CLDN16

Claudin-16, also known as paracellin-1, is a member of the claudin family of tight junction proteins. It is a four-pass transmembrane protein that localizes to tight junctions in epithelial cells and contributes to the paracellular barrier and ion selectivity of tight junction strands.

In the kidney, the CLDN16 gene encodes Claudin-16 and is expressed primarily in renal tubular epithelium, notably the thick ascending limb of the loop of Henle and, to a lesser extent, the distal tubule. There, Claudin-16 forms part of the paracellular pathway that regulates cation permeability, particularly magnesium and calcium ions, and thus participates in transcellular and paracellular reabsorption processes essential for electrolyte balance.

Mutations in CLDN16 cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), an autosomal recessive inherited tubulopathy. Pathogenic variants lead to loss of Claudin-16 function, resulting in impaired Mg2+ and Ca2+ reabsorption in the nephron and consequent magnesium wasting, hypercalciuria, and deposition of calcium salts in renal tissue (nephrocalcinosis). The clinical course typically features early-onset hypomagnesemia and may progress to chronic kidney disease over time.

Genetic variants include missense, nonsense, frameshift, and splice-site mutations, often affecting protein localization or stability. Management is supportive and focuses on magnesium supplementation and monitoring renal function; genetic counseling is advised due to the autosomal recessive inheritance. CLDN16-related disease is part of a broader group of hereditary tubulopathies affecting tubular reabsorption and electrolyte balance, with CLDN19 mutations representing a related but distinct clinical constellation.