Paracellin-1, a Renal Tight Junction Protein Required for Paracellular Mg ²⁺ Resorption

Abstract

Epithelia permit selective and regulated flux from apical to basolateral surfaces by transcellular passage through cells or paracellular flux between cells. Tight junctions constitute the barrier to paracellular conductance; however, little is known about the specific molecules that mediate paracellular permeabilities. Renal magnesium ion (Mg2+) resorption occurs predominantly through a paracellular conductance in the thick ascending limb of Henle (TAL). Here, positional cloning has identified a human gene, paracellin-1 (PCLN-1), mutations in which cause renal Mg2+ wasting. PCLN-1 is located in tight junctions of the TAL and is related to the claudin family of tight junction proteins. These findings provide insight into Mg2+ homeostasis, demonstrate the role of a tight junction protein in human disease, and identify an essential component of a selective paracellular conductance.

Tight junction-based epithelial microenvironment and cell proliferation

“…As an example, it is well known that paracellular ionic permeability dominates the transcellular ionic permeability in the small intestine (Frizzell and Schultz, 1972;Okada et al, 1977), and has an important function in the intestinal physiology, such as in the absorption of nutrients (Hopfer, 1977;Turk et al, 1991). Similarly, re-absorption of ions through paracellular pathways in the kidney is very important for regulating the ionic homeostasis of the body (Simon et al, 1999). Non-ionic solutes are thought to permeate through paracellular as well as transcellular pathways (Watson et al, 2001) and the molecular mechanisms for the permeabilities for ions and solutes appear to vary depending on the cell type, with the characteristics of the conductance-flux paradox (Yap et al, 1998;Van Itallie and Anderson, 2006a).…”

“…Hypomagnesemia was reported to result from mutations in paracellin (claudin-16) (Simon et al, 1999). Similarly, hypomagnesemia and hypercalcinuria were reported to be induced by mutations in claudin-19 as well as in claudin-16 (Konrad et al, 2006).…”

The specific fates of tight junction proteins in apoptotic epithelial cells

“…A mutation in the claudin-14 gene was found to be responsible for human hereditary deafness (Wilcox et al, 2001). Patients with hereditary hypomagnesaemia were shown to have a mutated claudin-16/paracelllin-1 gene (Simon et al, 1999;Weber et al, 2001). In inflammatory bowel disease tight junction dysfunction also appears to contribute to the clinical phenotype Schmitz et al, 1999b).…”

Clinical utility gene card for: familial hypomagnesemia with hypercalciuria and nephrocalcinosis with/without severe ocular involvement

“…1,2 These genes encode the tight-junction proteins claudin-16 (paracellin-1) and claudin-19, respectively, which are important for the paracellular reabsorption of calcium and magnesium in the thick ascending limb of Henle's loop. 3 Claudin-19 is also expressed in the retinal epithelium.…”