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URL of this page: https://medlineplus.gov/genetics/gene/idh2/

IDH2 gene

isocitrate dehydrogenase (NADP(+)) 2

Normal Function

The IDH2 gene provides instructions for making a type of enzyme called an isocitrate dehydrogenase. The IDH2 enzyme is found in mitochondria, which are the energy-producing centers within cells. Within mitochondria, the enzyme participates in reactions that produce energy for cell activities. Specifically, this enzyme helps convert a compound called isocitrate into another compound called 2-oxoglutarate. Other enzymes further process 2-oxoglutarate to produce energy.

Through its cellular processes, the IDH2 enzyme helps produce a molecule called NADPH, which is necessary for many cellular processes and helps protect cells from potentially harmful molecules called reactive oxygen species.

Health Conditions Related to Genetic Changes

2-hydroxyglutaric aciduria

Genetic changes that cause disease or increase the risk of disease are called pathogenic variants. Pathogenic variants in the IDH2 gene have been found to cause a type of 2-hydroxyglutaric aciduria known as D-2-hydroxyglutaric aciduria (D-2-HGA) type II. This condition has a variety of signs and symptoms that result from altered brain development that begins early in life.

The pathogenic variants that cause D-2-HGA type II are present in all of an affected person's cells. They prevent isocitrate from being converted into 2-oxoglutarate. Instead, the altered enzyme produces a compound called D-2-hydroxyglutarate. Because the pathogenic variants lead to the production of an enzyme with a new function, they are classified as "gain-of-function variants.”

In people with D-2-HGA type II, D-2-hydroxyglutarate builds up in cells. At high levels, this compound can damage cells and lead to cell death. Brain cells appear to be especially vulnerable to the toxic effects of this compound, which may explain why the signs and symptoms of D-2-HGA type II primarily involve the brain. However, some people with D-2-HGA type II also have a weakened and enlarged heart (cardiomyopathy). It is unclear why the buildup of D-2-hydroxyglutarate is sometimes associated with cardiomyopathy.

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Cytogenetically normal acute myeloid leukemia

Pathogenic variants in the IDH2 gene have been identified in some people with a form of acute myeloid leukemia called cytogenetically normal acute myeloid leukemia (CN-AML). The variants in the IDH2 gene that are involved in CN-AML are acquired during a person's lifetime (somatic) and are only present in certain cells. People with CN-AML do not appear to have the large chromosomal abnormalities that are sometimes involved in the development of AML.

The somatic variants in the IDH2 gene that are associated with CN-AML are only found in cancer cells. They typically change single protein building blocks (amino acids) in the IDH2 enzyme. This results in the production of a compound called D-2-hydroxyglutarate. Studies suggest that higher levels of D-2-hydroxyglutarate may interfere with the maturation (differentiation) of blood cells, which increases the number of immature cells that can divide uncontrollably.

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Maffucci syndrome

Somatic variants in the IDH2 gene can cause Maffucci syndrome, a disorder that primarily affects the bones and skin. Maffucci syndrome is characterized by blood vessel abnormalities and multiple enchondromas, which are noncancerous (benign) growths of cartilage that develop within bones.

The somatic variants in the IDH2 gene that are associated with Maffucci syndrome have been found in cells that make up the affected tissues, including enchondromas and abnormal blood vessels. In people with Maffucci syndrome, somatic variants in the IDH2 gene appear to be gain-of-function variants that lead to the production of D-2-hydroxyglutarate. However, the relationship between these gain-of-function variants and the signs and symptoms of Maffucci syndrome is not well understood.

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Ollier disease

Somatic variants in the IDH2 gene have also been associated with Ollier disease, a disorder that is similar to Maffucci syndrome but does not include blood vessel abnormalities.

As in people with Maffucci syndrome, the IDH2 gene variants in people with Ollier disease are gain-of-function variants. These variants have been found in the affected tissues in some people with Ollier disease, but the relationship between these somatic variants and the signs and symptoms of the disorder is not well understood.

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Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

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Primary myelofibrosis

MedlinePlus Genetics provides information about Primary myelofibrosis

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Other cancers

Somatic variants in the IDH2 gene have been associated with other forms of cancer, including brain tumors called gliomas. Like the genetic changes that cause the conditions described above, these IDH2 gene variants are typically gain-of-function variants that lead to the production of D-2-hydroxyglutarate. D-2-hydroxyglutarate likely blocks the maturation of cells, resulting in the overproduction of immature cells and the formation of tumors.

Other Names for This Gene

  • IDH-2
  • IDHM
  • isocitrate dehydrogenase 2 (NADP+), mitochondrial

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases

References

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