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      A polycystin-centric view of cyst formation and disease: the polycystins revisited

      1 , 2

      Kidney international

      ADPKD, PKD1, PKD2, polycystin-1, polycystin-2, TRPP2, primary cilia, cysts

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          It is 20 years since the identification of PKD1, the major gene mutated in autosomal dominant polycystic kidney disease (ADPKD), followed closely by the cloning of PKD2. These major breakthroughs have led in turn to a period of intense investigation into the function of the two proteins encoded, polycystin-1 and polycystin-2 and how defects in either protein lead to cyst formation and non-renal phenotypes. In this review, we summarise the major findings in this area and present a current model of how the polycystin proteins function in health and disease.

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          Most cited references 200

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          Identification and proteomic profiling of exosomes in human urine.

          Urine provides an alternative to blood plasma as a potential source of disease biomarkers. One urinary biomarker already exploited in clinical studies is aquaporin-2. However, it remains a mystery how aquaporin-2 (an integral membrane protein) and other apical transporters are delivered to the urine. Here we address the hypothesis that these proteins reach the urine through the secretion of exosomes [membrane vesicles that originate as internal vesicles of multivesicular bodies (MVBs)]. Low-density urinary membrane vesicles from normal human subjects were isolated by differential centrifugation. ImmunoGold electron microscopy using antibodies directed to cytoplasmic or anticytoplasmic epitopes revealed that the vesicles are oriented "cytoplasmic-side inward," consistent with the unique orientation of exosomes. The vesicles were small (<100 nm), consistent with studies of MVBs and exosomes from other tissues. Proteomic analysis of urinary vesicles through nanospray liquid chromatography-tandem mass spectrometry identified numerous protein components of MVBs and of the endosomal pathway in general. Full liquid chromatography-tandem MS analysis revealed 295 proteins, including multiple protein products of genes already known to be responsible for renal and systemic diseases, including autosomal dominant polycystic kidney disease, Gitelman syndrome, Bartter syndrome, autosomal recessive syndrome of osteopetrosis with renal tubular acidosis, and familial renal hypomagnesemia. The results indicate that exosome isolation may provide an efficient first step in biomarker discovery in urine.
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            A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis.

            Primary cilium dysfunction underlies the pathogenesis of Bardet-Biedl syndrome (BBS), a genetic disorder whose symptoms include obesity, retinal degeneration, and nephropathy. However, despite the identification of 12 BBS genes, the molecular basis of BBS remains elusive. Here we identify a complex composed of seven highly conserved BBS proteins. This complex, the BBSome, localizes to nonmembranous centriolar satellites in the cytoplasm but also to the membrane of the cilium. Interestingly, the BBSome is required for ciliogenesis but is dispensable for centriolar satellite function. This ciliogenic function is mediated in part by the Rab8 GDP/GTP exchange factor, which localizes to the basal body and contacts the BBSome. Strikingly, Rab8(GTP) enters the primary cilium and promotes extension of the ciliary membrane. Conversely, preventing Rab8(GTP) production blocks ciliation in cells and yields characteristic BBS phenotypes in zebrafish. Our data reveal that BBS may be caused by defects in vesicular transport to the cilium.
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                Author and article information

                Kidney Int
                Kidney Int.
                Kidney international
                16 June 2015
                22 July 2015
                October 2015
                01 April 2016
                : 88
                : 4
                : 699-710
                [1 ]Kidney Genetics Group, Academic Nephrology Unit, Department of Infection and Immunity, University of Sheffield Medical School, Sheffield, UK
                [2 ]Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
                Author notes
                Correspondence: Albert CM Ong ( ) or Peter C. Harris ( harris.peter@ )

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                adpkd, cysts, primary cilia, trpp2, polycystin-2, polycystin-1, pkd2, pkd1


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