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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; OMA:ISCU - orthologs
Gene location (Human) Chr. Chromosome 12 (human) Band 12q23.3 Start 108,562,582 bp End 108,569,368 bp
Gene location (Mouse) Chr. Chromosome 5 (mouse) Band 5|5 F Start 113,910,809 bp End 113,916,349 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right ventricle Pons renal medulla superior vestibular nucleus pars compacta external globus pallidus right adrenal cortex myocardium left adrenal cortex pars reticulata Top expressed in adrenal gland proximal tubule right kidney bone marrow human kidney white adipose tissue muscle tissue muscle of thigh quadriceps femoris muscle skeletal muscle tissue More reference expression data BioGPS More reference expression data
Gene ontology Molecular function iron ion binding molecular adaptor activity 4 iron, 4 sulfur cluster binding iron-sulfur cluster binding ferrous iron binding 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: 113.91 – 113.92 Mb PubMed search
Wikidata
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Iron-sulfur cluster assembly enzyme ISCU, mitochondrial is a protein that in humans is encoded by the ISCU gene. It encodes an iron-sulfur (Fe-S) cluster scaffold protein involved in and cluster synthesis and maturation. 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.

Structure

ISCU is located on the q arm of chromosome 12 in position 23.3 and has 8 exons. 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 and clusters. ISCU contains a transit peptide, 4 beta strands, 4 alpha helixes, and 4 turns. 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.

Function

ISCU encodes a component of the iron-sulfur (Fe-S) cluster scaffold responsible for the synthesis and maturation of and 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 cluster transiently assembles on ISCU and is then transferred to GLRX5 in a cysteine desulfurase complex NFS1-LYRM4/ISD11 dependent process.

ISCU has two isoforms, isoform 1, which is found in the mitochondrion and isoform 2, which is found in the nucleus and cytoplasm.

Clinical significance

ISCU mutations have been found in patients with a mitochondrial myopathy called hereditary myopathy with lactic acidosis (HML). It is also known as hereditary myopathy with exercise intolerance, Swedish type; myopathy with deficiency of succinate dehydrogenase and aconitase; myoglobinuria due to abnormal glycolysis; myopathy with deficiency of ISCU; Larsson–Linderholm syndrome; and Linderholm myopathy.

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. 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, may have a pseudoathletic appearance of hypertrophic calf muscles, and possibly weakness. Primarily affecting the skeletal muscles, rarely there is also hypertrophic cardiomyopathy and ptosis (drooping eyelid).

Biopsy of skeletal muscle shows deficiency of succinate dehydrogenase and aconitase, abnormal iron deposition and lipid droplet accumulation in the mitochondria. Histochemical studies show impaired respiratory chain complexes I, II, and III, impairing oxidative phosphorylation. Electromyography normal or myopathic increased polyphasic MUAPs. EMG results may be dynamic: more likely to have increased polyphasic MUAPs after exercise. There has been documented temporary restoration of succinate dehydrogenase in regenerating muscle after an episode of rhabdomyolysis; however, the effect does not last.

The disease is limited to muscle, with fibroblasts from skin biopsy being unaffected. As non-muscle tissues are unaffected, this necessitates the need for muscle biopsy when DNA testing using saliva or blood is inconclusive.

Genetics

This disorder has been associated with several different mutations and is inherited predominantly 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. ISCU deficiency has been linked to pathogenic variants including intronic variants c.418+382G>C, g.7044G>C, and IVS5+382 G>C as well as a c.149G>A missense mutation in exon 3. 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.

In 2016, an Italian male was found to have a de novo autosomal dominant mutation, c.287G>T (p.Gly96Val) in the ISCU gene, that caused hereditary mitochondrial myopathy with lactic acidosis (HML). This mutation resulted in a similar phenotype as seen in the recessive form of the disease.

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.

References

1. ^ GRCh38: Ensembl release 89: ENSG00000136003 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000025825 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Hwang DM, Dempsey A, Tan KT, Liew CC (November 1996). "A modular domain of NifU, a nitrogen fixation cluster protein, is highly conserved in evolution". Journal of Molecular Evolution. 43 (5): 536–40. Bibcode:1996JMolE..43..536H. doi:10.1007/BF02337525. PMID 8875867. S2CID 21873104.
6. ^ Tong WH, Rouault T (November 2000). "Distinct iron-sulfur cluster assembly complexes exist in the cytosol and mitochondria of human cells". The EMBO Journal. 19 (21): 5692–700. doi:10.1093/emboj/19.21.5692. PMC 305809. PMID 11060020.
7. ^ "Entrez Gene: ISCU iron-sulfur cluster scaffold homolog (E. coli)". This article incorporates text from this source, which is in the public domain.
8. ^ "ISCU - Iron-sulfur cluster assembly enzyme ISCU, mitochondrial precursor - Homo sapiens (Human) - ISCU gene & protein". www.uniprot.org. Retrieved 2018-09-04. This article incorporates text available under the CC BY 4.0 license.
9. ^ "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC 5210571. PMID 27899622.
10. ^ Mochel F, Haller RG (2009-03-31). "Myopathy with Deficiency of ISCU – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY". Myopathy with Deficiency of ISCU. GeneReviews. PMID 20301757. Updated 2011 Sep 1 This article incorporates text from this source, which is in the public domain.
11. ^ "Entry - #255125 - MYOPATHY WITH LACTIC ACIDOSIS, HEREDITARY; HML - OMIM". www.omim.org. Retrieved 2024-04-05.
12. Saltin B (2000). Exercise and Circulation in Health and Disease. Human Kinetics. ISBN 978-0-88011-632-9.
13. "Linderholms myopati". Socialstyrelsen (in Swedish). 2019-05-30. Retrieved 2024-04-05.
14. ^ Larsson LE, Linderholm H, Müller R, Ringqvist T, Sörnäs R (October 1964). "Hereditary metabolic myopathy with paroxysmal myoglobinuria due to abnormal glycolysis1". Journal of Neurology, Neurosurgery, and Psychiatry. 27 (5): 361–380. doi:10.1136/jnnp.27.5.361. ISSN 0022-3050. PMC 495765. PMID 14213465.
15. ^ Mochel F, Knight MA, Tong WH, Hernandez D, Ayyad K, Taivassalo T, Andersen PM, Singleton A, Rouault TA, Fischbeck KH, Haller RG (March 2008). "Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance". American Journal of Human Genetics. 82 (3): 652–60. doi:10.1016/j.ajhg.2007.12.012. PMC 2427212. PMID 18304497.
16. Crooks DR, Natarajan TG, Jeong SY, Chen C, Park SY, Huang H, Ghosh MC, Tong WH, Haller RG, Wu C, Rouault TA (2014-01-01). "Elevated FGF21 secretion, PGC-1α and ketogenic enzyme expression are hallmarks of iron–sulfur cluster depletion in human skeletal muscle". Human Molecular Genetics. 23 (1): 24–39. doi:10.1093/hmg/ddt393. ISSN 0964-6906. PMC 3857942. PMID 23943793.
17. ^ Legati A, Reyes A, Ceccatelli Berti C, Stehling O, Marchet S, Lamperti C, Ferrari A, Robinson AJ, Mühlenhoff U, Lill R, Zeviani M, Goffrini P, Ghezzi D (December 2017). "A novel de novo dominant mutation in ISCU associated with mitochondrial myopathy". Journal of Medical Genetics. 54 (12): 815–824. doi:10.1136/jmedgenet-2017-104822. ISSN 1468-6244. PMC 5740555. PMID 29079705.
18. Kollberg G, Melberg A, Holme E, Oldfors A (2011-02-01). "Transient restoration of succinate dehydrogenase activity after rhabdomyolysis in iron–sulphur cluster deficiency myopathy". Neuromuscular Disorders. 21 (2): 115–120. doi:10.1016/j.nmd.2010.11.010. ISSN 0960-8966. PMID 21196119.
19. ^ Sanaker PS, Toompuu M, Hogan VE, He L, Tzoulis C, Chrzanowska-Lightowlers ZM, Taylor RW, Bindoff LA (June 2010). "Differences in RNA processing underlie the tissue specific phenotype of ISCU myopathy". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1802 (6): 539–44. doi:10.1016/j.bbadis.2010.02.010. PMID 20206689.
20. Kollberg G, Melberg A, Holme E, Oldfors A (February 2011). "Transient restoration of succinate dehydrogenase activity after rhabdomyolysis in iron-sulphur cluster deficiency myopathy". Neuromuscular Disorders. 21 (2): 115–20. doi:10.1016/j.nmd.2010.11.010. PMID 21196119. S2CID 38626230.
21. Kollberg G, Tulinius M, Melberg A, Darin N, Andersen O, Holmgren D, Oldfors A, Holme E (August 2009). "Clinical manifestation and a new ISCU mutation in iron-sulphur cluster deficiency myopathy". Brain. 132 (Pt 8): 2170–9. doi:10.1093/brain/awp152. PMID 19567699.
22. "235 binary interactions found for search term ISCU". IntAct Molecular Interaction Database. EMBL-EBI. Retrieved 2018-09-05.

Further reading

• Mochel F, Knight MA, Tong WH, Hernandez D, Ayyad K, Taivassalo T, Andersen PM, Singleton A, Rouault TA, Fischbeck KH, Haller RG (March 2008). "Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance". American Journal of Human Genetics. 82 (3): 652–60. doi:10.1016/j.ajhg.2007.12.012. PMC 2427212. PMID 18304497.
• Li K, Tong WH, Hughes RM, Rouault TA (May 2006). "Roles of the mammalian cytosolic cysteine desulfurase, ISCS, and scaffold protein, ISCU, in iron-sulfur cluster assembly". The Journal of Biological Chemistry. 281 (18): 12344–51. doi:10.1074/jbc.M600582200. PMID 16527810.
• Tong WH, Rouault TA (March 2006). "Functions of mitochondrial ISCU and cytosolic ISCU in mammalian iron-sulfur cluster biogenesis and iron homeostasis". Cell Metabolism. 3 (3): 199–210. doi:10.1016/j.cmet.2006.02.003. PMID 16517407.
• Acquaviva F, De Biase I, Nezi L, Ruggiero G, Tatangelo F, Pisano C, Monticelli A, Garbi C, Acquaviva AM, Cocozza S (September 2005). "Extra-mitochondrial localisation of frataxin and its association with IscU1 during enterocyte-like differentiation of the human colon adenocarcinoma cell line Caco-2". Journal of Cell Science. 118 (Pt 17): 3917–24. doi:10.1242/jcs.02516. PMID 16091420. S2CID 6082284.
• Benzinger A, Muster N, Koch HB, Yates JR, Hermeking H (June 2005). "Targeted proteomic analysis of 14-3-3 sigma, a p53 effector commonly silenced in cancer". Molecular & Cellular Proteomics. 4 (6): 785–95. doi:10.1074/mcp.M500021-MCP200. PMID 15778465.

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.

• Genes on human chromosome 12