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      Motile and non-motile cilia in human pathology: from function to phenotypes : Motile and non-motile ciliopathies

      1 , 2 , 3
      The Journal of Pathology
      Wiley

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          Abstract

          Ciliopathies are inherited human disorders caused by both motile and non-motile cilia dysfunction that form an important and rapidly expanding disease category. Ciliopathies are complex conditions to diagnose, being multisystem disorders characterized by extensive genetic heterogeneity and clinical variability with high levels of lethality. There is marked phenotypic overlap among distinct ciliopathy syndromes that presents a major challenge for their recognition, diagnosis, and clinical management, in addition to posing an on-going task to develop the most appropriate family counselling. The impact of next-generation sequencing and high-throughput technologies in the last decade has significantly improved our understanding of the biological basis of ciliopathy disorders, enhancing our ability to determine the possible reasons for the extensive overlap in their symptoms and genetic aetiologies. Here, we review the diverse functions of cilia in human health and disease and discuss a growing shift away from the classical clinical definitions of ciliopathy syndromes to a more functional categorization. This approach arises from our improved understanding of this unique organelle, revealed through new genetic and cell biological insights into the discrete functioning of subcompartments of the cilium (basal body, transition zone, intraflagellar transport, motility). Mutations affecting these distinct ciliary protein modules can confer different genetic diseases and new clinical classifications are possible to define, according to the nature and extent of organ involvement. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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          Most cited references150

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          Ciliopathies.

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            Proteomic analysis of a eukaryotic cilium

            Cilia and flagella are widespread cell organelles that have been highly conserved throughout evolution and play important roles in motility, sensory perception, and the life cycles of eukaryotes ranging from protists to humans. Despite the ubiquity and importance of these organelles, their composition is not well known. Here we use mass spectrometry to identify proteins in purified flagella from the green alga Chlamydomonas reinhardtii. 360 proteins were identified with high confidence, and 292 more with moderate confidence. 97 out of 101 previously known flagellar proteins were found, indicating that this is a very complete dataset. The flagellar proteome is rich in motor and signal transduction components, and contains numerous proteins with homologues associated with diseases such as cystic kidney disease, male sterility, and hydrocephalus in humans and model vertebrates. The flagellum also contains many proteins that are conserved in humans but have not been previously characterized in any organism. The results indicate that flagella are far more complex than previously estimated.
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              Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity.

              Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterised by hypotonia, ataxia, cognitive impairment, abnormal eye movements, respiratory control disturbances and a distinctive mid-hindbrain malformation. JS demonstrates substantial phenotypic variability and genetic heterogeneity. This study provides a comprehensive view of the current genetic basis, phenotypic range and gene-phenotype associations in JS.
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                Author and article information

                Journal
                The Journal of Pathology
                J. Pathol.
                Wiley
                00223417
                January 2017
                January 2017
                December 19 2016
                : 241
                : 2
                : 294-309
                Affiliations
                [1 ]Genetics and Genomic Medicine Programme; University College London, UCL Great Ormond Street Institute of Child Health; 30 Guilford Street London WC1N 1EH UK
                [2 ]Department of Medicine and Surgery; University of Salerno; Salerno Italy
                [3 ]Neurogenetics Unit, IRCCS Santa Lucia Foundation; Via del Fosso di Fiorano 00143 Rome Italy
                Article
                10.1002/path.4843
                27859258
                78c05873-c65b-4671-bf72-7dddad25fc35
                © 2016

                http://doi.wiley.com/10.1002/tdm_license_1

                http://onlinelibrary.wiley.com/termsAndConditions

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