Novel CLCN3 variants expand our understanding of clinical manifestations and molecular mechanisms of CLCN3-related condition.

Insights into CLCN3-Related Pathogenesis from Electrophysiological and Morphological Analyses of CA2 and Dentate Gyrus Granule Cells in Clcn3T570I and Clcn3G327S Mouse Models

Toxic gain-of-function mechanisms associated with CLCN3 variants contribute to the pathogenesis and severity of CLCN3-related condition.

Dissecting the Role of ClC-3 Splice Variants in Neuronal Excitability Using Clcn3c-deficient Mice

Patient-Derived iPSCs Carrying CLCN3 and CLCN4 variants: Generation and Differentiation into Neural Lineages

• Phenotypic characterization of ClC-4 p.V523M knock-in mouse model.

• Understanding the cellular consequences of ClC-4 dysfunction in X-linked intellectual disability: a comprehensive electrophysiological and morphological characterization of hippocampal neurons from Clcn4^-/- and Clcn4^A549V rat models.

Carina Balduin, Guanxiao Qi, Michael Schöneck, Verena Trinkel, Sarah Schemmert, Gustavo A. Guzman, Stefanie Bungert-Plümke, Malte Klüssendorf, Bernd Neumaier, Dirk Feldmeyer, N. Jon Shah, Tobias Stauber, Karl-Josef Langen, Raul E. Guzman & Antje Willuweit. Disruption of ClC-3-mediated 2Cl−/H+ exchange leads to behavioural deficits and thalamic atrophy. Sci Rep 15, 33326 (2025). https://doi.org/10.1038/s41598-025-19757-2

Qi G., Diaz-Castillo A., Aretzweiler C., Steinmetz L., Bungert-Plümke S., Müller F., Feldmeyer D., Guzman R.E. (2025). Endosomal 2Cl^-/H⁺ exchangers regulate neuronal excitability by tuning Kv7/KCNQ channel density. Brain, awaf243, https://doi.org/10.1093/brain/awaf243

Sahly AN, Sierra-Marquez J, Bungert-Plümke S, Franzen A, Mougharbel L, Berrahmoune S, Dassi C, Poulin C, Srour M, Guzman RE, Myers KA. Genotype-phenotype correlation in CLCN4-related developmental and epileptic encephalopathy. Hum. Genet. (2024). https://doi.org/10.1007/s00439-024-02668-z.

He H, Li X., Guzman G.A., Bungert-Plümke S., Franzen A., Lin X., Zhu M., Peng G., Zhang W., Yu Y., Sun S., Huang Z., Zhai Q., Chen Z., Peng j., and Guzman R.E. (2024). Expanding the genetic and phenotypic relevance of CLCN4 variants in neurodevelopmental condition: 13 new patients. J. Neurol. https://doi.org/10.1007/s00415-024-12383-4

Comini, M., Sierra-Marquez, J., Guzman G.A, Franzen, A., Willuweit, A., Hidalgo, P., Fahlke, C., Guzman, R.E. (2022). CLC anion/proton exchangers regulate secretory vesicle filling and maturation in chromaffin cells. J. Neurosci. 42 (15) 3080-3095; DOI: https://doi.org/10.1523/JNEUROSCI.2439-21.2022:

Sierra-Marquez, J., Willuweit, A., Schöneck, M., Bungert-Plümke, S., Gehlen, J., Balduin, C., Müller, F., Lampert, A., Fahlke, C., Guzman, R.E. (2022). ClC-3 regulates the excitability of nociceptive neurons and suppresses inflammatory processes within the spinal sensory pathway. Front. Cell. Neurosci. DOI: 10.3389/fncel.2022.920075.

Guzman, R.E, Sierra-Marquez, J., Bungert-Plümke, Franzen, A., Fahlke, C. (2022). Functional characterization of CLCN4 variants associated with X-linked intellectual disability and epilepsy. Front. Mol. Neurosci. doi.org/10.3389/fnmol.2022.872407

He, H., Guzman, R. E., Cao, D., Sierra-Marquez, J., Yin, F., Fahlke, C., Peng, J., Stauber, T. (2021). The molecular and phenotypic spectrum of CLCN4-related epilepsy. Epilepsia 62, 1401-1415.

Grieschat, M*., Guzman, R. E*., Langschwager, K*., Fahlke, C., Alekov, A. K. (2020). Metabolic energy sensing by mammalian CLC anion/proton exchangers. EMBO Rep 21, e47872. *Equal contribution.

Member of the Review Editorial Board of Frontiers in Physiology / Membrane Physiology and Membrane Biophysics

Mice

Clcn3^-/-

Clcn4^-/-

Clcn3c-/-

Clcn3^td/td

Clcn3^td/td/Clcn4^-/-

Clcn3^T570I

Clcn3^G327S

Rats

Clcn4^-/-

Clcn4^A549V