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      Defective claudin-10 causes a novel variation of HELIX syndrome through compromised tight junction strand assembly


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          Formation of claudin-10 based tight junctions (TJs) is paramount to paracellular Na + transport in multiple epithelia. Sequence variants in CLDN10 have been linked to HELIX syndrome, a salt-losing tubulopathy with altered handling of divalent cations accompanied by dysfunctional salivary, sweat, and lacrimal glands. Here, we investigate molecular basis and phenotypic consequences of a newly identified homozygous CLDN10 variant that translates into a single amino acid substitution within the fourth transmembrane helix of claudin-10. In addition to hypohidrosis (H), electrolyte (E) imbalance with impaired urine concentrating ability, and hypolacrimia (L), phenotypic findings include altered salivary electrolyte composition and amelogenesis imperfecta but neither ichthyosis (I) nor xerostomia (X). Employing cellular TJ reconstitution assays, we demonstrate perturbation of cis- and trans-interactions between mutant claudin-10 proteins. Ultrastructures of reconstituted TJ strands show disturbed continuity and reduced abundance in the mutant case. Throughout, both major isoforms, claudin-10a and claudin-10b, are differentially affected with claudin-10b showing more severe molecular alterations. However, expression of the mutant in renal epithelial cells with endogenous TJs results in wild-type-like ion selectivity and conductivity, indicating that aberrant claudin-10 is generally capable of forming functional paracellular channels. Thus, mutant proteins prove pathogenic by compromising claudin-10 TJ strand assembly. Additional ex vivo investigations indicate their insertion into TJs to occur in a tissue-specific manner.

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          Most cited references42

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          Claudins and the modulation of tight junction permeability.

          Claudins are tight junction membrane proteins that are expressed in epithelia and endothelia and form paracellular barriers and pores that determine tight junction permeability. This review summarizes our current knowledge of this large protein family and discusses recent advances in our understanding of their structure and physiological functions.
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            Structure and function of claudins.

            Claudins are tetraspan transmembrane proteins of tight junctions. They determine the barrier properties of this type of cell-cell contact existing between the plasma membranes of two neighbouring cells, such as occurring in endothelia or epithelia. Claudins can completely tighten the paracellular cleft for solutes, and they can form paracellular ion pores. It is assumed that the extracellular loops specify these claudin functions. It is hypothesised that the larger first extracellular loop is critical for determining the paracellular tightness and the selective ion permeability. The shorter second extracellular loop may cause narrowing of the paracellular cleft and have a holding function between the opposing cell membranes. Sequence analysis of claudins has led to differentiation into two groups, designated as classic claudins (1-10, 14, 15, 17, 19) and non-classic claudins (11-13, 16, 18, 20-24), according to their degree of sequence similarity. This is also reflected in the derived sequence-structure function relationships for extracellular loops 1 and 2. The concepts evolved from these findings and first tentative molecular models for homophilic interactions may explain the different functional contribution of the two extracellular loops at tight junctions.
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              Modeller: generation and refinement of homology-based protein structure models.


                Author and article information

                Genes Dis
                Genes Dis
                Genes & Diseases
                Chongqing Medical University
                13 July 2021
                September 2022
                13 July 2021
                : 9
                : 5
                : 1301-1314
                [a ]Division of Nephrology, University of Leipzig Medical Center, Leipzig 04103, Germany
                [b ]Clinical Physiology/ Nutritional Medicine, Charité – Universitätsmedizin Berlin, Berlin 12203, Germany
                [c ]Division of Dermatology, Venereology, and Allergology, University of Leipzig Medical Center, Leipzig 04103, Germany
                [d ]Division of Prosthodontics and Materials Science, University of Leipzig Medical Center, Leipzig 04103, Germany
                [e ]Center for Human Genetics, Bioscientia, Ingelheim 55218, Germany
                [f ]Medizinische Genetik Mainz, Limbach Genetics, Mainz 55128, Germany
                Author notes
                []Corresponding author. Division of Nephrology, University of Leipzig Medical Center, Liebigstraße 20, 04103 Leipzig, Germany. Fax: +49 341 97 13389. jan.halbritter@ 123456medizin.uni-leipzig.de
                [∗∗ ]Corresponding author. Clinical Physiology/ Nutritional Medicine, Charité – Universitätsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany. Fax: +49 30 450 514962. joerg.piontek@ 123456charite.de dorothee.guenzel@ 123456charite.de

                These authors contributed equally.

                © 2021 Chongqing Medical University. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                : 22 December 2020
                : 1 June 2021
                : 7 June 2021
                Full Length Article

                claudin-10,helix syndrome,paracellular transport,salt-losing tubulopathy,tight junction


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