Journal Article

FZJ-2025-01482

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Expanding the genetic and phenotypic relevance of CLCN4 variants in neurodevelopmental condition: 13 new patients

He, H. ; Li, X. ; Guzman, G.FZJ* ; Bungert-Plümke, S.FZJ* ; Franzen, A.FZJ* ; Lin, X. ; Zhu, H. ; Peng, G. ; Zhang, H. ; Yu, Y. ; Sun, S. ; Huang, Z. ; Zhai, Q. ; Chen, Z. ; Peng, J. (Corresponding author) ; Guzman, R. E. (Corresponding author)FZJ*

2024
Steinkopff [Darmstadt]

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Please use a persistent id in citations: doi:10.1007/s00415-024-12383-4

Abstract: AbstractObjectives CLCN4 variations have recently been identified as a genetic cause of X-linked neurodevelopmental disorders. Thisstudy aims to broaden the phenotypic spectrum of CLCN4-related condition and correlate it with functional consequencesof CLCN4 variants.Methods We described 13 individuals with CLCN4-related neurodevelopmental disorder. We analyzed the functional consequenceof the unreported variants using heterologous expression, biochemistry, confocal fluorescent microscopy, patchclampelectrophysiology, and minigene splicing assay.Results We identified five novel (p.R41W, p.L348V, p.G480R, p.R603W, c.1576 + 5G > A) and three known (p.T203I,p.V275M, p.A555V) pathogenic CLCN4 variants in 13 Chinese patients. The p.V275M variant is found at high frequencyand seen in four unrelated individuals. All had global developmental delay (GDD)/intellectual disability (ID). Seizures werepresent in eight individuals, and 62.5% of them developed refractory epilepsy. Five individuals without seizures showed moderateto severe GDD/ID. Developmental delay precedes seizure onset in most patients. The variants p.R41W, p.L348V, andp.R603W compromise the anion/exchange function of ClC-4. p.R41W partially impairs ClC-3/ClC-4 association. p.G480Rreduces ClC-4 expression levels and impairs the heterodimerization with ClC-3. The c.1576 + 5G > A variant causes 22 bpdeletion of exon 10.Conclusions We further define and broaden the clinical and mutational spectrum of CLCN4-related neurodevelopmentalconditions. The p.V275M variant may be a potential hotspot CLCN4 variant in Chinese patients. The five novel variantscause loss of function of ClC-4. Transport dysfunction, protein instability, intracellular trafficking defect, or failure of ClC-4to oligomerize may contribute to the pathophysiological events leading to CLCN4-related neurodevelopmental disorder.

Note: This work was funded by the National Natural Science Foundationof China (82071462, 81771409 to PJ and 82201316 to HH),the Natural Science Foundation of Hunan Province (2022JJ40785 toHH), the China Postdoctoral Science Foundation (2023M733950 toHH), and the Key R&D Program of Hunan Province (2022SK2036 toPJ), the German Research Foundation (DFG) (GU 2042/2-1 to REG).

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Contributing Institute(s):

1. Molekular- und Zellphysiologie (IBI-1)
2. Materials Data Science and Informatics (IAS-9)

Research Program(s):

1. 5243 - Information Processing in Distributed Systems (POF4-524) (POF4-524)
2. Functional role of intracellular chloride/proton exchangers ClC-3, ClC-4 and ClC-5 in neurosecretion (430631456) (430631456)

Appears in the scientific report 2024; 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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