A new protein, named paracellin 1 (PCLN-1), expressed in human thick ascending limb
(TAL) tight junctions, possibly plays a critical role in the control of magnesium
and calcium reabsorption, since mutations of PCLN-1 are present in the hypomagnesemia
hypercalciuria syndrome (HHS). However, no functional experiments have demonstrated
that TAL magnesium and calcium reabsorption were actually impaired in patients with
HHS.
Genetic studies were performed in the kindred of two unrelated patients with HHS.
Renal magnesium and calcium reabsorption in TAL were analyzed in one homozygous affected
patient of each family, one patient with extrarenal hypomagnesemia (ERH), and two
control subjects (CSs).
We found two yet undescribed mutations of PCLN-1 (Gly 162 Val, Ala 139 Val). In patients
with HHS, renal magnesium and calcium reabsorptions were impaired as expected; NaCl
renal conservation during NaCl deprivation and NaCl tubular reabsorption in diluting
segment were intact. Furosemide infusion in CS markedly increased NaCl, Mg, and Ca
urinary excretion rates. In HHS patients, furosemide similarly increased NaCl excretion,
but failed to increase Mg and Ca excretion. Acute MgCl(2) infusion in CS and ERH patient
provoked a dramatic increase in urinary calcium excretion without change in NaCl excretion.
When combined with MgCl(2) infusion, furosemide infusion remained able to induce normal
natriuretic response, but was unable to increase urinary magnesium and calcium excretion
further. In HHS patients, calciuric response to MgCl(2) infusion was blunted.
This study is the first to our knowledge to demonstrate that homozygous mutations
of PCLN-1 result in a selective defect in paracellular Mg and Ca reabsorption in the
TAL, with intact NaCl reabsorption ability at this site. In addition, the study supports
a selective physiological effect of basolateral Mg(2+) and Ca(2+) concentration on
TAL divalent cation paracellular permeability, that is, PCLN-1 activity.