A patient with MEN2A has a pheochromocytoma and medullary thyroid carcinoma. The RET proto-oncogene mutation in MEN2A most commonly affects which codon, and what is the functional consequence?

• A Codon 634 (cysteine → arginine/other) — constitutive receptor dimerization without ligand binding ✓
• B Codon 918 (methionine → threonine) — kinase domain activation, most aggressive (MEN2B)
• C Codon 768 or 804 — low-penetrance mutations causing FMTC (familial MTC) only
• D Codon 620 — RET ectodomain mutation causing partial receptor loss of function

Explanation

MEN2A is most commonly caused by missense mutations in codon 634 (80-90% of MEN2A cases) in the extracellular cysteine-rich domain of RET. The cysteine substitution disrupts normal disulfide bonding, leaving an unpaired cysteine that forms an intermolecular disulfide bond with another RET molecule → constitutive (ligand-independent) receptor dimerization and activation of the RET tyrosine kinase. This drives medullary thyroid carcinoma (calcitonin-secreting C-cell tumors), pheochromocytoma, and parathyroid hyperplasia. Codon 918 (M918T) causes MEN2B with more aggressive MTC.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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