Renal disease with OCRL1 mutations: Dent-2 or Lowe syndrome?

Dent disease is an X-linked tubulopathy, characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and nephrolithiasis that may progress to advanced renal failure [1,2]. During the last decade, loss-of-function mutations of the CLCN5 gene, which is located in chromosome Xp11.22 and encodes the renal chloride/proton antiporter ClC-5, have been consistently reported in patients with Dent disease [3]. However, in about 40% of patients with a Dent-like phenotype, no CLCN5 mutations are found [4]. In 2005, Hoopes et al. [4] showed for the first time that the Dent phenotype may also be caused by mutations in the OCRL1 gene, which encodes a phophatidylinositol 4,5-phosphate (PIP2) 5-phosphatase, located in the trans-Golgi network. These findings were confirmed by other reports [4–6] and led to the definition of two types of Dent disease: Dent-1, caused by CLCN5 mutations (OMIM #300009) and Dent-2, caused by OCRL1 mutations (OMIM #300555), which accounts for about 15–20% of Dent cases [7]. PIP2 5-phosphatase, which is encoded by the OCRL1 gene, is expressed ubiquitously in human tissues, including the eyes, kidneys and brain, the main organs involved in Lowe syndrome. This protein is distributed predominantly in the Golgi complex, lysosomes and endosomes [8]. Both ClC-5 and PIP2 5-phosphatase are expressed in endosomes of the proximal tubular cells and thought to be related to the recycling of multi-ligand receptors, such as megalin and cubilin, which are commonly involved in both Dent-1 and Dent-2 disease. Further genetic heterogeneity is assumed to exist, since there are patients expressing the distinctive phenotype of Dent disease, in which no mutation was identified in either CLCN5 or OCRL1 genes [4]. The OCRL1 gene is also mutated in the oculocerebrorenal syndrome of Lowe (OMIM #309000), which is a rare X-linked disorder, characterized by bilateral congenital cataracts, mental retardation and a selective proximal tubular dysfunction very similar to the renal phenotype of patients with Dent disease [9]. However, progressive renal failure is common, and is typically more aggressive and occurs at an earlier age than in Dent-2 disease. Thus, loss of Ocrl1 function can cause a spectrum of renal, as well as systemic symptoms. In this issue of Journal of Pediatric Genetics, Bockenhauer et al. [10] report their study of 14CLCN5 negative patients from 12 families with a phenotype resembling Dent-2 disease, for defects in OCRL1. In six of these patients, they identified three novel mutations and another three known mutations in the OCRL1 gene. None of these mutations has been described in patients with the classic Lowe syndrome. The renal phenotype of these patients was similar to that of patients harboring the CLCN5 gene mutations, except for a lower prevalence of nephrocalcinosis. *Corresponding author: Dganit Dinour, Department of Nephrology and Hypertension, The Chaim Sheba Medical Center, Tel-Hashomer, Israel. E-mail: [email protected]. Journal of Pediatric Genetics 1 (2012) 3–5 DOI 10.3233/PGE-2012-002 IOS Press 3