Dissecting the dynamics and pathological mechanisms associated with TTTCA repeat expansions in Familial Adult Myoclonic epilepsy

• Applicant: Professorin Dr. Christel Depienne, Ph.D.
• Subject Area: Human Genetics ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 455314768

Familial adult myoclonic epilepsy (FAME) is an autosomal dominant disorder characterized by cortical or myoclonic tremor and frequent generalized seizures. Recently, intronic expansions of TTTTA/TTTCA repeats in different genes have been identified as the main cause of FAME. We have gathered a unique collection of 13 European families and 15 sporadic cases, and have identified expansions at two new loci on chromosomes 2 (STARD7) and 5 (MARCH6). The goal of this project is to dissect the mechanisms by which TTTCA repeat expansions occur and lead to this enigmatic disorder. More specifically, a first genetic part will aim to: i) characterize in more details the structure and length of expansions identified in at least 50 individuals from 7 FAME families; and ii) identify new sites of this repeat expansions in the 6 negative families.In a second functional part, we will develop appropriate cellular and animal models harboring MARCH6 expansions by generating IPSC that will be differentiated into cortical neurons and expressing the expansion by in utero electroporation in the mouse brain. We will study the dynamics and processes by which the expansion have formed and the contribution of DNA repair pathways to these processes. To clarify the impact of expansions on gene expression and RNA foci formation, we will study the neuronal and brain transcriptomes and perform RNA FISH experiments in IPSC-derived neurons and available post-mortem brain samples. Finally, since FAME expansions have a low GC content that can influence DNA breakage, we will study its impact on the creation of fragile sites. Overall, this project should provide new insights into the complex mechanisms causing FAME and lead to the development of tools and methodologies that could be used to identify and characterize tandem repeat expansions involved in other disorders.

• DFG Programme: Research Grants