The CLCN4 gene and

CLCN4-related conditions

Mutations in the CLCN4 gene and effects on CLC-4 protein function

The CLCN4 gene encodes the CLC-4 protein, a Cl-/H+ exchanger expressed primarily in brain and skeletal muscle. The CLC-4 protein is expressed in intracellular organelles and is thought to be involved in ion homeostasis of endosomes and intracellular trafficking. The CLCN4 gene is located on the X-chromosome and mutations in this gene lead to frameshift, missense and splice site variants, and chromosomal microdeletions in the CLC-4 protein. Dysfunction of this protein underlies the clinical phenotype of CLCN4-related conditions, symptoms of which include intellectual disability and other problems such as epilepsy, behavioural disorders, movement disorders and microcephaly.

CLCN4-related conditions are extremely rare, so far just over 120 individuals worldwide with a CLCN4 gene change have been identified. However, symptoms vary widely in their extent and severity and as genetic testing becomes more widely available, more individuals with undiagnosed intellectual disability are likely to be diagnosed with CLCN4-related conditions.

More research is desperately needed into CLCN4 and the protein, CLC-4. We are proud to support the Cure CLCN4 Annual Scientific Meeting to further the understanding of the basic biology of CIC-4 and investigate therapeutic options for these patients.



Tools to investigate CLCN4

Using electrophysiology to precisely understand CLC-4 function

We provide a range of electrophysiology platforms to study ion channels and transporters in native and heterologous cells, intracellular organelles and membranes:

  • Single channel recordings on Orbit mini and Orbit 16 TC platforms can resolve state transitions and ion permeation of individual ion channel proteins in native or artificial membranes.
  • Whole-cell recordings on Port-a-Patch, Patchliner and SyncroPatch 384 can reveal ion channel selectivity, voltage-dependent biophysics and ligand-activation, as well as pharmacology of modulators and the effects of accessory subunits and second messengers.
  • The SURFE2R N1 and SURFE2R 96SE platforms can measure ion channel and transporter activity in organellar membranes.

These platforms can be used to study basic mechanisms of CLC-4 function and could be used to investigate variants of unknown significance of CLCN4-related conditions, as well as screening for potential new drugs.