ISCU

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ISCU
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
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 MbChr 5: 113.91 – 113.92 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Iron-sulfur cluster assembly enzyme ISCU, mitochondrial is a

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

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

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 a mitochondrial myopathy called hereditary myopathy with lactic acidosis (HML).[11] It is also known as hereditary myopathy with exercise intolerance, Swedish type;[11] myopathy with deficiency of succinate dehydrogenase and aconitase;[11] myoglobinuria due to abnormal glycolysis;[11] myopathy with deficiency of ISCU;[10] Larsson–Linderholm syndrome;[12] and Linderholm myopathy.[13]

This disease is a result of a deficiency of ISCU that corresponds to the deficiency of mitochondrial

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.[14][15][8][9][10][16] Primarily affecting the skeletal muscles, rarely there is also hypertrophic cardiomyopathy and ptosis (drooping eyelid).[11][17]

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.[14] There has been documented temporary restoration of succinate dehydrogenase in regenerating muscle after an episode of rhabdomyolysis; however, the effect does not last.[18]

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.[19][17]

Genetics

This disorder has been associated with several different mutations and is inherited predominantly in an

cryptic splice site, resulting in the production of a splice variant that encodes a putatively non-functional protein.[10]

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.[17]

Interactions

ISCU has been shown to have 235 binary

dnaX, hscB, MAPk-Ak2, hale, and cv-c.[22]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000136003 – Ensembl, May 2017
  2. ^ a b c 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. S2CID 21873104
    .
  6. ^
    PMID 11060020
    .
  7. ^ a b c d e "Entrez Gene: ISCU iron-sulfur cluster scaffold homolog (E. coli)".Public Domain This article incorporates text from this source, which is in the public domain.
  8. ^ a b c d e "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. ^
    PMID 27899622
    .
  10. ^
    PMID 20301757. Updated 2011 Sep 1Public Domain This article incorporates text from this source, which is in the public domain
    .
  11. ^ a b c d e "Entry - #255125 - MYOPATHY WITH LACTIC ACIDOSIS, HEREDITARY; HML - OMIM". www.omim.org. Retrieved 2024-04-05.
  12. ISBN 978-0-88011-632-9
    .
  13. ^ "Linderholms myopati". Socialstyrelsen (in Swedish). 2019-05-30. Retrieved 2024-04-05.
  14. ^
    PMID 14213465
    .
  15. ^
    PMID 18304497
    .
  16. PMID 23943793
    .
  17. ^
    PMID 29079705
    .
  18. PMID 21196119
    .
  19. ^
    PMID 20206689
    .
  20. S2CID 38626230
    .
  21. PMID 19567699
    .
  22. ^ "235 binary interactions found for search term ISCU". IntAct Molecular Interaction Database. EMBL-EBI. Retrieved 2018-09-05.

Further reading

External links

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

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