A patient with pseudohypoparathyroidism type 1A has elevated PTH but hypocalcaemia and hyperphosphataemia. The target organ is unresponsive to PTH because of a mutation in which signalling component?

• A PTH receptor (PTHR1) — loss of hormone binding
• B Protein kinase A regulatory subunit — constitutive inhibition
• C Adenylyl cyclase isoform AC5 — loss of enzyme activity
• D Gsα protein (GNAS gene) — loss of adenylyl cyclase coupling ✓

Explanation

Pseudohypoparathyroidism type 1A (Albright hereditary osteodystrophy) results from a heterozygous inactivating mutation in GNAS encoding the Gsα subunit. Despite normal PTH receptor, Gsα cannot couple the receptor to adenylyl cyclase, so cAMP is not generated in kidney/bone in response to PTH, causing target organ resistance. The Ellsworth-Howard test shows blunted urinary cAMP response to exogenous PTH. Associated features include short stature, obesity, brachydactyly and round face due to imprinting effects.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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