Journal Article

FZJ-2025-01488

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Genotype-phenotype correlation in CLCN4-related developmental and epileptic encephalopathy

Sahly, A. N. ; Sierra-Marquez, J.FZJ* ; Bungert-Plümke, S.FZJ* ; Franzen, A.FZJ* ; Mougharbel, L. ; Berrahmoune, S. ; Dassi, C. ; Poulin, C. ; Srour, M. ; Guzman, R. E. (Corresponding author)FZJ* ; Myers, K. A. (Corresponding author)

2024
Springer Heidelberg

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Please use a persistent id in citations: doi:10.1007/s00439-024-02668-z

Abstract: CLCN4-related disorder is a rare X-linked neurodevelopmental condition with a pathogenic mechanism yet to be elucidated.CLCN4 encodes the vesicular 2Cl−/H+ exchanger ClC-4, and CLCN4 pathogenic variants frequently result inaltered ClC-4 transport activity. The precise cellular and molecular function of ClC-4 remains unknown; however, togetherwith ClC-3, ClC-4 is thought to have a role in the ion homeostasis of endosomes and intracellular trafficking. We reviewedour research database for patients with CLCN4 variants and epilepsy, and performed thorough phenotyping. We examinedthe functional properties of the variants in mammalian cells using patch-clamp electrophysiology, protein biochemistry,and confocal fluorescence microscopy. Three male patients with developmental and epileptic encephalopathy were identified,with differing phenotypes. Patients #1 and #2 had normal growth parameters and normal-appearing brains on MRI,while patient #3 had microcephaly, microsomia, complete agenesis of the corpus callosum and cerebellar and brainstemhypoplasia. The p.(Gly342Arg) variant of patient #1 significantly impaired ClC-4’s heterodimerization capability withClC-3 and suppressed anion currents. The p.(Ile549Leu) variant of patient #2 and p.(Asp89Asn) variant of patient #3 bothshift the voltage dependency of transport activation by 20 mV to more hyperpolarizing potentials, relative to the wildtype,with p.(Asp89Asn) favouring higher transport activity. We concluded that p.(Gly342Arg) carried by patient #1 andthe p.(Ile549Leu) expressed by patient #2 impair ClC-4 transport function, while the p.(Asp89Asn) variant results in again-of-transport function; all three variants result in epilepsy and global developmental impairment, but with differencesin epilepsy presentation, growth parameters, and presence or absence of brain malformations.

Note: This study was supported by funding from the Fonds de Recherchesdu Québec – Santé (KAM) and the German Research Foundation(DFG) (GU 2042/2–1) (REG). The authors have no relevantfinancial or non-financial interests to disclose.

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Contributing Institute(s):

1. Molekular- und Zellphysiologie (IBI-1)

Research Program(s):

1. 5243 - Information Processing in Distributed Systems (POF4-524) (POF4-524)
2. DFG project G:(GEPRIS)430631456 - Funktionelle Rolle der intrazellulären Chlorid/Proton Austauscher ClC-3, ClC-4 und ClC-5 in der Neurosekretion (430631456) (430631456)

Appears in the scientific report 2024; 2025

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Database coverage:
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