ISCU iron-sulfur cluster assembly enzyme [Homo sapiens (human)] - Gene

Summary

Official Symbol: ISCUprovided by HGNC
Official Full Name: iron-sulfur cluster assembly enzymeprovided by HGNC
Primary source: HGNC:HGNC:29882
See related: Ensembl:ENSG00000136003 MIM:611911; AllianceGenome:HGNC:29882
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: HML; ISU2; NIFU; NIFUN; hnifU; 2310020H20Rik
Summary: 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. [provided by RefSeq, Feb 2016]
Expression: Ubiquitous expression in adrenal (RPKM 47.9), heart (RPKM 43.2) and 25 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 12q23.3

Exon count:: 8

Annotation release	Status	Assembly	Chr	Location
RS_2024_08	current	GRCh38.p14 (GCF_000001405.40)	12	NC_000012.12 (108561463..108569384)
RS_2024_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	12	NC_060936.1 (108530831..108538753)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	12	NC_000012.11 (108955239..108963160)

Chromosome 12 - NC_000012.12 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Copper exerts cytotoxicity through inhibition of iron-sulfur cluster biogenesis on ISCA1/ISCA2/ISCU assembly proteins.
Title: Copper exerts cytotoxicity through inhibition of iron-sulfur cluster biogenesis on ISCA1/ISCA2/ISCU assembly proteins.
N-terminal tyrosine of ISCU2 triggers [2Fe-2S] cluster synthesis by ISCU2 dimerization.
Title: N-terminal tyrosine of ISCU2 triggers [2Fe-2S] cluster synthesis by ISCU2 dimerization.
Characterization and Reconstitution of Human Lipoyl Synthase (LIAS) Supports ISCA2 and ISCU as Primary Cluster Donors and an Ordered Mechanism of Cluster Assembly.
Title: Characterization and Reconstitution of Human Lipoyl Synthase (LIAS) Supports ISCA2 and ISCU as Primary Cluster Donors and an Ordered Mechanism of Cluster Assembly.
rs2072580T>A Polymorphism in the Overlapping Promoter Regions of the SART3 and ISCU Genes Associated with the Risk of Breast Cancer.
Title: rs2072580T>A Polymorphism in the Overlapping Promoter Regions of the SART3 and ISCU Genes Associated with the Risk of Breast Cancer.
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.
Title: Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism.
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
Title: Zinc(II) binding on human wild-type ISCU and Met140 variants modulates NFS1 desulfurase activity.
we report the first heterozygous dominant mutation in ISCU; notably, this alteration resulted in a similar phenotype as the recessive ISCU disease previously described.
Title: A novel de novo dominant mutation in ISCU associated with mitochondrial myopathy.
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).
Title: ISCU(M108I) and ISCU(D39V) Differ from Wild-Type ISCU in Their Failure To Form Cysteine Desulfurase Complexes Containing Both Frataxin and Ferredoxin.
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
Title: Use of antisense oligonucleotides to correct the splicing error in ISCU myopathy patient cell lines.
The NFS1/ISD11 complex further interacts with scaffold protein ISCU and regulator protein frataxin, thereby forming a quaternary complex for Fe-S cluster formation.
Title: The N-Terminus of Iron-Sulfur Cluster Assembly Factor ISD11 Is Crucial for Subcellular Targeting and Interaction with l-Cysteine Desulfurase NFS1.

Submit: New GeneRIF Correction See all GeneRIFs (38)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Hereditary myopathy with lactic acidosis due to ISCU deficiency MedGen: C1850718 OMIM: 255125 GeneReviews: Not available	not available

EBI GWAS Catalog

Description
Genome-wide association study identifies three novel susceptibility loci for severe Acne vulgaris. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

RH25375 (e-PCR)
- UniSTS:89125

G20365 (e-PCR)
- UniSTS:63822

A005N44 (e-PCR)
- UniSTS:63823

D12S1907 (e-PCR)
- UniSTS:67736

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables 2 iron, 2 sulfur cluster binding	IBA Inferred from Biological aspect of Ancestor more info
enables ferrous iron binding	IBA Inferred from Biological aspect of Ancestor more info
enables iron ion binding	TAS Traceable Author Statement more info	PubMed
enables molecular adaptor activity	IDA Inferred from Direct Assay more info	PubMed
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein homodimerization activity	IDA Inferred from Direct Assay more info	PubMed
enables zinc ion binding	IDA Inferred from Direct Assay more info	PubMed

Process	Evidence Code	Pubs
involved_in [2Fe-2S] cluster assembly	IDA Inferred from Direct Assay more info	PubMed
acts_upstream_of [4Fe-4S] cluster assembly	IDA Inferred from Direct Assay more info	PubMed
acts_upstream_of_positive_effect [4Fe-4S] cluster assembly	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in intracellular iron ion homeostasis	IBA Inferred from Biological aspect of Ancestor more info
involved_in intracellular iron ion homeostasis	IDA Inferred from Direct Assay more info	PubMed
involved_in iron-sulfur cluster assembly	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in iron-sulfur cluster assembly	NAS Non-traceable Author Statement more info	PubMed
involved_in iron-sulfur cluster assembly	TAS Traceable Author Statement more info	PubMed
involved_in negative regulation of iron ion import across plasma membrane	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of aconitate hydratase activity	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of mitochondrial electron transport, NADH to ubiquinone	IMP Inferred from Mutant Phenotype more info	PubMed

Component	Evidence Code	Pubs
is_active_in cytoplasm	IBA Inferred from Biological aspect of Ancestor more info
located_in cytoplasm	IDA Inferred from Direct Assay more info	PubMed
located_in cytosol	IDA Inferred from Direct Assay more info	PubMed
located_in cytosol	TAS Traceable Author Statement more info
part_of iron-sulfur cluster assembly complex	NAS Non-traceable Author Statement more info	PubMed
part_of mitochondrial [2Fe-2S] assembly complex	IDA Inferred from Direct Assay more info	PubMed
is_active_in mitochondrial matrix	IBA Inferred from Biological aspect of Ancestor more info
located_in mitochondrial matrix	TAS Traceable Author Statement more info
located_in mitochondrion	HTP more info	PubMed
located_in mitochondrion	IDA Inferred from Direct Assay more info	PubMed
located_in mitochondrion	NAS Non-traceable Author Statement more info	PubMed
located_in nucleus	TAS Traceable Author Statement more info	PubMed

General protein information

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Preferred Names: iron-sulfur cluster assembly enzyme ISCU

Names: IscU iron-sulfur cluster scaffold homolog; iron-sulfur cluster assembly enzyme ISCU, mitochondrial; nifU-like N-terminal domain-containing protein

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_011857.1 RefSeqGene

Range

5079..11851

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_001301140.1 → NP_001288069.1 iron-sulfur cluster assembly enzyme ISCU isoform 3 precursor

See identical proteins and their annotated locations for NP_001288069.1

Status: REVIEWED

Description

Transcript Variant: This variant (3) contains an alternate exon in the 3' region, resulting in a different 3' coding region and 3' UTR, compared to variant 2. Variants 3 and 5 encode the same protein (isoform 3), which has a distinct, shorter C-terminus, compared to isoform 2. Isoform 3 may not be stable (PMID:23035118). This variant may be preferentially produced in individuals containing an alternate intronic C vs G (rs767000507), which activates a cryptic splice acceptor site. The alternate C allele is associated with myopathy (PMIDs 18296749, 18304497).

Source sequence(s)

AK057251, BG702203, BQ020993

Consensus CDS

CCDS76597.1

UniProtKB/TrEMBL

B4DNC9, F5H5N2

Related

ENSP00000446606.1, ENST00000547005.5

Conserved Domains (1) summary

cl00528
Location:35 → 139

IscU_like; Iron-sulfur cluster scaffold-like proteins
NM_001301141.1 → NP_001288070.1 iron-sulfur cluster assembly enzyme ISCU isoform 4 precursor

See identical proteins and their annotated locations for NP_001288070.1

Status: REVIEWED

Description

Transcript Variant: This variant (4) contains an alternate exon in the 3' region, resulting in a different 3' coding region and 3' UTR, compared to variant 2. The encoded isoform (4) has a distinct, shorter C-terminus, compared to isoform 2.

Source sequence(s)

AC008119, AK057251, BQ020993

Consensus CDS

CCDS73518.1

UniProtKB/TrEMBL

B3KQ30, F5H5N2

Related

ENSP00000411108.2, ENST00000431221.6

Conserved Domains (1) summary

cl00528
Location:35 → 139

IscU_like; Iron-sulfur cluster scaffold-like proteins
NM_001320042.1 → NP_001306971.1 iron-sulfur cluster assembly enzyme ISCU isoform 3 precursor

Status: REVIEWED

Description

Transcript Variant: This variant (5) uses an alternate splice site in the 3' region, resulting in a different 3' coding region and 3' UTR, compared to variant 2. Variants 3 and 5 encode the same protein (isoform 3), which has a distinct, shorter C-terminus, compared to isoform 2. Isoform 3 may not be stable (PMID:23035118). This variant may be preferentially produced in individuals containing an alternate intronic C vs G (rs767000507), which activates a cryptic splice acceptor site. The alternate C allele is associated with myopathy (PMIDs 18296749, 18304497).

Source sequence(s)

AK057251, AK297862, BC061903, HY269565

Consensus CDS

CCDS76597.1

UniProtKB/TrEMBL

B4DNC9, F5H5N2

Related

ENSP00000445598.1, ENST00000535729.5

Conserved Domains (1) summary

cl00528
Location:35 → 139

IscU_like; Iron-sulfur cluster scaffold-like proteins
NM_014301.4 → NP_055116.1 iron-sulfur cluster assembly enzyme ISCU isoform 1

See identical proteins and their annotated locations for NP_055116.1

Status: REVIEWED

Description

Transcript Variant: This variant (1) contains an alternate exon in the 5' region and initiates translation at an alternate start codon compared to variant 2. The encoded isoform (1) has a distinct, shorter N-terminus, compared to isoform 2. Isoform 1 is localized to the cytosol.

Source sequence(s)

AK057251, AY009127, BQ020993

Consensus CDS

CCDS9118.1

Related

ENSP00000376554.4, ENST00000392807.8

Conserved Domains (1) summary

PRK11325
Location:11 → 133

PRK11325; scaffold protein; Provisional
NM_213595.4 → NP_998760.1 iron-sulfur cluster assembly enzyme ISCU isoform 2 precursor

See identical proteins and their annotated locations for NP_998760.1

Status: REVIEWED

Description

Transcript Variant: This variant (2) encodes the longest isoform (2). Isoform 2 is localized to the mitochondrion.

Source sequence(s)

AK057251, BC011906, BQ020993

Consensus CDS

CCDS44966.1

UniProtKB/Swiss-Prot

Q6P713, Q99617, Q9H1K1, Q9H1K2

UniProtKB/TrEMBL

F5H5N2

Related

ENSP00000310623.9, ENST00000311893.14

Conserved Domains (1) summary

PRK11325
Location:35 → 158

PRK11325; scaffold protein; Provisional

RNA

NR_135127.1 RNA Sequence

Status: REVIEWED

Description

Transcript Variant: This variant (6) contains an alternate exon in the 5' region and an alternate exon in the 3' region, compared to variant 2. This variant is represented as non-coding because the use of the 5'-most expected translational start codon, as used in variant 1, renders the transcript a candidate for nonsense-mediated mRNA decay (NMD). This variant may be preferentially produced in individuals containing an alternate intronic C vs G (rs767000507), which activates a cryptic splice acceptor site. The alternate C allele is associated with myopathy (PMIDs 18296749, 18304497).

Source sequence(s)

AK057251, BC061903, EU329002