ISCU
protein-codingiron-sulfur cluster assembly enzyme, the group of Mitochondrial iron-sulfur assembly components
Gene 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]
- NIFUN
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~6.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *ISCU* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of October 19, 2023. The *ISCU* gene encodes an iron-sulfur (Fe-S) cluster assembly enzyme. This is a scaffold protein necessary for the de novo synthesis of Fe-S clusters within mitochondria. This is also important in iron homeostasis and for aconitase activity. There are two isoforms, one cytosolic and one mitochondrial, due to alternative splicing of pre-mRNA. *ISCU* was first reported in relation to autosomal recessive primary mitochondrial disease in 2008 (PMID: 18304497) in three individuals with myopathy and myoglobinuria (although these individuals were reported in manuscripts from 1991 and 1995, PMIDS: 1918374, 7616539, respectively). While various names have been given to the constellation of features seen in those with *ISCU*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *ISCU* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting the gene-disease relationship between *ISCU* and primary mitochondrial disease includes case-level data and experimental data. This curation includes two variants (one splicing founder variant and one missense variant) in eleven probands across five publications (PMIDs: 18296749, 18304497, 19567699, 20206689, 35079622) although additional cases have been reported in the medical literature. Features seen in affected individuals include childhood-onset exercise intolerance/early fatigue, dyspnea, hyperkinetic circulation with tachycardia and palpitations on trivial exercise, ptosis, metabolic acidosis, and rhabdomyolysis. This condition is typically non-progressive with periods of stability. Muscle biopsy shows a distinctive deficiency of several mitochondrial Fe-S proteins (complex I, II, and III; mitochondrial aconitase) as well as iron overload in muscle fibers. Brain imaging was generally normal and affected individuals had variably elevated lactate at rest. Loss of function is implicated as the mechanism of disease. This gene-disease relationship is also supported by known biochemical function, functional alteration in patient cells, yeast models, and a transgenic mouse model expressing human mutated *ISCU* (PMIDs: 33340416, 1918374, 8254022, 20206689, 24573684, 27783661). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. No convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on October 19, 2023 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0009706
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0009706
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009706
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009706
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Musculoskeletal; Renal
Intervention: Musculoskeletal; Renal
Rationale: In addition to cardiovascular features, the condition can include rhabdomyolysis, and appropriate precautions and prompt recognition may be beneficial
Comments: Treatment (using an antisense phosphorodiamidate morpholino oligonucleotide) of cultured fibroblasts from three individuals with a homozygous splice-site variant resulted in restoration of the normal splicing pattern
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ISCU variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_213595.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 49 | 2 | 52 | ||
| missense | 1 | 56 | 4 | 1 | 62 | |
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 2 | 2 | ||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 0 | 1 | 62 | 53 | 3 | 119 |
Highest pathogenic variant AF is 0.000060579136
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_998760.1 | 5 | MANE Select | |
| Ensembl | ENSP00000310623.9 | 5 | MANE Select | |
| RefSeq | NP_001288069.1 | 5 | Standard | |
| RefSeq | NP_001288070.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Mitochondrial iron-sulfur cluster biogenesis
- Metabolism
Biological Process
- cellular iron ion homeostasis
- iron-sulfur cluster assembly
- small molecule metabolic process
Molecular Function
- iron ion binding
- protein binding
- ferrous iron binding
- protein-containing complex scaffold activity
- 2 iron, 2 sulfur cluster binding
Cellular Component
- nucleus
- cytoplasm
- mitochondrion
- mitochondrial matrix
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000311893
- Coding exons
- 5
- Length
- 6803
- Individuals with no LoFs
- 125739
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 9
- Defined
- 125748
- p
- 0.0000358
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.207 | 77 | 82.3 | 0.936 | 0.00000424 | 1026 |
| Missense (PolyPhen) | 32 | 48.449 | 0.66049 | 557 | ||
| Synonymous | -0.927 | 42 | 35.0 | 1.20 | 0.00000204 | 332 |
| Loss of Function | 1.32 | 3 | 6.69 | 0.449 | 2.84e-7 | 93 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000087 | 0.000087 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000035 | 0.000035 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Scaffold protein for the de novo synthesis of iron- sulfur (Fe-S) clusters within mitochondria, which is required for maturation of both mitochondrial and cytoplasmic [2Fe-2S] and [4Fe-4S] proteins (PubMed:11060020). First, a [2Fe-2S] cluster is transiently assembled on the scaffold protein ISCU. In a second step, the cluster is released from ISCU, transferred to a glutaredoxin GLRX5, followed by the formation of mitochondrial [2Fe-2S] proteins, the synthesis of [4Fe-4S] clusters and their target-specific insertion into the recipient apoproteins. Cluster assembly on ISCU depends on the function of the cysteine desulfurase complex NFS1-LYRM4/ISD11, which serves as the sulfur donor for cluster synthesis, the iron-binding protein frataxin as the putative iron donor, and the electron transfer chain comprised of ferredoxin reductase and ferredoxin, which receive their electrons from NADH (By similarity). {ECO:0000250|UniProtKB:Q03020, ECO:0000269|PubMed:11060020}.;
Recessive Scores
- pRec
- 0.193
Intolerance Scores
- LoFtool
- 0.304
- RVIS EVS
- 0.06
- RVIS percentile EVS
- 58
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.860
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |