Dent disease with mutation in OCRL1

Department of Medicine, SUNY Upstate Medical University, Syracuse, NY, USA.
The American Journal of Human Genetics (Impact Factor: 10.99). 03/2005; 76(2):260-7. DOI: 10.1086/427887
Source: PubMed

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.

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Available from: Velibor Tasic, Aug 25, 2015
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    • "Therefore , mutations in CLCN5 or OCRL impair these cellular processes resulting in the defects observed in Dent's disease. Dent disease-2 patients tend to manifest some signs of Lowe syndrome such as ocular abnormalities, short stature, and mild mental impairment [8]. We have previously reported fifteen Spanish families with Dent's disease and CLCN5 mutations [3] [14] [15]. "
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    ABSTRACT: Dent’s disease is an X-linked proximal tubulopathy characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis and progressive renal failure. This disorder is frequently caused by mutations in the CLCN5 gene encoding the electrogenic chloride/proton exchanger ClC-5. Occasionally, Dent’s disease has been associated to atypical cases of asymptomatic proteinuria with focal glomerulosclerosis. Twelve unrelated patients with Dent’s disease, including two who presented with asymptomatic proteinuria and developed glomerulosclerosis, were studied. Mutational analysis of the CLCN5 gene was performed by DNA sequencing. We identified thirteen distinct CLCN5 mutations in the twelve patients. Seven of these mutations, p.P416fsX*17, p.[H107P, V108fs*27], p.G466D, p.G65R, p.G462S, p.Y164* and c.723+1G >T, were novel and possibly pathogenic. In one family, the patient’s mother was not a carrier of the respective mutation. Our results increased the spectrum of CLCN5 disease causing defects with seven new pathogenic mutations and established a de novo origin in one of them. Remarkably, three new missense mutations, p.G466D, p.G65R and p.G462S, affect highly conserved glycine residues located in transmembrane α-helix GxxxG packing motifs. The two atypical cases further support that the diagnosis of Dent’s disease should be considered in children with asymptomatic proteinuria and focal glomerulosclerosis and without evidence of primary glomerular disease.
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    • "disorder characterized by congenital cataracts, mental retardation, and renal Fanconi syndrome (Attree et al., 1992). OCRL mutations were also identified in a subset of Dent disease patients, a condition that, like Lowe syndrome , is associated with loss of low-molecular weight proteins and electrolytes in the urine (Hoopes et al., 2005). OCRL has a multidomain structure, with a central 5- phosphatase domain, whose preferred substrates are PI(4,5)P 2 and PI(3,4,5)P 3 (Schmid et al., 2004; Zhang et al., 1995), followed by a sequence recently defined as an ASH domain (ASPM, SPD2, Hydin) (Ponting, 2006) and by a COOH-terminal, catalytically inactive RhoGAP domain. "
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    ABSTRACT: Mutations in the inositol 5-phosphatase OCRL are responsible for Lowe syndrome, whose manifestations include mental retardation and renal Fanconi syndrome. OCRL has been implicated in membrane trafficking, but disease mechanisms remain unclear. We show that OCRL visits late-stage, endocytic clathrin-coated pits and binds the Rab5 effector APPL1 on peripheral early endosomes. The interaction with APPL1, which is mediated by the ASH-RhoGAP-like domains of OCRL and is abolished by disease mutations, provides a link to protein networks implicated in the reabsorptive function of the kidney and in the trafficking and signaling of growth factor receptors in the brain. Crystallographic studies reveal a role of the ASH-RhoGAP-like domains in positioning the phosphatase domain at the membrane interface and a clathrin box protruding from the RhoGAP-like domain. Our results support a role of OCRL in the early endocytic pathway, consistent with the predominant localization of its preferred substrates, PI(4,5)P(2) and PI(3,4,5)P(3), at the cell surface.
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