Mechanisms and disease models of neurodevelopmental disorders involving CLC anion transporters

Variants in more than 1000 different genes have been implicated in various forms of intellectual disability, neurodevelopmental delay, neurodegeneration and other forms of neurological disease afflicting pediatric patients. Among these, members of a gene family encoding anion transporting proteins that are important in intracellular structures of neurons (endosomes and lysosomes), are found to be affected in an increasing number of patients, most of which show signs of disease early after birth. These genes are called CLCN3, CLCN4, CLCN6 and CLCN7. Our group has long-term experience in investigating the proteins encoded by these genes and has recently been involved in the investigation of a large number of CLCN3, CLCN4 and CLCN6 variants found in patients. Our studies have revealed novel mechanisms of CLC related disorders. In the present project, we intend to extend these studies to novel emerging CLC variants and to decipher novel molecular mechanisms of how genetic mutations in CLC genes cause specific alterations in protein function. These insights are prerequisite for future gene-therapeutic or pharmacological interventions. In a second aim, in collaboration with the patient organization CureCLCN4 (https://cureclcn4.org/) we intend to establish an animal (rat) neuronal model for CLCN4 related disease, hoping to obtain essential information of how mutations of CLCN4 cause the neurological symptoms seen in patients, and to provide a model in which to test gene or pharmacological therapies.