Succinate dehydrogenase (complex II / SDH) is unique among TCA cycle enzymes because it is embedded in the inner mitochondrial membrane and also functions as complex II of the electron transport chain. Mutations in SDHB, SDHC, or SDHD subunits are associated with which cancer predisposition syndrome?

• A Von Hippel-Lindau syndrome
• B Multiple endocrine neoplasia type 2
• C Hereditary paraganglioma-pheochromocytoma syndrome ✓
• D Li-Fraumeni syndrome

Explanation

Germline mutations in SDH subunit genes (SDHA, SDHB, SDHC, SDHD, SDHAF2) cause hereditary paraganglioma-pheochromocytoma (PGL-PCC) syndrome, an autosomal dominant condition. SDH loss leads to succinate accumulation, which competitively inhibits prolyl hydroxylases (PHDs) that normally hydroxylate HIF-1α for proteasomal degradation. Succinate is therefore an 'oncometabolite,' causing pseudo-hypoxia and HIF-driven tumorigenesis. SDHB mutations carry the highest risk of malignancy. VHL syndrome involves loss of pVHL, which itself mediates HIF-1α degradation. MEN2 involves RET proto-oncogene mutations.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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