Anglani, Franca

Dent disease is a rare X-linked renal tubulopathy due to CLCN5 and OCRL (DD2) mutations. OCRL mutations also cause Lowe syndrome (LS) involving the eyes, brain and kidney. DD2 is frequently described as a mild form of LS because some patients may present with extra-renal symptoms (ESs). Since DD2 is a rare disease and there are a low number of reported cases, it is still unclear whether it has a clinical picture distinct from LS. We retrospectively analyzed the phenotype and genotype of our cohort of 35 DD2 males and reviewed all published DD2 cases. We analyzed the distribution of mutations along the OCRL gene and evaluated the type and frequency of ES according to the type of mutation and localization in OCRL protein domains. The frequency of patients with at least one ES was 39%. Muscle findings are the most common ES (52%), while ocular findings are less common (11%). Analysis of the distribution of mutations revealed (1) truncating mutations map in the PH and linker domain, while missense mutations map in the 5-phosphatase domain, and only occasionally in the ASH-RhoGAP module; (2) five OCRL mutations cause both DD2 and LS phenotypes; (3) codon 318 is a DD2 mutational hot spot; (4) a correlation was found between the presence of ES and the position of the mutations along OCRL domains. DD2 is distinct from LS. The mutation site and the mutation type largely determine the DD2 phenotype.

AbstractThis review examines calcium and phosphate transport in the kidney through the lens of the rare X‐linked genetic disorder Dent disease. Dent disease type 1 (DD1) is caused by mutations in the CLCN5 gene encoding ClC‐5, a Cl−/H+ antiporter localized to early endosomes of the proximal tubule (PT). Phenotypic features commonly include low molecular weight proteinuria (LMWP), hypercalciuria, focal global sclerosis and chronic kidney disease; calcium nephrolithiasis, nephrocalcinosis and hypophosphatemic rickets are less commonly observed. Although it is not surprising that abnormal endosomal function and recycling in the PT could result in LMWP, it is less clear how ClC‐5 dysfunction disturbs calcium and phosphate metabolism. It is known that the majority of calcium and phosphate transport occurs in PT cells, and PT endocytosis is essential for calcium and phosphorus reabsorption in this nephron segment. Evidence from ClC‐5 KO models suggests that ClC‐5 mediates parathormone endocytosis from tubular fluid. In addition, ClC‐5 dysfunction alters expression of the sodium/proton exchanger NHE3 on the PT apical surface thus altering transcellular sodium movement and hence paracellular calcium reabsorption. A potential role for NHE3 dysfunction in the DD1 phenotype has never been investigated, either in DD models or in patients with DD1, even though patients with DD1 exhibit renal sodium and potassium wasting, especially when exposed to even a low dose of thiazide diuretic. Thus, insights from the rare disease DD1 may inform possible underlying mechanisms for the phenotype of hypercalciuria and idiopathic calcium stones.

Intrahepatic bile duct cells (cholangiocytes) play an important role in the secretion and alkalinization of bile. Both Na+/H+exchange (NHE) and Cl−/[Formula: see text]exchange (AE) contribute to these functions, but their functional distribution between the apical and basolateral membrane domains remains speculative. We have addressed this issue in a normal rat cholangiocyte cell line (NRC-1), which maintains a polarized distribution of membrane markers. Gene expression of AE and NHE isoforms was studied by RT-PCR. For functional studies, cells were placed in a chamber that allowed separate perfusion of the apical and basolateral aspect of the epithelial sheet; intracellular pH (pHi) was measured by 2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein microfluorometry. In[Formula: see text]-CO2free medium and in the presence of apical amiloride, pHirecovery from an acid load was Na+dependent and was inhibited by basolateral amiloride and by HOE-642 (10 μM), consistent with basolateral localization of the NHE1 isoform, which had clearly expressed mRNA. Apical Na+readmission induced a slow pHirecovery that was inhibited by apical administration of 1 mM HOE-642 or amiloride. Among the apical NHE isoforms, NHE2 but not NHE3 gene expression was detected. The AE1 gene was not expressed, but two different variants of AE2 mRNAs (AE2a and AE2b) were detected; pHiexperiments disclosed AE activities at both sides of the membrane, but only apical AE was activated by cAMP. In conclusion, these studies provide the first functional description of acid-base transporters in a polarized cholangiocyte cell line. NHE1, NHE2, AE2a, and AE2b isoforms are expressed and show different membrane polarity, functional properties, and sensitivity to inhibitors. These observations add a considerable level of complexity to current models of electrolyte transport in cholangiocytes.