In pseudohypoparathyroidism type Ia (PHP-Ia), PTH levels are high but the end-organ response is absent. The molecular defect is in:

• A Loss-of-function mutation in Gs-alpha (GNAS gene) ✓
• B Gain-of-function mutation in the PTH receptor
• C Absence of adenylyl cyclase in renal tubular cells
• D Deficiency of protein kinase A catalytic subunit

Explanation

PHP-Ia (Albright's hereditary osteodystrophy) is caused by a heterozygous loss-of-function mutation in the GNAS gene encoding the alpha-subunit of the stimulatory G protein (Gsα). Without functional Gsα, PTH cannot activate adenylyl cyclase, so cAMP fails to rise and the kidney does not respond, causing hypocalcaemia and hyperphosphataemia despite elevated PTH. The PTH receptor itself is intact.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.