Dent's disease is an X-linked recessive renal tubulopathy characterized by low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive renal failure. LMWP is the most constant feature, while the other clinical manifestations show wide variability. Patients also present variable manifestations of proximal tubule dysfunctions, such as aminoaciduria, glucosuria, hyperphosphaturia, kaliuresis, and uricosuria, consistent with renal Fanconi syndrome. Dent's disease affects mainly male children, and female carriers are generally asymptomatic. In two-thirds of patients, the disease is caused by mutations in the CLCN5 gene, which encodes the electrogenic chloride/proton exchanger ClC-5. A few patients have mutations in OCRL1, the gene associated with the oculocerebrorenal syndrome of Lowe, which encodes a phosphatidylinositol-4,5-biphosphate-5-phosphatase (OCRL1). Both ClC-5 and OCRL1 are involved in the endocytic pathway for reabsorption of LMW proteins in the proximal tubule. This review will provide an overview of the important phenotypic characteristics of Dent's disease and summarize the molecular data that have significantly increased our comprehension of the mechanisms causing this disease.
T he correct splicing of precursormRNA depends on the actual splice sites plus exonic and intronic regulatory elements recognized by the splicing machinery. Surprisingly, an increasing number of examples reveal that exonic mutations disrupt the binding of splicing factors to these sequences or generate new splice sites or regulatory elements, causing disease. This contradicts the general assumption that missense mutations disrupt protein function and that synonymous mutations are merely polymorphisms. Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder caused mainly by mutations in the PKD1 gene. Recently, we analyzed a substantial number of PKD1 missense or synonymous mutations to further characterize their consequences on pre-mRNA splicing. Our results showed that one missense and 2 synonymous mutations induce significant defects in pre-mRNA splicing. Thus, it appears that aberrant splicing as a result of exonic mutations is a previously unrecognized cause of ADPKD.
The experimental transfer of the vanA gene cluster from Enterococcus faecalis to Staphylococcus aureus has raised fears about the occurrence of such genetic transfer in clinical isolates of methicillin-resistant staphylococci. Recently, infections by a S. aureus strain carrying the enterococcal vancomycin resistance vanA gene cluster were reported. The possible emergence and dissemination of these strains is a serious health threat and makes optimization of prevention strategies and fast detection methods absolutely necessary. In the present study, we developed a PCR protocol for simultaneous detection of enterococcal vanA and vanB genes, the staphylococcal methicillin and mupirocin resistance markers mecA and ileS-2, and identification of S. aureus. As no vancomycin-resistant S. aureus isolates were available for our study, we used mixtures of enterococcal and staphylococcal colonies that harbored the different resistance markers to show that these genes could be detected simultaneously. This protocol could be used to facilitate the detection and identification of predictable S. aureus or methicillin-resistant strains carrying vanA or vanB.
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