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ISCA2 gene
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Gene

ISCA2 gene

The ISCA2 gene encodes a protein essential for the formation and transport of iron-sulfur clusters, which are critical for mitochondrial energy production.

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. 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

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 versions 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

Genomic Location

The ISCA2 gene is found on chromosome 14.

Frequently Asked Questions

The Gly77Ser variant is the most common pathogenic change in the ISCA2 gene and results in a substitution of the amino acid glycine with serine at position 77. This change disrupts the protein's ability to properly interact with ISCA1, which is essential for the assembly and transport of iron-sulfur clusters. This disruption leads to a deficiency in mitochondrial energy production, resulting in the severe neurological and visual symptoms characteristic of multiple mitochondrial dysfunctions syndrome type 4. The specific impact on severity can vary, but this variant is strongly associated with the classic presentation of the disease.
Both ISCA1 (type 5) and ISCA2 (type 4) mutations cause multiple mitochondrial dysfunctions syndrome with similar core features, including spasticity, vision problems, encephalopathy, and developmental regression. Clinically, they are very difficult to distinguish based on symptoms alone, which is why genetic testing is required for a definitive diagnosis. The primary difference lies in the specific gene affected and the particular amino acid changes in the proteins, but the resulting mitochondrial dysfunction and clinical course are largely comparable, with both conditions leading to shortened life expectancy and severe neurological impairment.
Parents can undergo carrier testing to check for pathogenic variants in the ISCA2 gene. If both parents are identified as carriers, they can consult with a genetic counselor to discuss options for future pregnancies, such as preimplantation genetic testing (PGT) with in vitro fertilization or prenatal diagnosis via chorionic villus sampling (CVS) or amniocentesis. Knowing the carrier status allows families to make informed reproductive decisions and prepare for the potential medical needs of an affected child.
There is currently no cure for multiple mitochondrial dysfunctions syndrome type 4. Treatment is supportive and focuses on managing symptoms to improve quality of life. This may include physical and occupational therapy to address spasticity and maintain mobility, anticonvulsant medications to control seizures, and nutritional support to ensure adequate growth. Regular monitoring of vision and hearing is also important. Research into gene therapy and metabolic interventions is ongoing, but no specific therapeutic agents have been approved for this condition yet.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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