Impaired paracellular ion transport in the loop of Henle causes familial hypomagnesemia with hypercalciuria and nephrocalcinosis

Abstract

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare tubular disorder caused by mutations in genes coding for tight junction (TJ) proteins. TJs define the paracellular path between adjacent cells and thereby play a pivotal role for the regulation of the paracellular ion permeability of epithelia. The family of TJ proteins comprise a variety of transmembrane proteins, including the claudins. Multiple distinct mutations in the genes for claudin-16 and -19 have been described to be responsible for FHHNC. Both encoded proteins are especially important for the paracellular reabsorption of Mg(2+) and Ca(2+) in the thick ascending limb of Henle's loop. Interestingly, in addition to ion disturbances, FHHNC leads to chronic renal failure and may be associated with extrarenal symptoms.