Joubert syndrome (JBTS) is a recessive ciliopathy in which a subset of affected individuals also have the skeletal dysplasia Jeune asphyxiating thoracic dystrophy (JATD). Here, we have identified biallelic truncating CSPP1 (centrosome and spindle pole associated protein 1) mutations in 19 JBTS-affected individuals, four of whom also have features of JATD. CSPP1 mutations explain ∼5% of JBTS in our cohort, and despite truncating mutations in all affected individuals, the range of phenotypic severity is broad. Morpholino knockdown of cspp1 in zebrafish caused phenotypes reported in other zebrafish models of JBTS (curved body shape, pronephric cysts, and cerebellar abnormalities) and reduced ciliary localization of Arl13b, further supporting loss of CSPP1 function as a cause of JBTS. Fibroblasts from affected individuals with CSPP1 mutations showed reduced numbers of primary cilia and/or short primary cilia, as well as reduced axonemal localization of ciliary proteins ARL13B and adenylyl cyclase III. In summary, CSPP1 mutations are a major cause of the Joubert-Jeune phenotype in humans; however, the mechanism by which these mutations lead to both JBTS and JATD remains unknown.

Polarized vesicle trafficking is mediated by small GTPase proteins, such as Rabs and Arls/Arfs. These proteins have essential roles in maintaining normal cellular function, in part, through regulating intracellular trafficking. Moreover, these families of proteins have recently been implicated in the formation and function of the primary cilium. The primary cilium, which is found on almost every cell type in vertebrates, is an organelle that protrudes from the surface of the cell and functions as a signaling center. Interestingly, it has recently been linked to a variety of human diseases, collectively referred to as ciliopathies. The primary cilium has an exceptionally high density of receptors on its membrane that are important for sensing and transducing extracellular stimuli. Moreover, the primary cilium serves as a separate cellular compartment from the cytosol, providing for unique spatial and temporal regulation of signaling molecules to initiate downstream events. Thus, functional primary cilia are essential for normal signal transduction. Rabs and Arls/Arfs play critical roles in early cilia formation but are also needed for maintenance of ciliary function through their coordination with intraflagellar transport (IFT), a specialized trafficking system in primary cilia. IFT in cilia is pivotal for the proper movement of proteins into and out of this highly regulated organelle. In this review article, we explore the involvement of polarized vesicular trafficking in cilia formation and function, and discuss how defects in these processes could subsequently lead to the abnormalities observed in ciliopathies.

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Background: Na ϩ -NQR is the main sodium pump in Vibrio cholerae.

Hyponatremia propitiates and increases susceptibility to seizure episodes. In vitro, hyposmolarity induces hyperexcitability and epileptiform activity and increases the amplitude of excitatory postsynaptic potentials. Synaptic (increased glutamate vesicular release) and non-synaptic (swelling-induced extracellular space shrinkage and ephaptic interactions) might be responsible for the hyposmolarity effects on brain excitability. Neuronal volume constancy in hyponatremia is preserved by the isovolumetric regulation, relying importantly on organic osmolytes. Changes in cell volume are closely linked to neuronal death: swelling characterizes necrotic death as in acute ischemic episodes or brain trauma, whereas volume decrease is typical of apoptotic death. Swelling in necrotic death results from the intracellular Na(+) increase followed by Cl(-) and water influx. Na(+) accumulation is due initially to the Na(+)/K(+)ATPase dysfunction and subsequently from the Na(+) influx through the overactivated ionotropic glutamate receptors. A second wave of swelling generates by excitotoxic derived formation of reactive oxygen species, membrane lipoperoxidation and further ion overload. Excessive swelling contributes to membrane rupture and release of cell debris, propagating the damage to adjacent cells. Apoptotic death is characterized by cell volume decrease termed apoptotic volume decrease, which in neurons seems to occur by mechanisms remarkably similar to those operating in the hyposmotic swelling-activated volume regulatory decrease, i.e. channel-mediated efflux of K(+) and Cl(-). A variety of K(+) channels and the volume-regulated anion channel participate in apoptotic volume decrease. K(+) has a protagonic role as an early element in neuronal apoptosis since a delayed rectifier K(+) current IK(DR) is enhanced by apoptosis prior to the caspase activation, increased extracellular K(+) and IK(DR) blockers attenuate apoptosis and intracellular K(+) loss through ionophores induces apoptosis. Volume-regulated anion channel participates as well in the Cl(-) efflux although its role and hierarchy in the apoptotic program are not well defined. Efflux of organic osmolytes, such as taurine participate as well in apoptotic volume decrease.