Thesis defense Michelle Geryk

Equipe

Team II - Ion channels and cardiopathies

Directeur de thèse

Flavien Charpentier

Rapporteurs

Albano Meli, PhD, CR, INSERM, PhyMedExp, Montpellier 
Hendrik Milting, PhD, Professor, Heart and Diabetes Center NRW, Erich & Hanna Klessmann-Institute, Bad Oeynhausen, Germany

Examinatrices

Isabelle Baro, PhD, DR, L’institut du Thorax, Inserm UMR 1087 / CNRS UMR 6291
Kirstine CALLØ, PhD, Associate professor, Dept. of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen
Ana-Maria Gomez, PhD, Associate professor, Dept. of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen

Abstract

Desmin related myopathy, or desminopathy, is a rare genetic disorder caused by mutations in the intermediate filament desmin. Desmin interconnects several components of the cell including the contractile apparatus and positions organelles within cells, including the nucleus and mitochondria. Desminopathy is most often associated with skeletal and/or cardiac myopathy and is commonly associated with intracellular aggregate formation. Over 70 mutations have been reported along the desmin gene that codes for the filaments 470 amino acids. Although many studies have focused on these mutations over the years, the precise mechanism of the structure-function relationship of desmin within cardiomyocytes has yet to be elucidated.   Genetic testing of a patient presenting with a complex cardiac history, including sudden cardiac death, a persistent depression of the ST-segment on he ECG and arrhythmic storms, revealed a desmin mutation at position p.R406W.   The challenge of this study was to use the patient's induced pluripotent stem cells and isogenic cell lines to understand the genotype-phenotype relationship at hand. Furthermore, a 3-dimensional model of engineered heart tissue was applied. The underlying electrical consequences of this mutation were analyzed using the patch-clamp technique, revealing abnormal repolarization. Simultaneously, we performed proteomic and transcriptomic studies to investigate the complex mechanisms at play, which revealed mitochondrial and conduction defects. Subsequently, electron microscopy revealed structural changes within cells. In conclusion, this work combined functional and molecular approaches to facilitate our understanding of desminopathy.