Dominant mutations in ATP1A1, encoding the alpha-1 isoform of the Na<sup>+</sup> /K<sup>+</sup> -ATPase, have been recently reported to cause an axonal to intermediate type of Charcot-Marie-Tooth disease (ie, CMT2DD) and a syndrome with hypomagnesemia, intractable seizures and severe intellectual disability.
To better understand the role of the inward-rectifying K channel Kir4.1 (KCNJ10) in the distal nephron, we initially studied a global Kir4.1 knockout mouse (gKO), which demonstrated the hypokalemia and hypomagnesemia seen in SeSAME/EAST syndrome and was associated with reduced Na/Cl cotransporter (NCC) expression.
Gitelman syndrome (GS) is an autosomal recessive disease characterized by hypokalemic metabolic alkalosis in combination with significant hypomagnesemia and hypocalciuria which is caused by mutations in the SLC12A3 gene.
Loss of function of mutated solute carrier family 12 member 3 (SLC12A3) gene is the most frequent etiology for Gitelman syndrome (GS), which is mainly manifested by hypokalemia, hypomagnesemia and hypocalciuria.
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is a rare autosomal recessive renal disease caused by mutations in genes for the tight junction transmembrane proteins Claudin-16 (CLDN16) and Claudin-19 (CLDN19).
The molecular mechanism by which gamma-Na(+)/K(+)-ATPase is involved in DCT Mg(2+) handling remains unknown; (v) a high percentage of patients with mutations in the renal transcription factor HNF1B (hepatocyte nuclear factor 1 homeobox B) gene develop hypomagnesemia; and (vi) Gitelman and EAST/SeSAME syndrome patients suffer from a similar tubulopathy due to mutations in NCC (NaCl cotransporter) and Kir4.1, respectively.
Dent's disease, an X-linked disorder characterized by low molecular weight proteinuria, hypercalciuria and nephrolithiasis, is due to mutations of the chloride/proton antiporter 5, CLC-5; ADHH is associated with activating mutations of the CaSR, which is a G-protein-coupled receptor; hypophosphatemic hypercalciuric nephrolithiasis associated with rickets is due to mutations in the type 2c sodium-phosphate co-transporter (NPT2c); and familial hypomagnesemia with hypercalciuria is due to mutations of paracellin-1, which is a member of the claudin family of membrane proteins that form the intercellular tight junction barrier in a variety of epithelia.
Mutations in the claudin 16 (paracellin) paracellular protein in the thick ascending limb (TAL) of Henle's loop and in the transient receptor potential cation channel, subfamily 6, member 6 (TRPM6) magnesium channel expressed in distal tubules found in patients with renal magnesium wasting and hypomagnesemia underscore the importance of these transport proteins.
Dent's disease, an X-linked disorder characterized by low molecular weight proteinuria, hypercalciuria, and nephrolithiasis, is due to mutations of the chloride/proton antiporter, CLC-5; ADHH is associated with activating mutations of the calcium-sensing receptor, which is a G protein-coupled receptor; hypophosphatemic hypercalciuric nephrolithiasis associated with rickets is due to mutations in the type 2c sodium-phosphate cotransporter (NPT2c); and familial hypomagnesemia with hypercalciuria is due to mutations of paracellin-1, which is a member of the claudin family of membrane proteins that form the intercellular tight junction barrier in a variety of epithelia.
These results suggest that Gitelman syndrome requires 2 compound heterozygotic mutations and the coexistence of the large deletion in the C-terminal domain with Met672Ile substitution of the TSC could impair the transporter activity underling the hypokalemia and hypomagnesemia in this patient.
The latter has been exemplified by the discovery of claudin 16 (paracellin-1) as the gene product responsible for the hypomagnesaemia with hypercalciuria syndrome.
This case indicates the pathogenetic role of paracellin-1 mutation in familial hypomagnesemia with hypercalciuria and nephrocalcinosis and further underlines the risk of stone formation in heterozygous mutation carriers.
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: blocking endocytosis restores surface expression of a novel Claudin-16 mutant that lacks the entire C-terminal cytosolic tail.