Normal Function
The ISCA2 gene provides instructions for making a protein that is involved in the formation and transport of molecules called iron-sulfur (Fe-S) clusters. Certain proteins require Fe-S clusters to function properly.
The ISCA2 protein attaches to a similar protein called ISCA1. This allows the Fe-S assembly process to proceed and allows Fe-S clusters to attach to proteins.
The ISCA2 protein is found in cellular structures called mitochondria. Mitochondria are the energy-producing centers of cells. In these structures, several proteins carry out a series of chemical steps called oxidative phosphorylation to convert the energy in food into a form that cells can use. Many of the proteins that play a role in this process require Fe-S clusters to function. Proteins that contain Fe-S clusters are involved in many functions in the body, including DNA repair and the regulation of gene activity.
Health Conditions Related to Genetic Changes
Multiple mitochondrial dysfunctions syndrome
Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in the ISCA2 gene cause multiple mitochondrial dysfunctions syndrome type 4. This condition is characterized by vision problems and muscle stiffness (spasticity). People with type 4 have additional health problems that are common to all forms of multiple mitochondrial dysfunctions syndrome, such as severe brain dysfunction (encephalopathy) and a loss of mental abilities and acquired skills (developmental regression). Affected individuals have a shortened life expectancy.
Pathogenic variants in the ISCA2 gene cause cells to produce altered version of the ISCA2 protein that do not function properly or at all. The most common variant (written as Gly77Ser or G77S) changes a single protein building block (amino acid) in the ISCA2 protein. Without normal ISCA2 proteins, Fe-S clusters are not attached to proteins, and this means that certain proteins cannot perform their normal functions. Ultimately, this reduces energy produced by mitochondria and impairs other cellular functions, leading to the severe signs and symptoms seen in people with multiple mitochondrial dysfunctions syndrome type 4.
Other Names for This Gene
- c14_5557
- HBLD1
- ISA2
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
References
- Al-Hassnan ZN, Al-Dosary M, Alfadhel M, Faqeih EA, Alsagob M, Kenana R, Almass R, Al-Harazi OS, Al-Hindi H, Malibari OI, Almutari FB, Tulbah S, Alhadeq F, Al-Sheddi T, Alamro R, AlAsmari A, Almuntashri M, Alshaalan H, Al-Mohanna FA, Colak D, Kaya N. ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder. J Med Genet. 2015 Mar;52(3):186-94. doi: 10.1136/jmedgenet-2014-102592. Epub 2014 Dec 24. Citation on PubMed
- Al-Hassnan ZN, Kaya N. ISCA2-Related Mitochondrial Disorder. 2018 Feb 22. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK481904/ Citation on PubMed
- Alfadhel M. Multiple Mitochondrial Dysfunctions Syndrome 4 Due to ISCA2 Gene Defects: A Review. Child Neurol Open. 2019 May 7;6:2329048X19847377. doi: 10.1177/2329048X19847377. eCollection 2019. Citation on PubMed
- Lebigot E, Schiff M, Golinelli-Cohen MP. A Review of Multiple Mitochondrial Dysfunction Syndromes, Syndromes Associated with Defective Fe-S Protein Maturation. Biomedicines. 2021 Aug 10;9(8):989. doi: 10.3390/biomedicines9080989. Citation on PubMed
- Suraci D, Saudino G, Nasta V, Ciofi-Baffoni S, Banci L. ISCA1 Orchestrates ISCA2 and NFU1 in the Maturation of Human Mitochondrial [4Fe-4S] Proteins. J Mol Biol. 2021 May 14;433(10):166924. doi: 10.1016/j.jmb.2021.166924. Epub 2021 Mar 10. Citation on PubMed
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