ISCU

Summary

ISCU (iron-sulfur cluster assembly enzyme, HGNC:29882) is a protein-coding gene on chromosome 12q23.3, encoding Iron-sulfur cluster assembly enzyme ISCU (Q9H1K1). Mitochondrial scaffold protein, of the core iron-sulfur cluster (ISC) assembly complex, that provides the structural architecture on which the [2Fe-2S] clusters are assembled. It is a common-essential gene (DepMap: required in 99.9% of cancer cell lines).

This gene encodes a component of the iron-sulfur (Fe-S) cluster scaffold. Fe-S clusters are cofactors that play a role in the function of a diverse set of enzymes, including those that regulate metabolism, iron homeostasis, and oxidative stress response. Alternative splicing results in transcript variants encoding different protein isoforms that localize either to the cytosol or to the mitochondrion. Mutations in this gene have been found in patients with hereditary myopathy with lactic acidosis. A disease-associated mutation in an intron may activate a cryptic splice site, resulting in the production of a splice variant encoding a putatively non-functional protein. A pseudogene of this gene is present on chromosome 1.

Source: NCBI Gene 23479 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 205 total — 1 pathogenic, 1 likely-pathogenic
• GTEx eGene: eQTL in 29 tissues, sQTL in 21 (q < 0.05)
• Phenotypes (HPO): 35
• Cancer dependency (DepMap): dependent in 99.9% of screened cell lines (common-essential)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.54 (unconstrained)
• MANE Select transcript: NM_213595
• Interaction hub: 1,924 STRING partners (top 8% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29882
Approved symbol	ISCU
Name	iron-sulfur cluster assembly enzyme
Location	12q23.3
Locus type	gene with protein product
Status	Approved
Aliases	ISU2, hnifU
Ensembl gene	ENSG00000136003
Ensembl biotype	protein_coding
OMIM	611911
Entrez	23479

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 10 protein_coding, 9 nonsense_mediated_decay, 5 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000311893

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 7, TSL 3: 3

ENST00000311893, ENST00000392807, ENST00000431221, ENST00000535405, ENST00000535729, ENST00000538193, ENST00000539580, ENST00000539593, ENST00000540154, ENST00000544493, ENST00000545932, ENST00000547005, ENST00000552072, ENST00000948249, ENST00000979633, ENST00001034678, ENST00001067395, ENST00001067397, ENST00001067398, ENST00001067401, ENST00001067402, ENST00001090905, ENST00001090906, ENST00001090907, ENST00001139515

RefSeq mRNA: 5 — MANE Select: NM_213595 NM_001301140, NM_001301141, NM_001320042, NM_014301, NM_213595

CCDS: CCDS44966, CCDS73518, CCDS76597, CCDS9118

Canonical transcript exons

ENST00000311893 — 5 exons

Exon	Start	End
ENSE00003497077	108568831	108569368
ENSE00003502794	108564279	108564392
ENSE00003540589	108567190	108567268
ENSE00003678625	108565321	108565431
ENSE00003901503	108562596	108562736

Expression profiles

Bgee: expression breadth ubiquitous, 301 present calls, max score 99.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 101.9265 / max 593.9629, expressed in 1825 samples.

Highest expression (Bgee): heart right ventricle, pons, renal medulla, superior vestibular nucleus, substantia nigra pars compacta.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ISCU is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 29 tissues and its splicing (sQTL) in 21 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 50 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Muscle Skeletal	eqtl	3.8e-46	+0.41	12:108536333:A:G
Testis	sqtl	1.7e-29	-1.21	12:108534398:G:A
Lung	sqtl	7.1e-27	-0.63	12:108538277:C:T
Testis	eqtl	4.2e-24	+0.55	12:108524369:C:T
Skin Not Sun Exposed Suprapubic	sqtl	4.6e-24	-0.71	12:108558756:A:G
Heart Atrial Appendage	eqtl	7.5e-24	+0.31	12:108538277:C:T
Esophagus Mucosa	sqtl	2.7e-16	-0.60	12:108538277:C:T
Whole Blood	sqtl	5.4e-16	-0.59	12:108541781:A:G
Cells Cultured fibroblasts	eqtl	6.4e-15	+0.17	12:108542743:C:T
Thyroid	eqtl	2.1e-13	-0.65	12:108517941:G:A
Whole Blood	eqtl	1.5e-12	-0.19	12:108555781:C:T
Spleen	eqtl	3.1e-12	-0.53	12:108572282:GA:G
Heart Left Ventricle	eqtl	1.8e-11	+0.18	12:108541781:A:G
Brain Cerebellum	sqtl	3.2e-11	-0.61	12:108535674:C:T
Skin Not Sun Exposed Suprapubic	eqtl	2.5e-10	+0.60	12:108571091:G:A
Cells EBV-transformed lymphocytes	sqtl	6.7e-09	+0.76	12:108517941:G:A
Brain Cerebellar Hemisphere	sqtl	3.0e-07	-0.33	12:108535674:C:T
Lung	eqtl	7.3e-06	-0.23	12:108514691:C:T
Cells Cultured fibroblasts	sqtl	5.1e-05	+0.68	12:108517941:G:A
Small Intestine Terminal Ileum	eqtl	5.2e-05	-0.33	12:108572282:GA:G

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
127886	100.1896	1825
127885	1.7369	979

Top tissues by expression

showing 100 of 302 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
heart right ventricle	UBERON:0002080	99.71	gold quality
pons	UBERON:0000988	99.70	gold quality
renal medulla	UBERON:0000362	99.59	gold quality
superior vestibular nucleus	UBERON:0007227	99.51	gold quality
substantia nigra pars compacta	UBERON:0001965	99.50	gold quality
lateral globus pallidus	UBERON:0002476	99.47	gold quality
right adrenal gland cortex	UBERON:0035827	99.47	gold quality
myocardium	UBERON:0002349	99.45	gold quality
adrenal cortex	UBERON:0001235	99.43	gold quality
right adrenal gland	UBERON:0001233	99.42	gold quality
left adrenal gland	UBERON:0001234	99.40	gold quality
left adrenal gland cortex	UBERON:0035825	99.40	gold quality
seminal vesicle	UBERON:0000998	99.38	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.38	gold quality
left ventricle myocardium	UBERON:0006566	99.37	gold quality
adult organism	UBERON:0007023	99.37	gold quality
urethra	UBERON:0000057	99.36	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.33	gold quality
apex of heart	UBERON:0002098	99.30	gold quality
cardiac ventricle	UBERON:0002082	99.29	gold quality
heart left ventricle	UBERON:0002084	99.28	gold quality
vena cava	UBERON:0004087	99.28	gold quality
nephron tubule	UBERON:0001231	99.27	gold quality
pituitary gland	UBERON:0000007	99.23	gold quality
parotid gland	UBERON:0001831	99.23	gold quality
thymus	UBERON:0002370	99.23	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.23	gold quality
postcentral gyrus	UBERON:0002581	99.22	gold quality
adrenal gland	UBERON:0002369	99.21	gold quality
calcaneal tendon	UBERON:0003701	99.21	gold quality
adenohypophysis	UBERON:0002196	99.18	gold quality
heart	UBERON:0000948	99.16	gold quality
vastus lateralis	UBERON:0001379	99.16	gold quality
parietal lobe	UBERON:0001872	99.16	gold quality
cardiac atrium	UBERON:0002081	99.16	gold quality
dorsal root ganglion	UBERON:0000044	99.15	gold quality
gluteal muscle	UBERON:0002000	99.15	gold quality
superior frontal gyrus	UBERON:0002661	99.15	gold quality
adult mammalian kidney	UBERON:0000082	99.14	gold quality
right atrium auricular region	UBERON:0006631	99.14	gold quality
nucleus accumbens	UBERON:0001882	99.13	gold quality
trabecular bone tissue	UBERON:0002483	99.13	gold quality
cardia of stomach	UBERON:0001162	99.12	gold quality
right coronary artery	UBERON:0001625	99.12	gold quality
inferior olivary complex	UBERON:0002127	99.12	gold quality
superficial temporal artery	UBERON:0001614	99.11	gold quality
kidney epithelium	UBERON:0004819	99.11	gold quality
Brodmann (1909) area 10	UBERON:0013541	99.11	gold quality
quadriceps femoris	UBERON:0001377	99.10	gold quality
frontal pole	UBERON:0002795	99.10	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.10	gold quality
metanephros cortex	UBERON:0010533	99.10	gold quality
right frontal lobe	UBERON:0002810	99.09	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.09	gold quality
biceps brachii	UBERON:0001507	99.08	gold quality
synovial joint	UBERON:0002217	99.08	gold quality
ventral tegmental area	UBERON:0002691	99.08	gold quality
triceps brachii	UBERON:0001509	99.07	gold quality
caput epididymis	UBERON:0004358	99.06	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.06	gold quality
popliteal artery	UBERON:0002250	99.05	gold quality
tibial artery	UBERON:0007610	99.05	gold quality
aorta	UBERON:0000947	99.04	gold quality
body of tongue	UBERON:0011876	99.04	gold quality
diaphragm	UBERON:0001103	99.03	gold quality
medulla oblongata	UBERON:0001896	99.03	gold quality
ascending aorta	UBERON:0001496	99.02	gold quality
thoracic aorta	UBERON:0001515	99.02	gold quality
hypothalamus	UBERON:0001898	99.02	gold quality
descending thoracic aorta	UBERON:0002345	99.02	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.02	gold quality
kidney	UBERON:0002113	99.00	gold quality
orbitofrontal cortex	UBERON:0004167	98.99	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.99	gold quality
cortex of kidney	UBERON:0001225	98.98	gold quality
coronary artery	UBERON:0001621	98.98	gold quality
cingulate cortex	UBERON:0003027	98.98	gold quality
left coronary artery	UBERON:0001626	98.97	gold quality
trigeminal ganglion	UBERON:0001675	98.97	gold quality
anterior cingulate cortex	UBERON:0009835	98.97	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.97	gold quality
midbrain	UBERON:0001891	98.95	gold quality
mucosa of stomach	UBERON:0001199	98.94	gold quality
muscle organ	UBERON:0001630	98.94	gold quality
gastrocnemius	UBERON:0001388	98.93	gold quality
metanephros	UBERON:0000081	98.92	gold quality
substantia nigra	UBERON:0002038	98.92	gold quality
endocervix	UBERON:0000458	98.91	gold quality
muscle of leg	UBERON:0001383	98.91	gold quality
occipital lobe	UBERON:0002021	98.90	gold quality
fundus of stomach	UBERON:0001160	98.89	gold quality
frontal cortex	UBERON:0001870	98.89	gold quality
frontal lobe	UBERON:0016525	98.89	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.89	gold quality
renal glomerulus	UBERON:0000074	98.88	gold quality
skeletal muscle tissue	UBERON:0001134	98.87	gold quality
pylorus	UBERON:0001166	98.87	gold quality
caudate nucleus	UBERON:0001873	98.86	gold quality
blood vessel layer	UBERON:0004797	98.86	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.86	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	25.53
E-MTAB-8142	yes	17.23
E-HCAD-25	yes	9.72
E-MTAB-6379	no	842.65
E-MTAB-6819	no	302.69
E-MTAB-8060	no	184.04
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Heart muscle	tissue	420.7	high
Tongue	tissue	356.2
Pons	tissue	335.6
Spinal cord	tissue	330.1
Medulla oblongata	tissue	327.0
Thalamus	tissue	317.3
Superior colliculi	tissue	316.0
Midbrain	tissue	302.3
Substantia nigra	tissue	301.4
Skeletal muscle	tissue	298.0	high
Periaqueductal gray	tissue	293.5
Adrenal gland	tissue	292.3	high
Kidney	tissue	288.2	high
Hypothalamus	tissue	282.0
Putamen	tissue	278.1
Prefrontal cortex	tissue	268.9
Cerebral cortex	tissue	268.9	medium
Parathyroid gland	tissue	268.4	high
Motor cortex	tissue	264.2
Septum	tissue	256.4
Basal ganglia	tissue	253.6	high
Hippocampal formation	tissue	249.2
Somatosensory cortex	tissue	248.1
Ventral pallidum	tissue	246.8
Occipital cortex	tissue	245.6
Choroid plexus	tissue	238.7
Entorhinal cortex	tissue	233.0
Cingulate cortex	tissue	228.6
Retrosplenial cortex	tissue	226.8
Temporal cortex	tissue	223.5
Pituitary gland	tissue	221.7
Postcentral gyrus	tissue	219.9
Cerebellum	tissue	213.5	high
Insular cortex	tissue	210.3
Corpus callosum	tissue	208.9
Amygdala	tissue	205.0
Olfactory bulb	tissue	185.3
Seminal vesicle	tissue	184.5	high
Locus coeruleus	tissue	179.2
Thyroid gland	tissue	172.5	high
Nucleus accumbens	tissue	148.5
Thymus	tissue	141.1
Epididymis	tissue	140.6	high
Ovary	tissue	140.0	high
Adipose tissue	tissue	130.7	not detected
Lymph node	tissue	130.0	medium
Tonsil	tissue	129.6	high
Vagina	tissue	128.8	high
Salivary gland	tissue	116.5	medium
Cervix	tissue	116.1	medium
Spleen	tissue	115.4	low
Smooth muscle	tissue	114.1	medium
Prostate	tissue	113.4	medium
Liver	tissue	111.1	high
Urinary bladder	tissue	110.0	high
Breast	tissue	108.6	medium
Hippocampus	tissue	108.6	medium
Rectum	tissue	105.2	high
Placenta	tissue	104.4	medium
Fallopian tube	tissue	103.0	high

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Ventral spinal cord (330.1), Dorsal spinal cord (291.1), Blood vessel (282.8), Dorsal hippocampus (249.2), Medial vestibular nucleus (240.8).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TBP, ZNF335

miRNA regulators (miRDB)

Targeting ISCU by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 38 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-891B	99.59	69.81	1083
HSA-MIR-182-3P	99.57	67.57	825
HSA-MIR-892A	99.54	68.16	1141
HSA-MIR-892C-5P	99.16	70.56	2116

Functional genomics

gnomAD constraint: pLI 0.00214, LOEUF 1.54, missense Z -0.837 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000311893 — one region, missense o/e 1.10. DepMap (CRISPR cell-line fitness): dependent in 99.9% of screened cell lines, common-essential.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): K-562 (-3.402), UACC-893 (-3.308), CAS-1 (-3.146), HPAF-II (-3.125), KLE (-3.098), HCC-33 (-3.058), MFE-280 (-3.015), LN382 (-2.999), NMC-G1 (-2.951), GAMG (-2.947), INA6 (-2.92), SNU-410 (-2.918), NCI-H1694 (-2.904), KP-N-YN (-2.903), NCI-N87 (-2.875).

Literature-anchored findings (GeneRIF, showing 37)

• Data suggest that frataxin may be involved in the biosynthesis of iron-sulphur proteins such as IscU1 not only within the mitochondria, but also in the extramitochondrial compartment. (PMID:16091420)
• Functional analysis of the mitochondrial and cytosolic isoforms of the human Fe-S cluster scaffold protein, ISCU. (PMID:16517407)
• the cytosolic form of ISCS is a functional cysteine desulfurase that can collaborate with cytosolic ISCU to promote de novo iron-sulfur cluster formation (PMID:16527810)
• Intron mutation in the ISCU gene, leading to incorrectly spliced mRNA, is the cause of myopathy with lactic acidosis in this family. (PMID:18296749)
• Gene ISCU was identified as a candidate within a region of shared homozygosity among patients with myopathy with severe exercise intolerance and myoglobinuria. (PMID:18304497)
• the iron-dependent binding affinity of each frataxin derivative to the iron-sulfur cluster scaffold protein ISU is found to be similar to that of native frataxin (PMID:18425540)
• a new ISCU mutation in iron-sulphur cluster deficiency myopathy (PMID:19567699)
• Results identify the iron-sulfur cluster assembly proteins (ISCU1/2) as direct targets for repression by the hypoxia-induced microRNA-210. (PMID:19808020)
• miR-210 mediates a new mechanism of adaptation to hypoxia, by regulating mitochondrial function via iron-sulfur cluster metabolism and free radical generation (PMID:20436681)
• ISCU and COX10 are target genes of miR-210 related to mitochondrial metabolism (PMID:20498629)
• Data show that the highest level of incorrectly spliced ISCU mRNA was found in skeletal muscle. (PMID:21165651)
• Exchange of [2Fe-2S] centers between glutaredoxin 2 and the cluster scaffold protein ISU, supports a direct link for glutaredoxin 2 and glutathione involvement in ISU promoted Fe-S cluster biosynthesis. (PMID:21437321)
• iron-sulfur cluster scaffold homologue down-regulation by miR-210 perturbing trophoblast iron metabolism is associated with defective placentation (PMID:21801864)
• The defective splicing caused by the ISCU intron mutation in patients with myopathy with lactic acidosis is repressed by PTBP1 but can be derepressed by IGF2BP1. (PMID:22125086)
• Photoreactive heterotrifunctional chemical cross-linking confirmed the interaction between frataxin and ISCU in the presence of iron and validated that transient interactions can be covalently trapped with this method. (PMID:22897349)
• this study unveiled a signaling axis of HIF-1alpha/miRNA-210/iron-sulfur cluster scaffold protein in a subset of head and neck paragangliomas that could have an impact on SDHB protein stability by a mechanism independent of succinate dehydrogenase mutations (PMID:22977270)
• ISCU protein deficiency in patients results from muscle-specific mis-splicing and oxidative stress. (PMID:23035118)
• MicroRNA-210 correlates negatively with its gene target ISCU at the protein and mRNA level. MicroRNA-210 correlated with positive outcome variables (PMID:23449350)
• mTORC1 associates with ISCU and phosphorylates ISCU at serine 14. This phosphorylation stabilized ISCU protein. (PMID:23508953)
• NFS1 binds preferentially to the D-state of ISCU while mtHSP70 binds preferentially to the D-state of ISCU and HSC20 binds preferentially to the S-state of ISCU. (PMID:23940031)
• the G50E iron-sulfur cluster scaffold protein (ISCU) mutation has a role in mitochondrial myopathy (PMID:24573684)
• Fe-S assembly protein (ISCU2) and frataxin convert substrates l-cysteine, ferrous iron, and electrons into Fe-S clusters. (PMID:24971490)
• IscU is a new substrate of MK2 both in Drosophila cells and in human cells (PMID:25204651)
• Thus, driven by acquired (hypoxia) or genetic causes, the miR-210-ISCU1/2 regulatory axis is a pathogenic lynchpin causing iron-sulfur deficiency and pulmonary hypertension. (PMID:25825391)
• The core Fe-S biosynthetic enzymatic complex generated [2Fe-2S] cluster intermediates that converted to stable [2Fe-2S] clusters bound to uncomplexed ISCU2. (PMID:26016389)
• ISCU expression was decreased in the majority of human liver cancer tissues, and its reduced expression was significantly associated with p53 mutation. (PMID:26560363)
• Molecular dynamics flexible fitting of protein structures docked into the EM map of the model revealed a [FXN(42-210)]24.[NFS1]24.[ISD11]24.[ISCU]24 complex, consistent with the measured 1:1:1:1 stoichiometry of its four components. (PMID:27519411)
• We have shown that ASO treatment diminished aberrant splicing and increased ISCU protein levels in both patient fibroblasts and patient myotubes in a concentration dependent fashion. Upon ASO treatment, levels of SDHB in patient myotubular cell lines increased to levels observed in control myotubular cell lines (PMID:28007899)
• The NFS1/ISD11 complex further interacts with scaffold protein ISCU and regulator protein frataxin, thereby forming a quaternary complex for Fe-S cluster formation. (PMID:28271877)
• we report the first heterozygous dominant mutation in ISCU; notably, this alteration resulted in a similar phenotype as the recessive ISCU disease previously described. (PMID:29079705)
• When ISCU was replaced by the fully structured variant ISCU(M108I), the addition of rdFDX2 to the [NIA-ISCU(M108I)-FXN]2 complex led to the release of FXN. Thus, the displacement of FXN by rdFDX2 explains the failure of FXN to stimulate Fe-S cluster assembly on ISCU(M108I). (PMID:29406711)
• identifies an important regulatory role for zinc-bound ISCU in modulation of the human Fe-S assembly system in vitro and reports no ‘FXN bypass’ effect on mutations at position Met140 in human ISCU (PMID:30031876)
• Study reports 3.2 A resolution cryo-electron microscopy structure of the FXN-bound active human iron-sulfur clusters biosynthesis complex. FXN binds at the interface of two NFS1 and one ISCU subunits, modifying the local environment of a bound zinc ion that would otherwise inhibit NFS1 activity in complexes without FXN. (PMID:31101807)
• rs2072580T>A Polymorphism in the Overlapping Promoter Regions of the SART3 and ISCU Genes Associated with the Risk of Breast Cancer. (PMID:32495170)
• Characterization and Reconstitution of Human Lipoyl Synthase (LIAS) Supports ISCA2 and ISCU as Primary Cluster Donors and an Ordered Mechanism of Cluster Assembly. (PMID:33562493)
• N-terminal tyrosine of ISCU2 triggers [2Fe-2S] cluster synthesis by ISCU2 dimerization. (PMID:34824239)
• Copper exerts cytotoxicity through inhibition of iron-sulfur cluster biogenesis on ISCA1/ISCA2/ISCU assembly proteins. (PMID:37225108)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	iscub	ENSDARG00000026582
danio_rerio	iscua	ENSDARG00000035596
mus_musculus	Iscu	ENSMUSG00000025825
rattus_norvegicus	Iscu	ENSRNOG00000000701
drosophila_melanogaster	IscU	FBGN0037637
caenorhabditis_elegans		WBGENE00012885

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1913633) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 1 distinct phenotype terms.

Mouse phenotype (MP)	Records
embryonic lethality between implantation and placentation, complete penetrance	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Escherichia coli K-12	P0ACD4	100.0%	Diamond
Escherichia coli CFT073	P0ACD5	100.0%	Diamond
Escherichia coli O157:H7	P0ACD6	100.0%	Diamond
Shigella flexneri	P0ACD7	100.0%	Diamond
Archaeoglobus fulgidus DSM 4304	P0DMG1	100.0%	Diamond
Nostoc sp. PCC 7120 = FACHB-418	P20628	98.3%	Diamond
Trichormus azollae	Q43885	98.3%	Diamond
Buchnera aphidicola str. Sg (Schizaphis graminum)	O51885	92.0%	Diamond
Buchnera aphidicola str. APS (Acyrthosiphon pisum)	P57658	92.0%	Diamond
Saccharomyces cerevisiae S288C	Q03020	89.8%	Diamond
Nakaseomyces glabratus CBS 138	Q6FJY3	89.8%	Diamond
Kluyveromyces lactis NRRL Y-1140	Q6CRQ9	88.6%	Diamond
Eremothecium gossypii ATCC 10895	Q75C07	88.6%	Diamond
Buchnera aphidicola str. Bp (Baizongia pistaciae)	Q89A18	87.1%	Diamond
Haemophilus influenzae Rd KW20	Q57074	86.4%	Diamond
Debaryomyces hansenii CBS767	Q6BGU0	81.9%	Diamond
Oryza sativa Japonica Group	Q8LR34	81.5%	Diamond
Azotobacter vinelandii	O31270	81.0%	Diamond
Rickettsia prowazekii str. Madrid E	Q9ZD61	80.3%	Diamond
Trachipleistophora hominis	B0YLW7	78.9%	Diamond
Encephalitozoon cuniculi GB-M1	Q8SSM2	78.9%	Diamond
Azotobacter chroococcum (strain mcd 1)	P23121	78.0%	Diamond
Arabidopsis thaliana	O49627	77.8%	Diamond
Yarrowia lipolytica CLIB122	Q6CFQ0	77.5%	Diamond
Schizosaccharomyces pombe 972h-	Q9UTC6	74.6%	Diamond
Plasmodium falciparum 3D7	Q8IKT4	63.5%	Diamond
Klebsiella pneumoniae	P05343	55.9%	Diamond
Aquifex aeolicus VF5	O67045	55.6%	Diamond
Azospirillum brasilense	Q43909	54.4%	Diamond
Streptococcus pyogenes serotype M1	Q9A1G2	50.7%	Diamond
Bacillus subtilis subsp. subtilis str. 168	O32163	50.0%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
MIR4496	ncRNA	100616240
CORO1C	protein-coding	23603
TMEM119	protein-coding	338773
SELPLG	protein-coding	6404
LINC01498	ncRNA	102723562
CMKLR1	protein-coding	1240
SART3	protein-coding	9733
FICD	protein-coding	11153

Protein

Protein identifiers

Iron-sulfur cluster assembly enzyme ISCU — Q9H1K1 (reviewed: Q9H1K1)

Alternative names: NifU-like N-terminal domain-containing protein, NifU-like protein

All UniProt accessions (5): B3KQ30, B4DNC9, Q9H1K1, F5H5N2, F5H672

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial scaffold protein, of the core iron-sulfur cluster (ISC) assembly complex, that provides the structural architecture on which the [2Fe-2S] clusters are assembled. The core iron-sulfur cluster (ISC) assembly complex is involved in the de novo synthesis of a [2Fe-2S] cluster, the first step of the mitochondrial iron-sulfur protein biogenesis. This process is initiated by the cysteine desulfurase complex (NFS1:LYRM4:NDUFAB1) that produces persulfide which is delivered on the scaffold protein ISCU in a FXN-dependent manner. Then this complex is stabilized by FDX2 which provides reducing equivalents to accomplish the [2Fe-2S] cluster assembly. Finally, the [2Fe-2S] cluster is transferred from ISCU to chaperone proteins, including HSCB, HSPA9 and GLRX5. Exists as two slow interchanging conformational states, a structured (S) and disordered (D) form. May modulate NFS1 desulfurase activity in a zinc-dependent manner. Modulates the interaction between FXN and the cysteine desulfurase complex. Cytoplasmic scaffold protein, of the cytoplasmic core iron-sulfur cluster (ISC) assembly complex that provides the structural architecture on which the Fe-S clusters are assembled and may be involved in the cytoplasmic iron-sulfur protein biogenesis.

Subunit / interactions. Homodimer; Tyr-35-mediated dimerization of two iron- and sulfide-containing ISCU subunit bind to the cysteine desulfurase complex. Component of the mitochondrial core iron-sulfur cluster (ISC) complex composed of NFS1, LYRM4, NDUFAB1, ISCU, FXN, and FDX2; this complex is an heterohexamer containing two copies of each monomer. Interacts (D-state) with NFS1 (homodimer form); each monomer interacts with the C-terminal regions of each NFS1 monomer. Interacts (monomer form) with FXN (via ferrous form); the interaction is possible when both are bound to the dimeric form of the cysteine desulfurase complex (NFS1:LYRM4) and enhances FXN interaction to the dimeric form of the cysteine desulfurase complex (NFS1:LYRM4). Interacts with GLRX5. Interacts (D-state) with HSPA9. Interacts (S-state) with HSCB; this interaction stimulates the ATPase activity of HSPA9. Component of the cytoplasmic core iron-sulfur cluster (ISC) complex composed at least of NFS1, LYRM4, and ISCU; this complex interacts with FXN. Monomer; each monomer binds to the C-terminal regions of NFS1 (cytoplasmic and homodimer form). Interacts with NFS1 (cytoplasmic and homodimer form); this interaction promotes de novo iron-sulfur cluster formation. Interacts with HSCB (cytoplasmic form); this interaction stabilizes the (Fe-S) clusters on ISCU.

Subcellular location. Mitochondrion Cytoplasm. Nucleus.

Tissue specificity. Detected in heart, liver, skeletal muscle, brain, pancreas, kidney, lung and placenta.

Post-translational modifications. Phosphorylation at Ser-14 is required for ISCU protein stabilization in the cytosol, whereas dephosphorylation of Ser-14, due to the inhibition of mTORC1 (mammalian target of rapamycin complex 1) complex, leads to degradation of the precursor form and ultimately to a decrease in the mitochondrial mature form. Cysteine persulfide is reduced by thiol-containing molecules such as glutathione and L-cysteine.

Disease relevance. Myopathy with exercise intolerance Swedish type (MEIS) [MIM:255125] Autosomal recessive metabolic disease characterized by lifelong severe exercise intolerance, in which minor exertion causes fatigue of active muscles, shortness of breath, and cardiac palpitations in association with lactic acidosis. The biochemical phenotype is characterized by a deficiency in mitochondrial iron-sulfur proteins and impaired muscle oxidative metabolism. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the NifU family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H1K1-1	1, ISCU2	yes
Q9H1K1-2	2, ISCU1

RefSeq proteins (5): NP_001288069, NP_001288070, NP_001306971, NP_055116, NP_998760* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002871	NIF_FeS_clus_asmbl_NifU_N	Domain
IPR011339	ISCU	Family

Pfam: PF01592

UniProt features (45 total): mutagenesis site 16, helix 7, binding site 6, strand 5, modified residue 3, active site 2, transit peptide 1, chain 1, splice variant 1, sequence variant 1, sequence conflict 1, site 1

Structure

Experimental structures (PDB)

18 structures by resolution:

PDB	Title	Method	Resolution (Å)
6UXE	Structure of the human mitochondrial desulfurase complex Nfs1-ISCU2(M140I)-ISD11 with …	X-RAY DIFFRACTION	1.57
6W1D	Structure of human mitochondrial complex Nfs1-ISCU2 (WT)-ISD11 with E.coli ACP1 at 1.8 A …	X-RAY DIFFRACTION	1.79
6WIH	N-terminal mutation of ISCU2 (L35H36) traps Nfs1 Cys loop in the active site of ISCU2 …	X-RAY DIFFRACTION	1.9
6WI2	Structure of human mitochondrial complex Nfs1-ISCU2-ISD11 with E.coli ACP1 at 1.95 A …	X-RAY DIFFRACTION	1.95
8TVT	Structure of human Cysteine desulfurase Nfs1 with L-propargylglycine bound to active site …	X-RAY DIFFRACTION	2
8RMC	Structure of the FDX2-bound core ISC complex (proximal conformation)	ELECTRON MICROSCOPY	2.26
8RMF	Structure of the core ISC complex under turnover conditions (FDX2-bound in proximal …	ELECTRON MICROSCOPY	2.33
8RMG	Structure of the core ISC complex under turnover conditions (FDX2-bound in distal …	ELECTRON MICROSCOPY	2.46
8PK8	Structure of the human mitochondrial iron-sulfur cluster biosynthesis complex during …	ELECTRON MICROSCOPY	2.49
8RME	Structure of the core ISC complex under turnover conditions (frataxin-bound)	ELECTRON MICROSCOPY	2.49
7RTK	Structure of the (NIAU)2 complex with N-terminal mutation of ISCU2 Y35D at 2.5 A …	X-RAY DIFFRACTION	2.5
8RMD	Structure of the FDX2-bound core ISC complex (distal conformation)	ELECTRON MICROSCOPY	2.52
8PK9	Structure of the human mitochondrial iron-sulfur cluster biosynthesis complex during …	ELECTRON MICROSCOPY	2.58
8PKA	Structure of the human mitochondrial iron-sulfur cluster biosynthesis complex during …	ELECTRON MICROSCOPY	2.75
5WKP	Crystal Structure of the Human mitochondrial Cysteine Desulfurase in complex with ISD11 …	X-RAY DIFFRACTION	3.15
6NZU	Structure of the human frataxin-bound iron-sulfur cluster assembly complex	ELECTRON MICROSCOPY	3.2
5WLW	Crystal Structure of the Human Mitochondrial Cysteine Desulfurase with active Cysteine …	X-RAY DIFFRACTION	3.32
5KZ5	Architecture of the Human Mitochondrial Iron-Sulfur Cluster Assembly Machinery: the …	ELECTRON MICROSCOPY	14.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H1K1-F1	85.17	0.70

Human Protein Atlas

Protein class: Predicted intracellular proteins, Disease related genes, Human disease related genes, Congenital disorders of metabolism, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; mitochondria

Antibody reliability (HPA): IH approved · IF supported

Functional residue map

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

Catalytic / active sites (3)

Position	Role
69	cysteine persulfide intermediate
138	cysteine persulfide intermediate
35	mediates iscu dimerization and de novo [2fe-2s] cluster assembly

Ligand- & substrate-binding residues (6)

Position	Role
71	Zn(2+)
46	Zn(2+)
70	Zn(2+)
112	Zn(2+)
95	Zn(2+)
138	Zn(2+)

Post-translational modifications (3)

Type	Positions
Cysteine persulfide	138, 69
Phosphoserine	14

Mutagenesis-validated functional residues (16)

Position	Phenotype
14	loss of phosphorylation. does not affect phosphorylation.
35	does not affect mitochondrial localization. loss of iron-sulfur cluster biogenesis. does not affect reductive cleavage of the …
69	does not affect isc complex formation. does not affect the unstimulated cysteine desulfurase activity in the absence of fxn. does not …
69	does not affect the cysteine desulfurase activity in the presence of fxn. does not affect iron based stimulation of the cysteine …
71	stabilizes the d-state.
71	stabilizes the s-state.
95	does not affect isc complex formation. does not affect the unstimulated cysteine desulfurase activity in the absence of fxn. does not …
95	slightly decrease the cysteine desulfurase activity in the presence of fxn. does not affect iron based stimulation of the cysteine …
122	stabilizes the s-state.
130	does not affect the unstimulated cysteine desulfurase activity in the absence of fxn. does not affect the cysteine desulfurase activity in …
137	stabilizes the d-state.
138	does not affect isc complex formation. does not affect the unstimulated cysteine desulfurase activity in the absence of fxn. loss of …
138	loss of iron-based stimulation of the cysteine desulfurase activity in the presence of fxn.
140	does not affect the sda complex formation. abolishes desulfurase activity of sda complex when zinc ion is bound. activated by fxn when …

Function

Pathways and Gene Ontology

Reactome pathways

4 curated (TAS) of 11; 8 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

11 pathways:

ID	Pathway	Evidence
R-HSA-9694301	Maturation of replicase proteins ⚕	curated
R-HSA-9865881	Complex III assembly	curated
R-HSA-9854311	Maturation of TCA enzymes and regulation of TCA cycle	curated
R-HSA-1362409	Mitochondrial iron-sulfur cluster biogenesis	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-9772572	Early SARS-CoV-2 Infection Events ⚕	—
R-HSA-5663205	Infectious disease ⚕	—
R-HSA-9679506	SARS-CoV Infections ⚕	—
R-HSA-9694516	SARS-CoV-2 Infection ⚕	—
R-HSA-9694676	Translation of Replicase and Assembly of the Replication Transcription Complex ⚕	—
R-HSA-9824446	Viral Infection Pathways ⚕	—

MSigDB gene sets: 307 (showing top): GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, PAX4_01, MORF_RAB5A, GOBP_TRANSITION_METAL_ION_TRANSPORT, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, TGACCTY_ERR1_Q2, GOBP_IRON_ION_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, LINDGREN_BLADDER_CANCER_CLUSTER_2A_DN, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT, CEBALLOS_TARGETS_OF_TP53_AND_MYC_DN, YY1_02, GOBP_OXIDATIVE_PHOSPHORYLATION, TGCTGAY_UNKNOWN

GO Biological Process (6): intracellular iron ion homeostasis (GO:0006879), iron-sulfur cluster assembly (GO:0016226), [2Fe-2S] cluster assembly (GO:0044571), [4Fe-4S] cluster assembly (GO:0044572), positive regulation of mitochondrial electron transport, NADH to ubiquinone (GO:1902958), negative regulation of iron ion import across plasma membrane (GO:1904439)

GO Molecular Function (10): iron ion binding (GO:0005506), ferrous iron binding (GO:0008198), zinc ion binding (GO:0008270), protein homodimerization activity (GO:0042803), 2 iron, 2 sulfur cluster binding (GO:0051537), molecular adaptor activity (GO:0060090), iron-sulfur cluster chaperone activity (GO:0140132), protein binding (GO:0005515), metal ion binding (GO:0046872), iron-sulfur cluster binding (GO:0051536)

GO Cellular Component (6): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), mitochondrial [2Fe-2S] assembly complex (GO:0099128)

Reactome top-level categories

10 top-level categories:

Category	Pathways
Translation of Replicase and Assembly of the Replication Transcription Complex	1
Metabolism	1
Citric acid cycle (TCA cycle)	1
Respiratory electron transport	1
Disease	1
Viral Infection Pathways	1
SARS-CoV Infections	1
Early SARS-CoV-2 Infection Events	1
SARS-CoV-2 Infection	1
Infectious disease	1

GO top-level categories

29 GO namespaces:

Category	Terms
iron-sulfur cluster assembly	2
transition metal ion binding	2
iron-sulfur cluster binding	2
binding	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
cytoplasm	2
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
metallo-sulfur cluster assembly	1
mitochondrial electron transport, NADH to ubiquinone	1
positive regulation of cellular respiration	1
regulation of mitochondrial electron transport, NADH to ubiquinone	1
negative regulation of iron ion transmembrane transport	1
iron ion import across plasma membrane	1
regulation of iron ion import across plasma membrane	1
iron ion binding	1
identical protein binding	1
protein dimerization activity	1
molecular_function	1
metallochaperone activity	1
cation binding	1
metal cluster binding	1
intracellular anatomical structure	1
mitochondrion	1
intracellular organelle lumen	1
mitochondrial protein-containing complex	1
L-cysteine desulfurase complex	1
iron-sulfur cluster assembly complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 15 of 22 annotations. The rest are phylogenetic / computational / electronic (IEA).

15 experimentally-supported GO terms:

GO term	NS	Evidence
[2Fe-2S] cluster assembly	BP	direct assay
[4Fe-4S] cluster assembly	BP	direct assay
intracellular iron ion homeostasis	BP	direct assay
iron-sulfur cluster assembly	BP	mutant phenotype
negative regulation of iron ion import across plasma membrane	BP	mutant phenotype
positive regulation of mitochondrial electron transport, NADH to ubiquinone	BP	mutant phenotype
cytoplasm	CC	direct assay
cytosol	CC	direct assay
mitochondrial [2Fe-2S] assembly complex	CC	direct assay
mitochondrion	CC	direct assay
ferrous iron binding	MF	direct assay
iron-sulfur cluster chaperone activity	MF	direct assay
molecular adaptor activity	MF	direct assay
protein homodimerization activity	MF	direct assay
zinc ion binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,924 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ISCU	NFS1	Q9Y697	980
ISCU	ACO1	P21399	966
ISCU	NFU1	Q9UMS0	959
ISCU	LYRM4	Q9HD34	953
ISCU	FXN	Q16595	942
ISCU	ACO2	Q99798	904
ISCU	HSPA9	P30036	844
ISCU	ISCA1	Q9BUE6	826
ISCU	ISCA2	Q86U28	812
ISCU	FDX1	P10109	804
ISCU	IBA57	Q5T440	801
ISCU	FDX2	Q6P4F2	791
ISCU	HSCB	Q8IWL3	790
ISCU	FECH	P22830	790
ISCU	IREB2	P48200	754

IntAct

Human interaction partners of ISCU in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

22 partners by confidence:

Partner	Interaction type	MIscore	Records
NUP62	physical association	0.720	6
HPRT1	physical association	0.670	4
SDHB	physical association	0.660	1
SFN	physical association	0.590	2
NECAB2	physical association	0.560	4
AGTRAP	physical association	0.560	3
BANP	physical association	0.560	3
CBY2	physical association	0.560	3
CCDC172	physical association	0.560	3
FAM9B	physical association	0.560	3
GOLGA2	physical association	0.560	3
GOLGA6L9	physical association	0.560	3
IKZF1	physical association	0.560	3
KRT34	physical association	0.560	3
KRT40	physical association	0.560	3
LNX1	physical association	0.560	3
MID2	physical association	0.560	3
PICK1	physical association	0.560	3
YWHAE	physical association	0.560	2
HSPA9	association	0.500	1
E7	physical association	0.370	1
YWHAB	physical association	0.000	1

BioGRID (65 interactions; top human partners by supporting records): HSCB (Reconstituted Complex; 4 records), LONRF1 (Affinity Capture-MS; 2 records), LYRM4 (Affinity Capture-MS; 2 records), NECAB2 (Two-hybrid; 2 records), NFS1 (Reconstituted Complex; 2 records), NUP62 (Two-hybrid; 2 records), TMEM184A (Affinity Capture-MS; 2 records), YWHAH (Affinity Capture-MS; 2 records), AGTRAP (Two-hybrid), BANP (Two-hybrid), CCDC136 (Two-hybrid), CCDC172 (Two-hybrid), CLIC1 (Affinity Capture-MS), CS (Proximity Label-MS), CUL3 (Affinity Capture-MS)

SIGNOR signaling

3 signaling interactions:

A	Effect	B	Mechanism
MTOR	up-regulates	ISCU	phosphorylation
mTORC1	up-regulates	ISCU	phosphorylation
ISCU	“form complex”	“Mitochondrial Fe-S Cluster Assembly Complex”	binding

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
FXN42-ISD11-ISCU-NFS1 complex	4	LYRM4, NFS1, FXN, ISCU

Disease & clinical

Genetic variants

Variant evidence for ISCU: 205 ClinVar records (2 pathogenic / likely pathogenic); 2 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	65
Likely benign	95
Benign	34

Top pathogenic / likely-pathogenic (2)

Showing all 2 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
223141	NM_213595.4(ISCU):c.418+382G>C	Pathogenic	criteria provided, multiple submitters, no conflicts	5
783	NM_213595.4(ISCU):c.149G>A (p.Gly50Glu)	Likely pathogenic	criteria provided, single submitter	3

Per-variant reference — Sugi Variant

Explore ISCU’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 34 predictions of 431):

Position(s)	Effect	Δscore	Sites
12:108562737–108562738	donor_loss	1.0000	5
12:108564277–108564278	acceptor_loss	1.0000	5
12:108564393–108564394	donor_loss	1.0000	4
12:108565425	donor_gain	1.0000
12:108567180	acceptor_gain	1.0000
12:108567188–108567189	acceptor_loss	1.0000	5
12:108567269–108567270	donor_loss	1.0000	5
12:108564278	acceptor_loss	0.9900
12:108564393	donor_loss	0.9900
12:108565432–108565433	donor_loss	0.9900	6

AlphaMissense

620 missense substitutions predicted likely pathogenic (of 1,064 scored), across 118 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M73	9	0.947	0.999
D71	8	0.998	0.999
H137	8	0.993	0.999
F90	8	0.989	1.000
H42	8	0.982	0.997
N122	8	0.982	0.996
D144	8	0.970	0.994
F93	8	0.969	1.000
S102	8	0.963	1.000
N48	8	0.960	0.996
D152	8	0.939	0.989
H36	8	0.860	0.936
C138	7	0.999	1.000
C95	7	0.998	1.000
C69	7	0.997	0.999
K135	7	0.984	0.999
E143	7	0.971	0.995
Q76	7	0.962	0.999
I99	7	0.957	1.000
K91	7	0.938	0.999

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.00017

Disease associations

OMIM: gene MIM:611911 | disease phenotypes: MIM:255125

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
hereditary myopathy with lactic acidosis due to ISCU deficiency	Strong	Autosomal recessive	4

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (11 panels, 11 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

11 panels:

Panel	Rating
Acute rhabdomyolysis	green
Hypotonic infant	green
Leukodystrophy, childhood onset	green
Likely inborn error of metabolism	green
Mitochondrial disorders	green
Other rare neuromuscular disorders	green
Paediatric disorders	green
Possible mitochondrial disorder, nuclear genes	green
Rhabdomyolysis and metabolic muscle disorders	green
Undiagnosed metabolic disorders	green
Unexplained death in infancy and sudden unexplained death in childhood	green

Mondo (1): hereditary myopathy with lactic acidosis due to ISCU deficiency (MONDO:0009706)

Orphanet (1): Hereditary myopathy with lactic acidosis due to ISCU deficiency (Orphanet:43115)

HPO phenotypes

35 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000597	Ophthalmoparesis
HP:0001252	Hypotonia
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001324	Muscle weakness
HP:0001488	Bilateral ptosis
HP:0001882	Decreased total leukocyte count
HP:0001903	Anemia
HP:0001924	Sideroblastic anemia
HP:0001962	Palpitations
HP:0002094	Dyspnea
HP:0002151	Increased circulating lactate concentration
HP:0002359	Frequent falls
HP:0002460	Distal muscle weakness
HP:0002913	Myoglobinuria
HP:0003128	Lactic acidosis
HP:0003198	Myopathy
HP:0003201	Rhabdomyolysis
HP:0003202	Skeletal muscle atrophy
HP:0003236	Elevated circulating creatine kinase activity
HP:0003388	Easy fatigability
HP:0003394	Muscle spasm
HP:0003546	Exercise intolerance
HP:0003548	Subsarcolemmal accumulations of abnormally shaped mitochondria
HP:0003557	Increased variability in muscle fiber diameter
HP:0003621	Juvenile onset
HP:0003737	Mitochondrial myopathy
HP:0008306	Abnormal iron deposition in mitochondria
HP:0008314	Decreased activity of mitochondrial complex II
HP:0008347	Decreased activity of mitochondrial complex IV
HP:0011463	Childhood onset
HP:0011923	Decreased activity of mitochondrial complex I
HP:0011924	Decreased activity of mitochondrial complex III
HP:0012240	Increased intramyocellular lipid droplets

GWAS associations

2 associations:

Study	Trait	p-value
GCST005580_20	Intraocular pressure	5e-11
GCST002481_2	Acne (severe)	5e-6

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0004695	intraocular pressure measurement

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
C564972	Myopathy with Lactic Acidosis, Hereditary *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	affects expression, increases expression, increases methylation	5
sodium arsenite	affects cotreatment, increases abundance, increases expression	3
Acetaminophen	affects cotreatment, decreases expression, increases expression	3
Cisplatin	affects cotreatment, increases expression	3
bisphenol A	affects expression, affects cotreatment, increases expression	2
perfluorooctane sulfonic acid	increases expression	2
Benzo(a)pyrene	increases expression	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
chloroacetaldehyde	decreases expression	1
triphenyl phosphate	affects expression	1
methylparaben	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	increases expression	1
perfluorooctanoic acid	increases expression	1
K 7174	increases expression	1
perfluorohexanesulfonic acid	decreases expression	1
nutlin 3	affects cotreatment, increases expression	1
ICG 001	increases expression	1
jinfukang	affects cotreatment, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Temozolomide	decreases expression	1
Cidofovir	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Atrazine	decreases expression	1
Carbamazepine	affects expression	1
Dactinomycin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Diazinon	increases methylation	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

47 trials:

NCT	Phase	Status	Title
NCT00120055	Phase 4	COMPLETED	Association Between Systemic Exposure of Atorvastatin and Metabolites and Atorvastatin-induced Myotoxicity
NCT03633565	Phase 4	UNKNOWN	Comparative Study of Strategies for Management of Duchenne Myopathy (DM)
NCT01225614	Phase 3	UNKNOWN	Efficacy and Tolerance of Early Launching of Nocturnal Non Invasive
NCT00278564	Phase 1	TERMINATED	Stem Cell Transplantation in Idiopathic Inflammatory Myopathy Diseases
NCT01642056	Phase 1/2	COMPLETED	EPI-743 for Metabolism or Mitochondrial Disorders
NCT02124070	Phase 1/2	WITHDRAWN	Therapeutic Effect of Recombinant Human Growth Hormone (rhGH) on the Myopathy of Cystinosis
NCT00549029	Not specified	UNKNOWN	The Association of Genetic Polymorphisms With Statin-Induced Myopathy.
NCT00767130	Not specified	UNKNOWN	DNA Diagnostic System for Statin Safety and Efficacy
NCT00922428	Not specified	COMPLETED	PASCOE-Agil HOM-Injektopas in the Treatment of Rheumatic Disorders
NCT00937001	Not specified	ACTIVE_NOT_RECRUITING	Critical Illness Myopathy as a Cause of Debilitating ICU-Acquired Weakness
NCT00990834	Not specified	WITHDRAWN	Muscle Characteristics Associated With Statin Therapy
NCT01022450	Not specified	UNKNOWN	Study of the Causes of the Breakdown of Muscle Fibers in Hospitalized Patients
NCT01040650	Not specified	TERMINATED	Metabolic Features of Post-Myopathy Patients Associated With Statin Treatment
NCT01047163	Not specified	COMPLETED	Maintenance of Muscle Mass in Older People: the Negative Impact of Statin Therapy
NCT01270269	Not specified	COMPLETED	ACT-ICU Study: Activity and Cognitive Therapy in the Intensive Care Unit
NCT01353430	Not specified	RECRUITING	Characterization of Inclusion Body Myopathy Associated With Paget’s Disease of Bone and Frontotemporal Dementia (IBMPFD)
NCT01395563	Not specified	WITHDRAWN	Strength Training on Pancreatic Cancer
NCT01530841	Not specified	COMPLETED	Efficacy and Tolerance of AVAPS Mode in Myotonic Dystrophy
NCT01547767	Not specified	COMPLETED	Investigations Into ISCU Myopathy or Iron Sulfur Scaffold U Protein Myopathy
NCT01702987	Not specified	COMPLETED	Evaluation of Ubiquinol on Mitochondrial Oxidative Capacity in Statin Patients Using 31PMRS
NCT01790178	Not specified	COMPLETED	Ultrasound in Muscle Biopsy
NCT02011282	Not specified	COMPLETED	Electro-Neuro-Muscular Stimulation in ICU
NCT02104921	Not specified	COMPLETED	Innovative Ultrasound Technology in Neuromuscular Disease
NCT02118805	Not specified	COMPLETED	Innovative Measures of Speech and Swallowing Dysfunction in Neurological Disorders
NCT02235220	Not specified	UNKNOWN	Reduction of Masticatory Muscle Activity by Restoring Canine Guidance
NCT02247895	Not specified	TERMINATED	Treatment of Muscle Weakness in Critically Ill Patients
NCT02315339	Not specified	TERMINATED	European Home Mechanical Ventilation Registry
NCT02442986	Not specified	COMPLETED	Neurological Outcome in Surgical and Non-surgical Septic Patients
NCT02706314	Not specified	COMPLETED	Impact of Human Blood Serum From Critically Ill Patients on Human Colon Neuronal Networks.
NCT02765828	Not specified	COMPLETED	Identification of Tongue Involvement in Late-Onset Pompe Disease
NCT03042286	Not specified	UNKNOWN	SAPhIRE Statin Adverse Drug Reaction
NCT03141749	Not specified	COMPLETED	Venous Thromboembolism in DM1
NCT03660969	Not specified	ACTIVE_NOT_RECRUITING	Reliability of Cardiac Troponins for the Diagnosis of Myocardial Infarction in the Presence of Skeletal Muscle Disease
NCT03749538	Not specified	RECRUITING	Acute Transcranial Direct Current Stimulation in Patients With Systemic Autoimmune Myopathies
NCT03751644	Not specified	COMPLETED	Peripherical Neuromuscular Electrical Stimulation in Systemic Autoimmune Myopathies
NCT03998540	Not specified	UNKNOWN	Improvement of DIAgnostic and Phenotype-genotype Correlation Studies in Patients With MYOpathy Suspected of TITinopathy
NCT04678635	Not specified	RECRUITING	Chronic Transcranial Direct Current Stimulation in Patients With Systemic Autoimmune Myopathies
NCT04881214	Not specified	UNKNOWN	COVID-19 Pneumonia: Pulmonary Physiology, Health-related Quality of Life and Benefit of a Rehabilitation Program
NCT04941079	Not specified	UNKNOWN	Safety and Efficacy of Inactivated SARS-CoV-2 Vaccine in Immune-related Myopathy (Myasthenia Gravis and Inflammatory Myopathy) Patients ：a Prospective Observational Study
NCT05599568	Not specified	COMPLETED	Repeated Bout Effect i Neuromuscular Diseases
NCT05692349	Not specified	UNKNOWN	Magnetic Resonance Imaging and Ultrasonography in Evaluation of Muscle Diseases
NCT06374719	Not specified	RECRUITING	WiTNNess - TNNT1 Myopathy Natural History Study
NCT06666816	Not specified	RECRUITING	Observational Study to Observe Variations of Gait Parameters in Patients With Neuromuscular Diseases
NCT06837467	Not specified	COMPLETED	Differential SERCA Expression in Laryngeal Muscles
NCT07488806	Not specified	RECRUITING	Natural History Study for Patients With Nemaline Myopathy in Spain
NCT07502989	Not specified	RECRUITING	Muscle Health Measurements Using Electrical Impedance Myography
NCT07823101	Not specified	RECRUITING	Imaging Assessment of Swallowing and Speech Muscles in Inclusion Body Myositis