Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis: clinical and molecular characteristics

Abstract

Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal-recessive renal tubular disorder characterized by excessive urinary losses of magnesium and calcium, bilateral nephrocalcinosis and progressive chronic renal failure. Presentation with FHHNC symptoms generally occurs early in childhood or before adolescence. At present, the only therapeutic option is supportive and consists of oral magnesium supplementation and thiazide diuretics. However, neither treatment seems to have a significant effect on the levels of serum magnesium or urine calcium or on the decline of renal function. In end-stage renal disease patients, renal transplantation is the only effective approach. This rare disease is caused by mutations in the CLDN16 or CLDN19 genes. Patients with mutations in CLDN19 also present severe ocular abnormalities such as myopia, nystagmus and macular colobamata. CLDN16 and CLDN19 encode the tight-junction proteins claudin-16 and claudin-19, respectively, which are expressed in the thick ascending limb of Henle's loop and form an essential complex for the paracellular reabsorption of magnesium and calcium. Claudin-19 is also expressed in retinal epithelium and peripheral neurons. Research studies using mouse and cell models have generated significant advances on the understanding of the pathophysiology of FHHNC. A recent finding has established that another member of the claudin family, claudin-14, plays a key regulatory role in paracellular cation reabsorption by inhibiting the claudin-16-claudin-19 complex. Furthermore, several studies on the molecular and cellular consequences of disease-causing CLDN16 and CLDN19 mutations have provided critical information for the development of potential therapeutic strategies.

Keywords: claudin-16; claudin-19; genetic disease; magnesium; renal tubulopathy.

Fig. 1.

Schematic representation of tight junctions and putative location of claudin-16 and claudin-19. (A) TJs are the most apical intercellular junctions in epithelial cells of the nephron. They are composed of multiprotein complexes that include mainly claudins, occludin and the junctional adhesion molecules. (B) These protein components are arranged like beads on a string that span the adjacent membranes of each TJ. (C) Claudin-16 and claudin-19 are mainly found in TJs of epithelial cells of the TAL. They interact with each other, generating cation-selective pores.

Fig. 2.

Membrane model of claudins. The conserved structural features of claudins, four transmembrane domains (TM1–4), extracellular segments (ECS1 and ECS2) and ECH, are shown.

Fig. 3.

Paracellular reabsorption of magnesium and calcium in the TAL of Henle's loop. This transport depends on the lumen-positive electrical potential established by the transcellular reabsorption of other cations and anions. Reabsorption of Na⁺, K⁺ and Cl⁻ through the apical membrane occurs via the NKCC2 co-transporter. Na⁺ and Cl⁻ leave the epithelial cell through the Na⁺/K⁺-adenosine 5′-triphosphatase (ATPase) and the ClC-Kb channel at the basolateral membrane, respectively. K⁺ is excreted to the lumen by the ROMK channel. The backflow of Na⁺ through the paracellular channel, as a consequence of diminishing luminal Na⁺ concentrations, is an additional contributor to the lumen-positive voltage that forces magnesium and calcium reabsorption. Claudin-16 and claudin-19 facilitate the paracellular transport of magnesium and calcium. Activation of CaSR by extracellular calcium upregulates claudin-14, which in turn interacts with the claudin-16/claudin-19 complex and inhibits its cation permeability.