3% of cell lines).

The protein encoded by this gene is a subunit of the multisubunit NADH:ubiquinone oxidoreductase (complex I). Mammalian complex I is located at the mitochondrial inner membrane. This protein has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to ubiquinone. Mutations in the human gene are associated with linear skin defects with multiple congenital anomalies 3 and mitochondrial complex I deficiency.

Source: NCBI Gene 54539 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +3 more curated relationships
• Clinical variants (ClinVar): 102 total — 2 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 149
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 26.3% of screened cell lines
• MANE Select transcript: NM_001135998

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20372
Approved symbol	NDUFB11
Name	NADH:ubiquinone oxidoreductase subunit B11
Location	Xp11.3
Locus type	gene with protein product
Status	Approved
Aliases	ESSS, NP17.3, Np15
Ensembl gene	ENSG00000147123
Ensembl biotype	protein_coding
OMIM	300403
Entrez	54539

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000276062, ENST00000377811, ENST00000685599, ENST00000687244, ENST00000688286, ENST00000690053, ENST00000690204, ENST00000692649, ENST00000917104, ENST00000917105

RefSeq mRNA: 2 — MANE Select: NM_001135998 NM_001135998, NM_019056

CCDS: CCDS14273, CCDS48100

Canonical transcript exons

ENST00000377811 — 3 exons

Exon	Start	End
ENSE00000978832	47142216	47142440
ENSE00001432338	47142614	47142744
ENSE00001879712	47144473	47144702

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 99.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 252.9421 / max 1187.1997, expressed in 1828 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199082	252.0433	1828
199084	0.8987	552

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	99.45	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.28	gold quality
gastrocnemius	UBERON:0001388	99.19	gold quality
mucosa of transverse colon	UBERON:0004991	99.11	gold quality
heart left ventricle	UBERON:0002084	99.09	gold quality
cardiac ventricle	UBERON:0002082	99.07	gold quality
right adrenal gland	UBERON:0001233	99.04	gold quality
right atrium auricular region	UBERON:0006631	99.02	gold quality
right adrenal gland cortex	UBERON:0035827	98.97	gold quality
ganglionic eminence	UBERON:0004023	98.96	gold quality
left adrenal gland	UBERON:0001234	98.95	gold quality
cortical plate	UBERON:0005343	98.93	gold quality
left adrenal gland cortex	UBERON:0035825	98.93	gold quality
right lobe of thyroid gland	UBERON:0001119	98.89	gold quality
adenohypophysis	UBERON:0002196	98.86	gold quality
heart right ventricle	UBERON:0002080	98.83	gold quality
cardiac atrium	UBERON:0002081	98.79	gold quality
heart	UBERON:0000948	98.78	gold quality
left lobe of thyroid gland	UBERON:0001120	98.77	gold quality
vastus lateralis	UBERON:0001379	98.77	gold quality
muscle of leg	UBERON:0001383	98.76	gold quality
triceps brachii	UBERON:0001509	98.75	gold quality
adrenal cortex	UBERON:0001235	98.74	gold quality
muscle organ	UBERON:0001630	98.72	gold quality
pituitary gland	UBERON:0000007	98.71	gold quality
biceps brachii	UBERON:0001507	98.70	gold quality
body of stomach	UBERON:0001161	98.69	gold quality
quadriceps femoris	UBERON:0001377	98.66	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.65	gold quality
body of pancreas	UBERON:0001150	98.64	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-9689	no	370.67
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

9 targeting NDUFB11, 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-6801-5P	99.72	66.50	981
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-5691	98.23	67.02	1335
HSA-MIR-6805-3P	98.23	67.02	1334
HSA-MIR-1225-3P	97.29	64.60	876
HSA-MIR-4286	97.20	64.37	1587
HSA-MIR-3907	96.76	65.04	662
HSA-MIR-6769A-3P	94.91	61.36	412

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 26.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 9)

• NDUFB11 did not seem to influence risk and age at onset of visual loss in a total of 65 individuals from 35 Italian Leber hereditary optic neuropathy patients. (PMID:17292333)
• the post-transcriptional regulation of the Ndufb11 gene can be involved in the programmed cell death process (PMID:23246602)
• Mutations in NDUFB11, encoding a complex I component of the mitochondrial respiratory chain, cause microphthalmia with linear skin defects syndrome. (PMID:25772934)
• The novel NDUFB11 mutation may cause a complex 1 deficiency in synergy with additional unknown mtDNA variants. (PMID:25921236)
• This is the third report that describes a mutation in NDUFB11, but all are associated with a different phenotype. Our results further expand the molecular spectrum and associated clinical phenotype of NDUFB11 defects. (PMID:27102574)
• recurring mutation, c.276_278del, p.F93del, in NDUFB11, a mitochondrial respiratory complex I-associated protein encoded on the X chromosome, in 5 males with a variably syndromic, normocytic congenital sideroblastic anemia. (PMID:27488349)
• Our findings together with a review of the thirteen previously described patients demonstrate a wide spectrum of clinical features associated with NDUFB11-related complex I deficiency. However, histiocytoid cardiomyopathy and/or congenital sideroblastic anemia could be indicative for mutation in the NDUFB11 gene, while the clinical manifestation of the same mutation can be highly variable (PMID:30423443)
• A Novel Mutation Associated with Neonatal Lethal Cardiomyopathy Leads to an Alternative Transcript Expression in the X-Linked Complex I NDUFB11 Gene. (PMID:36675256)
• NDUFB11 and NDUFS3 play a role in atherosclerosis and chronic stress. (PMID:37642954)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndufb11	ENSDARG00000043467
mus_musculus	Ndufb11	ENSMUSG00000031059
mus_musculus	Ndufb11b	ENSMUSG00000061633
rattus_norvegicus	Ndufb11b	ENSRNOG00000005572
rattus_norvegicus	Ndufb11	ENSRNOG00000008329
drosophila_melanogaster	NP15.6	FBGN0027785
caenorhabditis_elegans		WBGENE00018361

Protein

Protein identifiers

NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mitochondrial — Q9NX14 (reviewed: Q9NX14)

Alternative names: Complex I-ESSS, NADH-ubiquinone oxidoreductase ESSS subunit, Neuronal protein 17.3

All UniProt accessions (5): Q9NX14, A0A8I5KQF7, A0A8I5KTD1, A0A8I5KTJ9, A0A8J8YU24

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. Complex I is composed of 45 different subunits. Interacts with BCAP31.

Subcellular location. Mitochondrion inner membrane.

Tissue specificity. Ubiquitous.

Disease relevance. Linear skin defects with multiple congenital anomalies 3 (LSDMCA3) [MIM:300952] A disorder characterized by dermal, ocular, neurological and cardiac abnormalities. LSDMCA3 clinical features include linear skin defects on face and neck at birth, lacrimal duct atresia, myopia, nystagmus, strabismus, cardiomyopathy, axial hypotonia, seizures, corpus callosum agenesis, and dilation of lateral ventricles. The disease is caused by variants affecting the gene represented in this entry. Mitochondrial complex I deficiency, nuclear type 30 (MC1DN30) [MIM:301021] 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 may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the complex I NDUFB11 subunit family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NX14-1	1	yes
Q9NX14-2	2

RefSeq proteins (2): NP_001129470, NP_061929 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019329	NADH_UbQ_OxRdtase_ESSS_su	Family

Pfam: PF10183

UniProt features (11 total): sequence variant 3, sequence conflict 2, transit peptide 1, chain 1, transmembrane region 1, region of interest 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

7 structures.

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

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NX14-F1	78.75	0.40

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: 402 (showing top): STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_ATP_BIOSYNTHETIC_PROCESS, GOBP_OXIDATIVE_PHOSPHORYLATION, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, GOBP_NUCLEOSIDE_TRIPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_TRIPHOSPHATE_BIOSYNTHETIC_PROCESS, GOCC_MITOCHONDRIAL_ENVELOPE, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_13, SPIELMAN_LYMPHOBLAST_EUROPEAN_VS_ASIAN_UP

GO Biological Process (2): aerobic respiration (GO:0009060), proton motive force-driven mitochondrial ATP synthesis (GO:0042776)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (9): acrosomal vesicle (GO:0001669), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), respiratory chain complex I (GO:0045271), sperm midpiece (GO:0097225), sperm principal piece (GO:0097228), sperm end piece (GO:0097229), sperm head-tail coupling apparatus (GO:0120212), 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
cellular anatomical structure	5
sperm flagellum	3
cellular respiration	1
mitochondrion	1
oxidative phosphorylation	1
proton motive force-driven ATP synthesis	1
binding	1
secretory granule	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
NADH dehydrogenase complex	1
respiratory chain complex	1
transmembrane transporter complex	1

Protein interactions and networks

STRING

1540 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NDUFB11	NDUFB5	O43674	929
NDUFB11	NDUFB10	O96000	922
NDUFB11	NDUFB1	O75438	896
NDUFB11	NDUFB4	O95168	876
NDUFB11	NDUFB6	O95139	866
NDUFB11	MT-ND4	P03905	849
NDUFB11	MT-ND1	P03886	819
NDUFB11	NDUFA7	O95182	810
NDUFB11	NDUFA1	O15239	789
NDUFB11	NDUFA13	Q9P0J0	781
NDUFB11	NDUFA5	Q16718	776
NDUFB11	NDUFA3	O95167	753
NDUFB11	NDUFB7	P17568	748
NDUFB11	NDUFV2	P19404	743
NDUFB11	NDUFB8	O95169	734

IntAct

105 interactions, top by confidence:

A	B	Type	Score
NDUFAF1	NDUFS3	psi-mi:“MI:0914”(association)	0.790
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
NDUFB11	FATE1	psi-mi:“MI:0915”(physical association)	0.720
FATE1	NDUFB11	psi-mi:“MI:0915”(physical association)	0.720
TIMMDC1	NDUFB11	psi-mi:“MI:0915”(physical association)	0.670
NDUFAF4	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFA13	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFA9	NDUFS4	psi-mi:“MI:0914”(association)	0.640
GJB1	NDUFB11	psi-mi:“MI:0915”(physical association)	0.560
HIBADH	NDUFB11	psi-mi:“MI:0915”(physical association)	0.560
GPR101	NDUFB11	psi-mi:“MI:0915”(physical association)	0.560
GPR152	NDUFB11	psi-mi:“MI:0915”(physical association)	0.560
EBP	NDUFB11	psi-mi:“MI:0915”(physical association)	0.560
GPR42	NDUFB11	psi-mi:“MI:0915”(physical association)	0.560
CLDN7	NDUFB11	psi-mi:“MI:0915”(physical association)	0.560
NDUFS5	NDUFS8	psi-mi:“MI:0914”(association)	0.530
NDUFA9	NDUFS8	psi-mi:“MI:0914”(association)	0.530
KSR2	POLR3A	psi-mi:“MI:0914”(association)	0.530
NDUFS5	NDUFS4	psi-mi:“MI:0914”(association)	0.530
NDUFC2	NDUFS4	psi-mi:“MI:0914”(association)	0.530
DNAJC30	NDUFS8	psi-mi:“MI:0914”(association)	0.530
TIMMDC1	NDUFS8	psi-mi:“MI:0914”(association)	0.530

BioGRID (199): FATE1 (Two-hybrid), NDUFB11 (Affinity Capture-MS), NDUFB11 (Affinity Capture-MS), NDUFB11 (Affinity Capture-MS), NDUFB11 (Affinity Capture-MS), NDUFB11 (Affinity Capture-MS), NDUFB11 (Affinity Capture-MS), NDUFB11 (Affinity Capture-MS), NDUFB11 (Affinity Capture-MS), NDUFB11 (Affinity Capture-MS), NDUFB11 (Affinity Capture-MS), NDUFB11 (Affinity Capture-MS), NDUFB11 (Affinity Capture-MS), NDUFB11 (Affinity Capture-MS), NDUFB11 (Affinity Capture-MS)

ESM2 similar proteins: A6ZZ82, B3LFH4, B5DFN3, C0NZ35, C5FGP0, C5GY53, C5K1L1, C6H5G5, C7GKT0, C8Z651, F1Q930, O09111, O75182, O76024, P56695, P82649, P82650, P83565, Q03429, Q0MQJ3, Q0MQJ4, Q0MQJ5, Q0VFC7, Q29259, Q2NL27, Q3SZ13, Q3ZBC2, Q5R4W7, Q5TC12, Q5ZKP2, Q66JD1, Q6AYQ6, Q6DGL8, Q6DGP7, Q6DQX6, Q6PBU7, Q811I0, Q8HXG5, Q8VE22, Q96Q45

Diamond homologs: O09111, Q0MQJ3, Q0MQJ4, Q0MQJ5, Q6DQX6, Q8HXG5, Q9NX14

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NDUFB11	“form complex”	“NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 90 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	24	67.3×	3e-37
Respiratory electron transport	22	35.5×	3e-27
Aerobic respiration and respiratory electron transport	22	33.0×	1e-26
Mitochondrial protein degradation	8	15.5×	2e-06

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	18	81.7×	1e-28
mitochondrial respiratory chain complex I assembly	13	67.6×	3e-19
proton motive force-driven mitochondrial ATP synthesis	20	66.7×	1e-29
aerobic respiration	19	59.6×	2e-27

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	7
Uncertain significance	42
Likely benign	25
Benign	5

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
190302	NM_001135998.3(NDUFB11):c.262C>T (p.Arg88Ter)	Pathogenic
190303	NM_001135998.3(NDUFB11):c.372del (p.Arg124fs)	Pathogenic
1064806	NM_001135998.3(NDUFB11):c.145_152dup (p.Thr52fs)	Likely pathogenic
1804013	NM_001135998.3(NDUFB11):c.286T>C (p.Ser96Pro)	Likely pathogenic
2499133	NM_001135998.3(NDUFB11):c.34del (p.Arg12fs)	Likely pathogenic
2584528	NM_001135998.3(NDUFB11):c.385C>T (p.Arg129Ter)	Likely pathogenic
4077077	NM_001135998.3(NDUFB11):c.338+12del	Likely pathogenic
4294507	NM_001135998.3(NDUFB11):c.176dup (p.Glu60fs)	Likely pathogenic
449223	NM_001135998.3(NDUFB11):c.338+2T>A	Likely pathogenic

SpliceAI

416 predictions. Top by Δscore:

Variant	Effect	Δscore
X:47142439:TC:T	acceptor_gain	1.0000
X:47142439:TCCTG:T	acceptor_loss	1.0000
X:47142440:CC:C	acceptor_gain	1.0000
X:47142441:C:CC	acceptor_gain	1.0000
X:47142447:G:GC	acceptor_gain	1.0000
X:47142450:C:CT	acceptor_gain	1.0000
X:47142740:GGGTT:G	acceptor_gain	1.0000
X:47142741:GGTT:G	acceptor_gain	1.0000
X:47142742:GTT:G	acceptor_gain	1.0000
X:47142743:TT:T	acceptor_gain	1.0000
X:47142745:C:CC	acceptor_gain	1.0000
X:47142747:G:C	acceptor_gain	1.0000
X:47144468:CTCA:C	donor_loss	1.0000
X:47144471:A:AT	donor_loss	1.0000
X:47144472:C:A	donor_loss	1.0000
X:47144472:CCTT:C	donor_gain	1.0000
X:47144492:T:TA	donor_gain	1.0000
X:47145216:T:TA	donor_gain	1.0000
X:47142436:TCATC:T	acceptor_gain	0.9900
X:47142437:CATC:C	acceptor_gain	0.9900
X:47142437:CATCC:C	acceptor_gain	0.9900
X:47142438:ATC:A	acceptor_gain	0.9900
X:47142444:G:C	acceptor_gain	0.9900
X:47142444:G:GC	acceptor_gain	0.9900
X:47142447:G:C	acceptor_gain	0.9900
X:47142451:A:T	acceptor_gain	0.9900
X:47142598:TGGAC:T	donor_gain	0.9900
X:47142604:C:CA	donor_gain	0.9900
X:47142612:A:AC	donor_loss	0.9900
X:47142614:C:G	donor_loss	0.9900

AlphaMissense

995 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:47142643:G:C	S103R	0.986
X:47142643:G:T	S103R	0.986
X:47142645:T:G	S103R	0.986
X:47142415:C:G	A122P	0.976
X:47142428:C:A	W117C	0.974
X:47142428:C:G	W117C	0.974
X:47142393:C:G	R129P	0.971
X:47142648:C:G	G102R	0.970
X:47142647:C:T	G102D	0.965
X:47142672:C:G	G94R	0.965
X:47142353:G:C	F142L	0.960
X:47142353:G:T	F142L	0.960
X:47142355:A:G	F142L	0.960
X:47142339:A:G	I147T	0.956
X:47142405:A:G	L125P	0.955
X:47142671:C:T	G94D	0.953
X:47142414:G:T	A122D	0.949
X:47142653:A:T	V100D	0.948
X:47142430:A:G	W117R	0.947
X:47142430:A:T	W117R	0.947
X:47142339:A:C	I147S	0.943
X:47142705:C:G	D83H	0.942
X:47142665:G:T	S96Y	0.939
X:47142668:A:T	V95D	0.939
X:47142726:A:C	Y76D	0.938
X:47142704:T:A	D83V	0.929
X:47142420:C:G	R120P	0.927
X:47142703:G:C	D83E	0.927
X:47142703:G:T	D83E	0.927
X:47142378:A:G	L134P	0.926

dbSNP variants (sampled 300 via entrez): RS1002499036 (X:47143116 C>T), RS1003669518 (X:47146383 G>A,T), RS1006508801 (X:47142799 C>A), RS1007920530 (X:47145356 C>A,G,T), RS1008410451 (X:47147055 A>C), RS1011895045 (X:47144006 G>C), RS1012264257 (X:47146513 G>A), RS1012623934 (X:47146952 G>A), RS1017860542 (X:47144974 T>C), RS1021513140 (X:47144032 C>T), RS1022305041 (X:47146999 G>A), RS1025371394 (X:47143033 T>G), RS1026299551 (X:47145091 C>G), RS1026371805 (X:47145372 C>G,T), RS1030157195 (X:47144087 T>C)

Disease associations

OMIM: gene MIM:300403 | disease phenotypes: MIM:301021, MIM:300952, MIM:500000, MIM:309801, MIM:252010

GenCC curated gene-disease

Disease	Classification	Inheritance
linear skin defects with multiple congenital anomalies 3	Strong	X-linked
mitochondrial complex I deficiency, nuclear type 30	Strong	X-linked
linear skin defects with multiple congenital anomalies	Supportive	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	XL

Mondo (10): NDUFB11-related disorders (MONDO:1040023), mitochondrial complex I deficiency, nuclear type 30 (MONDO:0026721), linear skin defects with multiple congenital anomalies 3 (MONDO:0010494), neurodevelopmental disorder (MONDO:0700092), histiocytoid cardiomyopathy (MONDO:0010771), linear skin defects with multiple congenital anomalies 1 (MONDO:0024552), mitochondrial complex I deficiency, nuclear type 1 (MONDO:0100224), intellectual disability (MONDO:0001071), mitochondrial complex I deficiency (MONDO:0100133), linear skin defects with multiple congenital anomalies (MONDO:0010672)

Orphanet (4): Microphthalmia with linear skin defects syndrome (Orphanet:2556), Histiocytoid cardiomyopathy (Orphanet:137675), Isolated complex I deficiency (Orphanet:2609), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

149 total (30 of 149 shown, HPO-id order):

HPO	Term
HP:0000013	Hypoplasia of the uterus
HP:0000035	Abnormal testis morphology
HP:0000036	Abnormal penis morphology
HP:0000037	Male pseudohermaphroditism
HP:0000039	Epispadias
HP:0000041	Chordee
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000062	Ambiguous genitalia
HP:0000114	Proximal tubulopathy
HP:0000175	Cleft palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000347	Micrognathia
HP:0000363	Abnormal earlobe morphology
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000431	Wide nasal bridge
HP:0000445	Wide nose
HP:0000486	Strabismus
HP:0000492	Abnormal eyelid morphology
HP:0000499	Abnormal eyelash morphology
HP:0000501	Glaucoma
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000528	Anophthalmia
HP:0000543	Optic disc pallor
HP:0000545	Myopia
HP:0000556	Retinal dystrophy

GWAS associations

0 associations (top):

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
C535584	Cardiomyopathy, infantile histiocytoid (supp.)
C537466	Microphthalmia, syndromic 7 (supp.)
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

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

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects methylation, affects cotreatment, increases abundance, increases expression	2
Cadmium Chloride	increases expression, increases abundance	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
arsenite	affects binding, increases reaction	1
methylparaben	decreases expression	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	increases expression, affects cotreatment, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
bisphenol B	increases expression	1
bisphenol S	affects expression	1
bisphenol AF	increases expression	1
Temozolomide	decreases expression	1
Acetaminophen	decreases expression	1
Cyclic AMP	increases phosphorylation, decreases reaction	1
Air Pollutants	affects expression, increases abundance	1
Ethanol	affects cotreatment, increases abundance, increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	increases abundance, increases expression	1
Doxorubicin	increases expression	1
Estradiol	decreases expression	1
Gasoline	affects cotreatment, increases abundance, increases expression	1
Ivermectin	decreases expression	1
Manganese	increases abundance, increases expression, affects cotreatment	1
Ozone	affects expression, increases abundance	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

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders