Blanchard A, Jeunemaitre X, Coudol P, Dechaux M, Froissart M, May A, Demontis R, Fournier A, Paillard M, Houillier P
Département de Physiologie et Radio-Isotopes, Université Pierre et Marie Curie, INSERM U356, Institut Fédératif de Recherche 58, Laboratoire de Génétique Moléculaire, Hôpital Universitaire Européen Georges Pompidou, Paris, France.
Kidney Int. 2001 Jun;59(6):2206-15. doi: 10.1046/j.1523-1755.2001.00736.x.
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.
一种名为paracellin 1（PCLN-1）的新蛋白质在人类厚壁升支（TAL）紧密连接中表达，可能在镁和钙重吸收的控制中起关键作用，因为低镁血症高钙尿综合征（HHS）中存在PCLN-1突变。然而，尚无功能实验证明HHS患者的TAL镁和钙重吸收实际上受损。
对两名无关的HHS患者的家族进行了基因研究。分析了每个家族中一名纯合患病患者、一名肾外低镁血症（ERH）患者和两名对照受试者（CSs）的TAL中肾镁和钙的重吸收情况。
我们发现了PCLN-1的两个尚未描述的突变（Gly 162 Val，Ala 139 Val）。在HHS患者中，肾镁和钙的重吸收如预期受损；在缺钠期间肾对氯化钠的保留以及稀释段中氯化钠的肾小管重吸收均正常。对CSs静脉注射速尿显著增加了氯化钠、镁和钙的尿排泄率。在HHS患者中，速尿同样增加了氯化钠排泄，但未能增加镁和钙排泄。对CSs和ERH患者静脉注射急性氯化镁会引起尿钙排泄显著增加，而氯化钠排泄无变化。当与氯化镁注射联合时，速尿注射仍能诱导正常的利钠反应，但无法进一步增加尿镁和钙排泄。在HHS患者中，对氯化镁注射的尿钙反应减弱。
据我们所知，本研究首次证明PCLN-1的纯合突变导致TAL中细胞旁镁和钙重吸收的选择性缺陷，而该部位氯化钠重吸收能力正常。此外，该研究支持基底外侧镁离子和钙离子浓度对TAL二价阳离子细胞旁通透性具有选择性生理作用，即PCLN-1活性。
