ISCU

ISCU
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1WFZ
Identifiers
Aliases	ISCU, 2310020H20Rik, HML, ISU2, NIFU, NIFUN, hnifU, iron-sulfur cluster assembly enzyme
External IDs	OMIM: 611911 MGI: 1913633 HomoloGene: 6991 GeneCards: ISCU
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12q23.3 Start 108,562,582 bp[1] End 108,569,368 bp[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)[2] Band 5|5 F Start 113,772,748 bp[2] End 113,778,288 bp[2]
RNA expression pattern Bgee Top expressed in left ventricle right ventricle adrenal gland pons myocardium renal cortex adrenal cortex pituitary gland Superior vestibular nucleus kidney More reference expression data BioGPS More reference expression data
Gene ontology Molecular function iron ion binding GO:0032947 molecular adaptor activity 4 iron, 4 sulfur cluster binding iron-sulfur cluster binding ferrous iron binding GO:0001948 protein binding metal ion binding iron-sulfur transferase activity 2 iron, 2 sulfur cluster binding Cellular component cytoplasm cytosol mitochondrial matrix mitochondrion nucleus Biological process protein maturation by iron-sulfur cluster transfer small molecule metabolic process iron-sulfur cluster assembly cellular iron ion homeostasis positive regulation of mitochondrial electron transport, NADH to ubiquinone positive regulation of aconitate hydratase activity negative regulation of iron ion import across plasma membrane Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	23479	66383
Ensembl	ENSG00000136003	ENSMUSG00000025825
UniProt	Q9H1K1	Q9D7P6
RefSeq (mRNA)	NM_001301140 NM_001301141 NM_014301 NM_213595 NM_001320042	NM_025526 NM_001363317
RefSeq (protein)	NP_001288069 NP_001288070 NP_001306971 NP_055116 NP_998760	NP_079802 NP_001350246
Location (UCSC)	Chr 12: 108.56 – 108.57 Mb	Chr 5: 113.77 – 113.78 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Iron-sulfur cluster assembly enzyme ISCU, mitochondrial is a protein that in humans is encoded by the ISCU gene.^[5] It encodes an iron-sulfur (Fe-S) cluster scaffold protein involved in [2Fe-2S] and [4Fe-4S] cluster synthesis and maturation.^[6][7][8][9] A deficiency of ISCU is associated with a mitochondrial myopathy with lifelong exercise intolerance where only minor exertion causes tachycardia, shortness of breath, muscle weakness and myalgia.^[10]

Structure[]

ISCU is located on the q arm of chromosome 12 in position 23.3 and has 8 exons.^[7] ISCU, the protein encoded by this gene, is a member of the NifU family. It is an iron-sulfur transferase that contains binding sites for [2Fe-2S] and [4Fe-4S] clusters. ISCU contains a transit peptide, 4 beta strands, 4 alpha helixes, and 4 turns.^[8][9] Alternative splicing results in transcript variants encoding different protein isoforms that localize either to the cytosol or to the mitochondrion. A pseudogene of this gene is present on chromosome 1.^[7]

Function[]

ISCU encodes a component of the iron-sulfur (Fe-S) cluster scaffold responsible for the synthesis and maturation of [2Fe-2S] and [4Fe-4S] clusters. 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. In one process, the [2Fe-2S] cluster transiently assembles on ISCU and is then transferred to GLRX5 in a cysteine desulfurase complex NFS1-LYRM4/ISD11 dependent process.^[7][6][8][9]

ISCU has two isoforms, isoform 1, which is found in the mitochondrion and isoform 2, which is found in the nucleus and cytoplasm.^[8][9]

Clinical significance[]

ISCU mutations have been found in patients with hereditary mitochondrial myopathy with exercise intolerance and lactic acidosis. This disease is a result of a deficiency of ISCU that corresponds to the deficiency of mitochondrial iron-sulfur proteins and impaired muscle oxidative metabolism.^[7] Characteristics of mitochondrial myopathy with deficiency of ISCU may include lifelong exercise intolerance in which exertion can cause tachycardia, dyspnoea, cardiac palpitations, shortness of breath, fatigue, pain of active muscles, rhabdomyolysis, myoglobinuria, elevated lactate and pyruvate, decreased oxygen utilization, large calves, and possibly weakness.^{[11][8][9][10]}

Genetics[]

This disorder has been associated with several different mutations and is inherited in an autosomal recessive manner. It was originally believed to affect only those of northern Swedish ancestry, however the disease has been found in those of Norwegian and Finnish decent as well. The carrier rate in northern Sweden has been estimated at 1:188.^[11] ISCU deficiency has been linked to pathogenic variants including intronic variants c.418+382G>C, g.7044G>C,^[12] and IVS5+382 G>C^[13] as well as a c.149G>A missense mutation in exon 3.^[14] The intronic mutations have been suggested to activate a cryptic splice site, resulting in the production of a splice variant that encodes a putatively non-functional protein.^[10]

Interactions[]

ISCU has been shown to have 235 binary protein-protein interactions including 79 co-complex interactions. ISCU appears to interact with ISCS, NUP62, SDHB, HPRT1, CCDC172, GOLGA2, IKZF1, KRT40, AGTRAP, NECAB2, FAM9B, BANP, LNX1, MID2, GOLGA6L9, ccdc136, KRT34, SPERT, PICK1, YWHAB, SFN, mbl, E7, dnaX, hscB, MAPk-Ak2, hale, and cv-c.^[15]

References[]

Further reading[]

External links[]

• GeneReviews/NCBI/NIH/UW entry on Myopathy with Deficiency of ISCU
• GeneReviews/NIH/NCBI/UW entry on Myopathy with Deficiency of ISCU

This article incorporates text from the United States National Library of Medicine, which is in the public domain.