A patient with McCune-Albright syndrome has constitutively active Gs-alpha protein in multiple tissues due to a somatic activating mutation. The biochemical consequence of a constitutively active Gs-alpha is:

• A Persistent inhibition of adenylate cyclase and reduced cAMP production
• B Persistent activation of phospholipase C, elevated IP3 and DAG
• C Constitutive activation of adenylate cyclase, persistently elevated cAMP activating PKA in affected tissues ✓
• D Constitutive activation of receptor tyrosine kinase downstream signalling

Explanation

Gs-alpha normally exchanges GDP for GTP when activated by a Gs-coupled receptor, then stimulates adenylate cyclase to produce cAMP; intrinsic GTPase activity terminates signalling by hydrolysing GTP to GDP. The McCune-Albright mutation (Arg201Cys or Arg201His) abolishes GTPase activity of Gs-alpha, causing it to remain permanently GTP-bound and constitutively active. This leads to continuous adenylate cyclase activation, persistent cAMP elevation, and constitutive PKA activation in affected tissues. In gonads this causes precocious puberty; in thyroid, hyperthyroidism; in adrenal, Cushing's syndrome; in bone, fibrous dysplasia. The same Gsp mutation mechanism underlies ~40% of somatotroph adenomas causing acromegaly.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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