Pathophysiology of an autosomal recessive neurodevelopmental disorder caused by SLC4A10 loss-of-function

• Applicant: Professor Dr. Christian Andreas Hübner
• Subject Area: Human Genetics
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 525280258

Together with a team of geneticists and clinicians, we were recently able to identify mutations in the SLC4A10 gene in patients with a characteristic autosomal recessive disease. Patients show slit cerebral ventricles and severe intellectual disability with autistic behavior. SLC4A10 codes for an ion transporter located in the plasma membrane, which uses the sodium gradient to transport bicarbonate into the cell and thus buffers intracellular acid equivalents. Our preliminary work shows that constitutive Slc4a10 knockout mice also show behavioral abnormalities and collapsed cerebral ventricles and therefore represent a promising model for the disease. In addition to indications of impaired production of the cerebrospinal fluid (CSF), we observed compromised GABAergic inhibition in acute brain slices of knockout mice. This is consistent with the exceptional expression in epithelial cells of the choroid plexus and in the somata of excitatory and inhibitory neurons. The latter also express Slc4a10 at their terminal nerve endings. The complex expression pattern complicates the elucidation of the putatively overlapping different mechanisms in constitutive knockout mice. Therefore, I propose to study brain morphology, behavior and network properties in choroid plexus and interneuron-specific conditional Slc4a10 knockout mice in order to elucidate the pathophysiology of the disease. The following questions should be answered: 1. What role does SLC4A10 play in CSF secretion and the composition of the interstitial fluid of the brain? 2. Does impaired CSF production in Slc4a10 knockout mice affect brain development? 3. Are there long-term effects of impaired CSF production in Slc4a10 knockout mice? 4. What role does Slc4a10 play for the neural network, seizure tendency, and cognition? 5. Can modulation of GABAergic transmission improve network properties or even behavioral abnormalities in constitutive Slc4a10 knockout mice? In the long term, we hope that this approach will not only provide insights into basic mechanisms but also indications for possible therapeutic interventions in patients.

• DFG Programme: Research Grants