Dent Disease with Mutations in OCRL1

Abstract

Dent disease is an X-linked renal proximal tubulopathy associated with mutations in the chloride channel gene CLCN5. Lowe syndrome, a multisystem disease characterized by renal tubulopathy, congenital cataracts, and mental retardation, is associated with mutations in the gene OCRL1, which encodes a phosphatidylinositol 4,5-bisphosphate (PIP(2)) 5-phosphatase. Genetic heterogeneity has been suspected in Dent disease, but no other gene for Dent disease has been reported. We studied male probands in 13 families, all of whom met strict criteria for Dent disease but lacked mutations in CLCN5. Linkage analysis in the one large family localized the gene to a candidate region at Xq25-Xq27.1. Sequencing of candidate genes revealed a mutation in the OCRL1 gene. Of the 13 families studied, OCRL1 mutations were found in 5. PIP(2) 5-phosphatase activity was markedly reduced in skin fibroblasts cultured from the probands of these five families, and protein expression, measured by western blotting, was reduced or absent. Slit-lamp examinations performed in childhood or adulthood for all five probands showed normal results. Unlike patients with typical Lowe syndrome, none of these patients had metabolic acidosis. Three of the five probands had mild mental retardation, whereas two had no developmental delay or behavioral disturbance. These findings demonstrate that mutations in OCRL1 can occur with the isolated renal phenotype of Dent disease in patients lacking the cataracts, renal tubular acidosis, and neurological abnormalities that are characteristic of Lowe syndrome. This observation confirms genetic heterogeneity in Dent disease and demonstrates more-extensive phenotypic heterogeneity in Lowe syndrome than was previously appreciated. It establishes that the diagnostic criteria for disorders resulting from mutations in the Lowe syndrome gene OCRL1 need to be revised.

All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding

“…Recently, mutations in this gene have also been described in patients with Dent disease, a condition involving kidney reabsorption defects similar to those observed in Lowe syndrome [2]. Inositol 5-phosphtases dephosphorylate the five position of inositol polyphosphates and of phosphoinositides [3].…”

Two closely related endocytic proteins that share a common OCRL-binding motif with APPL1

“…This condition, also referred to as "Lowe syndrome," is a severe X-linked disorder characterized by congenital cataracts (12), kidney readsorption defects caused by proximal tubule dysfunction, cognitive impairment, muscle hypotonia, and autism spectrum behavioral disorders (13,14). The other condition is Dent disease, an X-linked disorder involving kidney defects very similar to those associated with Lowe syndrome but, for reasons not yet known, few other dysfunctions (15)(16)(17)(18)(19).OCRL comprises an N-terminal Pleckstrin Homology (PH) domain followed in sequence by a central inositol 5′-phosphatase domain, an ASPM-SPD-2-Hydin (ASH) domain, and a catalytically inactive RhoGAP (GTPase Activating Protein)-like domain (20). OCRL interacts with several endocytic proteins, including clathrin (20-23), the clathrin adaptor AP2 (21, 24), and several endocytic (e. g., Rab5) (25, 26) and nonendocytic Rab GTPases (20, 26, 27).…”

An atypical Dent’s disease phenotype caused by co-inheritance of mutations at CLCN5 and OCRL genes

“…Excepting very few cases, the OCRL mutations associated with Dent disease 2 do not overlap with those causing Lowe syndrome. 10,20,24 Missense mutations occur in the middle region of the gene (exons 9-15), whereas truncating mutations are found exclusively in the first 7 exons; the OCRL mutations associated with Lowe syndrome are located instead in the 3 0 region of the gene (exons [9][10][11][12][13][14][15][16][17][18][19][20][21][22] and involve all three functional OCRL1 domains, whereas frameshift and nonsense mutations cluster in exons [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. The different distribution of OCRL mutations in Dent disease 2 and Lowe syndrome suggests a genotype-phenotype correlation that has yet to be thoroughly explored.…”

“…7,8 No CLCN5 gene mutations are detected in approximately 40% of patients with the classic symptoms of Dent's disease, suggesting a locus heterogeneity. The OCRL gene located on chromosome Xq26.1, whose mutations cause Lowe syndrome, has recently been found altered in 20% Dent's patients, 9 but about 20% of patients carry neither CLCN5 nor OCRL mutations. [10][11][12][13] Dent's disease tends to become manifest in childhood or early adult life.…”