SDHD

Mutations in the SDHD gene are a rare cause of gastrointestinal stromal tumor (GIST), which is a type of tumor that occurs in the gastrointestinal tract. Mutation of 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. People with SDH-deficient GIST caused by SDHD gene mutations tend to also develop paragangliomas (described below); this combination of tumors is a condition known as Carney-Stratakis syndrome.

An inherited (germline) mutation in the SDHD 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. 

SDHD gene mutations associated with GIST prevent the production of functional SDHD 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 100 mutations in the SDHD gene have been identified in people with hereditary paraganglioma-pheochromocytoma type 1. People with this condition have paragangliomas, pheochromocytomas, or both. These noncancerous (benign) tumors are associated with the nervous system. An inherited SDHD gene mutation predisposes an individual to the condition. An additional, somatic mutation that deletes the normal copy of the gene is needed to cause hereditary paraganglioma-pheochromocytoma type 1. 

Most of the inherited SDHD gene mutations associated with hereditary paraganglioma-pheochromocytoma type 1 change single protein building blocks (amino acids) in the SDHD 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 SDHD 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 these mutations change single amino acids in the SDHD protein. As in GIST and hereditary paraganglioma-pheochromocytoma type 1 (described above), these mutations are expected to decrease SDH enzyme activity, which 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.

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