Lerche Lab

Genetics and pharmacogenetics of epilepsy

Epilepsy affects up to 3% of people during their lifetime, with a genetic component playing a major pathophysiological role in almost 50% of cases. To analyze the genetic architecture of epilepsy we have initiated running national research networks (Treat-ION, DFG FOR-2715) and have initiated or been part of still ongoing European (ESF: EuroEPINOMICS, FP7: EpiPGX, ERANet Neuron:  SNAREopathies) and international (ILAE consortium on the genetics of complex epilepsies, Epi25, ILAE Genomics) networks confi ned to the recruitment of large cohorts of affected individuals and/or families and their genetic analyses. Major achievements in the last years were the prolongation of our DFG-Research Unit FOR 2715, entitled Epileptogenesis of Genetic Epilepsies, establishing Treat-ION, a
BMBF-funded network for rare ion channel disorders in 2019 (prolongation pending), and founding ILAE
Genomics to collect all available exomes sequenced in epilepsy patients wolrdwide. Important examples from recent studies are the identifi cation of 4-aminopyridine as a new and specifi c (‘precision’) treatment for a severe epilepsy with developmental problems of early childhood caused
by mutations in KCNA2 (Hedrich, Lauxmann et al. Sci Transl Med 2021), the identifi cation of a new mechanism for migraine aura in an Scn1a mouse model (Auffenberg, Hedrich et al., JCI 2021), and very clear genotype-phenotype correlations with high relevance for clinical management for SCN8A-related epilepsies (Johannesen, Liu et al., Brain 2021). A bioinformatic study in a large dataset of whole exomes from more than 8000 affected individuals with common epilepsies revealed that important functional gene groups, such as those of synaptic genes and ion channels / receptors, show specifi c
patterns of enrichment of pathological variants compared to controls in generalized vs. focal epilepsies (e.g. affecting inhibitory vs. excitatory pathways), and also show that signals from common and rare variants converge and contrast in generalized vs. focal epilepsies.

Functional investigations of genetic defects in ion channels

With the BMBF-funded Treat-ION consortium on Neurological Ion Channel and Transporter Disorders we focus on therapeutic studies in cellular, animal and human models, which are complemented by in silico searches for new treatments, better predictions for the functional consequences of mutations
for therapeutic purposes and cellular drug screens. The use of approved and available ‘repurposed’ drugs such as 4-aminopyridine is a a specific goal to enable precision treatment. Our findings are directly delivered to patients through molecular therapeutic boards attached to the German academy of
rare neurological diseases (DASNE) and the centers for rare diseases (ZSEs) in Baden-Württemberg and through a structured process for drug repurposing. Functional implications of selected mutations are examined in neuronal expression systems, such as transfected murine primary neurons,
in utero electroporated neurons and genetically altered animal models carrying a human mutation (so-called “humanized mouse models”). The advantage of both in utero electroporated neurons and gene-targeted mouse models is that altered channels can be studied in their natural environment
and additionally, the consequences on intrinsic neuronal properties and network activity can be studied
using single cell patch clamp, extracellular recording or multielectrode array (MEA) techniques. We perform 256 electrode MEA recordings and high-resolution electrical imaging (CMOS with 4000 electrodes) to analyze single cell compartments and neuronal network activity in brain slices of transgenic animals and study network dysfunction of our mouse models in vivo together with
O. Garaschuk (Inst. Neurophysiology) using Ca²⁺imaging in the frame of the DFG Research Unit. To gain insight into the exact mechanisms as to how epilepsy develops as a consequence of
a genetic defect, we investigate brain region- and time-specific RNA expression using single cell RNA sequencing in distinct neuronal subpopulations in mouse models.