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Normal Function
The ISCA1 gene provides instructions for making a protein that is involved in the process of assembling molecules called iron-sulfur (Fe-S) clusters and attaching these clusters to other proteins. Certain proteins require Fe-S clusters to function properly.
The ISCA1 protein attaches to a similar protein called ISCA2. This allows the Fe-S assembly process to proceed and allows Fe-S clusters to attach to proteins.
The ISCA1 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 ISCA1 gene cause multiple mitochondrial dysfunctions syndrome type 5. This condition is characterized by vision problems and muscle stiffness (spasticity). People with type 5 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 ISCA1 gene lead to changes in single protein building blocks (amino acids) in the ISCA1 protein. These changes reduce the amount of functional ISCA1 proteins in the mitochondria. Without normal ISCA1 proteins, Fe-S clusters are not attached to proteins, and this means that certain proteins cannot perform their normal functions. Ultimately, this reduces the amount of energy produced by mitochondria and impairs cellular functions, leading to the severe signs and symptoms seen in people with multiple mitochondrial dysfunctions syndrome type 5.
Other Names for This Gene
- HBLD2
- hIscA
- hIscA1
- ISA1
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
References
- Beilschmidt LK, Ollagnier de Choudens S, Fournier M, Sanakis I, Hograindleur MA, Clemancey M, Blondin G, Schmucker S, Eisenmann A, Weiss A, Koebel P, Messaddeq N, Puccio H, Martelli A. ISCA1 is essential for mitochondrial Fe4S4 biogenesis in vivo. Nat Commun. 2017 May 11;8:15124. doi: 10.1038/ncomms15124. 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
- Shukla A, Kaur P, Girisha KM. Report of the Third Family with Multiple Mitochondrial Dysfunctions Syndrome 5 Caused by the Founder Variant p.(Glu87Lys) in ISCA1. J Pediatr Genet. 2018 Sep;7(3):130-133. doi: 10.1055/s-0038-1641177. Epub 2018 Apr 5. Citation on PubMed
- Shukla A, Narayanan DL, Kaur P, Girisha KM. ISCA1-Related Multiple Mitochondrial Dysfunctions Syndrome. 2019 Oct 3. 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/NBK547304/ 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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