Xenbase Image ID: 171500

Figure 4. Genotypic information, three-dimensional modeling and functional studies of CLCN4 variants. (a) Position of CLCN4 variants in families A–P (information adapted from Protein Data Bank P51793). Missense variants in families D (p.Gly78Ser), G (p.Val212Gly), L (p.Ala555Val) and O (p.Gly544Arg) are within helical transmembrane domains of the protein. Missense variants in families F (p.Val536Met), I (p.Ser534Leu) and N (p.Val275Met) are within helical-intramembrane domains. Missense variants in families E (p.Leu221Val) and H (p.Leu221Pro) lie within a loop between transmembrane domains. Missense variants in families C (p.Gly731Arg) and M (p.Arg718Trp) lie within the second cytosolic cystathionine-β-synthase (CBS) domain and therefore may affect gating. (b) Analogous positions of amino acids mutated in ClC-4 highlighted in the crystal structure of CmClC. Amino acids are displayed as spheres in colors. CLC transporters are (homo)dimers of identical subunits with two ion translocation pathways. Each subunit is composed of a transmembrane domain (TMD) containing several intramembrane helices and cytosolic CBS domains. Asterisks indicate previously published analogous positions of amino acids.5, 6 (c) Current voltage relationships of the electrogenic 2Cl−/H+ exchanger ClC-4 and the CIC-4 variants expressed in Xenopus oocytes, shown as mean values of normalized steady-state currents from several oocytes (numbers indicated in figure, in parentheses: number of independent cRNA batches injected). The current of wild-type (WT) CIC-4 is strongly outwardly rectifying, that is, increases steeply at inside-positive voltages. The human missense mutations p.Val212Gly, p.Leu221Pro, p.Val275Met, p.Ser543Leu, p.Ala555Val and p.Arg718Trp reduced, or even abolished, these ClC-4 currents. Only variant p.Asp15Asn exhibited normal wild-type like currents. Error bars, s.e.m. Noninjected (n.i.) oocytes served as control. Image published in: Palmer EE et al. (2018) Copyright © 2018 The Author(s). This image is reproduced with permission of the journal and the copyright holder. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives license Larger Image Printer Friendly View

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