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      The primary cilium calcium channels and their role in flow sensing.

      Pflügers Archiv : European journal of physiology

      Springer Nature America, Inc

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          Abstract

          The primary cilium has been the focus of intense research since it was discovered that mutations in ciliary/basal body localized proteins give rise to a multitude of disorders. While these studies have revealed the contribution of this sensory organelle to multiple signalling pathways, little is known about how it actually mediates downstream events and why its loss causes disease states. Ciliopathies are linked to defects in either structure or function of cilia and are often associated with kidney cysts. The ciliopathy, autosomal dominant polycystic kidney disease (ADPKD), is caused by mutations to the PKD1 or PKD2 gene. The PKD gene products localize to the primary cilium, where they have been proposed to form a mechanosensory complex, sensitive to flow. Since mouse knockout models of Pkd1 or Pkd2 develop structurally normal cilia, it has been hypothesized that the loss of polycystins may lead to an impairment of flow sensing. Today, technically challenging patch clamp recordings of the primary cilium have become available, and the genetic relationship between polycystins (TRPPs) and the primary cilium has recently been dissected in detail.

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          Most cited references 63

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          Autosomal dominant polycystic kidney disease.

          Autosomal dominant polycystic kidney disease is the most prevalent, potentially lethal, monogenic disorder. It is associated with large interfamilial and intrafamilial variability, which can be explained to a large extent by its genetic heterogeneity and modifier genes. An increased understanding of the disorder's underlying genetic, molecular, and cellular mechanisms and a better appreciation of its progression and systemic manifestations have laid out the foundation for the development of clinical trials and potentially effective treatments.
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            Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein.

            Microtubule-dependent motor, murine KIF3B, was disrupted by gene targeting. The null mutants did not survive beyond midgestation, exhibiting growth retardation, pericardial sac ballooning, and neural tube disorganization. Prominently, the left-right asymmetry was randomized in the heart loop and the direction of embryonic turning. lefty-2 expression was either bilateral or absent. Furthermore, the node lacked monocilia while the basal bodies were present. Immunocytochemistry revealed KIF3B localization in wild-type nodal cilia. Video microscopy showed that these cilia were motile and generated a leftward flow. These data suggest that KIF3B is essential for the left-right determination through intraciliary transportation of materials for ciliogenesis of motile primary cilia that could produce a gradient of putative morphogen along the left-right axis in the node.
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              PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.

              A second gene for autosomal dominant polycystic kidney disease was identified by positional cloning. Nonsense mutations in this gene (PKD2) segregated with the disease in three PKD2 families. The predicted 968-amino acid sequence of the PKD2 gene product has six transmembrane spans with intracellular amino- and carboxyl-termini. The PKD2 protein has amino acid similarity with PKD1, the Caenorhabditis elegans homolog of PKD1, and the family of voltage-activated calcium (and sodium) channels, and it contains a potential calcium-binding domain.
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                Author and article information

                Journal
                10.1007/s00424-014-1516-0
                24764075

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