A 19-year-old woman from rural India presents with recurrent muscle cramps, fatigue, and carpopedal spasm. Laboratory investigations reveal serum potassium 2.8 mEq/L, serum magnesium 1.2 mg/dL, HCO3− 31 mEq/L, and notably LOW urinary calcium excretion (FE-Ca

Question

A 19-year-old woman from rural India presents with recurrent muscle cramps, fatigue, and carpopedal spasm. Laboratory investigations reveal serum potassium 2.8 mEq/L, serum magnesium 1.2 mg/dL, HCO3− 31 mEq/L, and notably LOW urinary calcium excretion (FE-Ca <1%). Blood pressure is normal. Genetic testing confirms a homozygous missense mutation in the gene located on the structure marked **A** in the diagram. Which of the following best describes the primary functional consequence of this mutation?

Accepted Answer

C. Loss of thiazide-sensitive NaCl cotransporter function in the distal convoluted tubule, leading to salt wasting and secondary hyperaldosteronism. ## Why option 1 is correct

The structure marked **A** is Chromosome 16q13, which harbors the SLC12A3 gene encoding the thiazide-sensitive NaCl cotransporter (NCCT/NCC) in the distal convoluted tubule. Homozygous inactivating mutations in SLC12A3 cause Gitelman syndrome, an autosomal recessive tubulopathy. Loss of NCCT function phenocopies chronic thiazide diuretic use: impaired NaCl reabsorption in the DCT → mild volume contraction → activation of the renin-angiotensin-aldosterone system → secondary hyperaldosteronism → increased renal potassium and hydrogen ion wasting → hypokalemic metabolic alkalosis. The characteristic LOW urinary calcium (hypocalciuria) distinguishes Gitelman from Bartter and occurs because thiazide-type blockade paradoxically enhances proximal tubular calcium reabsorption. This is the pathophysiologic cornerstone of Gitelman syndrome (Harrison 21e Ch 311; Simon Nat Genet 1996).

## Why each distractor is wrong

- **Option 2**: This describes the function of SLC12A1 (NKCC2) on Chromosome 15, which causes Bartter syndrome when mutated. Bartter presents with hypercalciuria (not hypocalciuria) and normal serum magnesium, distinguishing it from Gitelman.
- **Option 3**: This describes SCNN1A (epithelial sodium channel) mutations on Chromosome 12, which cause autosomal dominant pseudohyperaldosteronism (PHA) with hypertension, hyperkalemia, and metabolic acidosis—the opposite electrolyte pattern.
- **Option 4**: Although TRPM6 (Chromosome 9) is downregulated in Gitelman and contributes to the profound hypomagnesemia, primary TRPM6 mutations cause familial hypomagnesemia with secondary hypocalciuria (FHHNC), a distinct disorder. The anchor mutation is in SLC12A3, not TRPM6.

**High-Yield:** Gitelman = SLC12A3 (NCCT) on Chr 16q13 → hypocalciuria + hypomagnesemia; Bartter = SLC12A1 (NKCC2) on Chr 15 → hypercalciuria + normal Mg.

[cite: Harrison 21e Ch 311; Simon Nat Genet 1996 SLC12A3]

Answer

A. Loss of Na-K-2Cl cotransporter function in the thick ascending limb, causing impaired positive charge-driven paracellular calcium reabsorption

Answer

B. Loss of epithelial sodium channel function in the collecting duct, resulting in sodium retention and hypertension

Answer

D. Loss of TRPM6 magnesium channel function in the distal convoluted tubule, causing primary magnesium wasting

Explanation

Why option 1 is correct

Why each distractor is wrong

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