SDHB

At least four mutations in the SDHB gene have been found in people with a gastrointestinal stromal tumor (GIST), which is a type of tumor that occurs in the gastrointestinal tract. Mutations in this gene cause SDH-deficient GIST, which accounts for less than 10 percent of GIST cases. SDH-deficient GISTs usually occur in childhood or early adulthood and are almost always found in the stomach. Individuals with an SDH-deficient GIST have a high risk of developing other types of tumors, particularly noncancerous tumors in the nervous system called paragangliomas (described below) and noncancerous lung tumors called pulmonary chondromas. People with SDH-deficient GIST caused by SDHB gene mutations often also develop paragangliomas; this combination of tumors is a condition known as Carney-Stratakis syndrome. Rarely, individuals with these mutations develop only GIST or a different combination of tumors. The combination of GIST, paraganglioma, and pulmonary chondroma is known as Carney triad; and the combination of GIST and pulmonary chondroma is known as incomplete Carney triad.

An inherited (germline) mutation in the SDHB gene increases the risk that an individual will develop a GIST. However, an additional mutation that alters or deletes the normal copy of the gene is needed to cause tumor formation. This second mutation, called a somatic mutation, is acquired during a person's lifetime and is present only in tumor cells. SDHB gene mutations associated with GIST prevent the production of functional SDHB protein. Without this subunit, the SDH enzyme either cannot form or is unstable and broken down quickly. As a result, there is little or no SDH enzyme activity. Without the SDH enzyme, succinate is not converted to fumarate, and succinate builds up in the cell. The excess succinate abnormally stabilizes the HIF protein, which also builds up in cells. Excess HIF protein stimulates cells to divide and triggers the production of blood vessels when they are not needed. Rapid and uncontrolled cell division, along with the formation of new blood vessels, can lead to the development of tumors.

More than 150 mutations in the SDHB gene have been identified in people with hereditary paraganglioma-pheochromocytoma type 4. People with this condition have paragangliomas, pheochromocytomas, or both. Paragangliomas and pheochromocytomas (a type of paraganglioma) are noncancerous tumors associated with the nervous system. An inherited SDHB gene mutation predisposes an individual to the condition, and a somatic mutation that deletes the normal copy of the gene is needed to cause hereditary paraganglioma-pheochromocytoma type 4.

Most of the inherited SDHB gene mutations involved in hereditary paraganglioma-pheochromocytoma type 4 change single protein building blocks (amino acids) in the SDHB protein sequence or result in a shortened protein. As a result, there is little or no SDH enzyme activity. As in GIST (described above), the reduction of SDH enzyme activity stabilizes the HIF protein, causing it to build up in cells. Excess HIF protein abnormally stimulates cell division and the formation of blood vessels, which can lead to tumor formation.

Mutations in the SDHB gene are found in some cases of nonsyndromic paraganglioma or pheochromocytoma, which are forms of the condition that occur in people with no history of these tumors in their families. Most of the SDHB gene mutations involved in nonsyndromic paraganglioma change single amino acids in the SDHB protein. As in other tumors (described above), these mutations are expected to reduce SDH enzyme activity, which stabilizes the HIF protein. As a result, HIF builds up in cells. Excess HIF protein abnormally stimulates cell division and the formation of blood vessels, which can lead to tumor formation.

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The SDHB gene is involved in several cancers. Mutations in the SDHB gene have been found in a small number of people with renal cell carcinoma, which is a type of kidney cancer. SDHB gene mutations have also been identified in people with both renal cell cancer and paraganglioma (described above). An inherited SDHB gene mutation predisposes an individual to cancer formation. An additional, somatic mutation that deletes the normal copy of the gene is needed to cause renal cell cancer and other tumor types.

Mutations of the SDHB gene lead to a reduction in the amount of SDHB protein in the cell and loss of SDH enzyme activity. Lack of SDH enzyme activity results in abnormal hypoxia signaling and formation of tumors.