A 28-year-old woman is diagnosed with pseudohypoparathyroidism type Ia (Albright hereditary osteodystrophy). Labs show hypocalcemia, hyperphosphatemia, and elevated PTH. The underlying molecular defect is:

• A Inactivating mutation in the PTH receptor ligand-binding domain
• B Loss-of-function mutation in the Gsα subunit (GNAS gene) causing cAMP generation failure ✓
• C Gain-of-function mutation in calcium-sensing receptor (CaSR)
• D Deficiency of vitamin D 1-alpha-hydroxylase

Explanation

Pseudohypoparathyroidism type Ia is caused by heterozygous inactivating mutations in GNAS (encoding the Gsα protein). PTH binds its receptor normally, but Gsα cannot activate adenylyl cyclase sufficiently, resulting in inadequate cAMP generation in renal tubules. Without cAMP-mediated PKA activation, renal phosphate excretion fails and calcium reabsorption is impaired, producing the biochemical pattern of hypoparathyroidism despite elevated PTH levels. PTH receptor mutations cause type Ib, CaSR gain-of-function causes autosomal dominant hypocalcemia, and 1-alpha-hydroxylase deficiency causes vitamin D-dependent rickets type 1.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.