Prof. Roland Wedlich–Söldner, Institute of Cell Dynamics and Imaging, Cells in Motion Interfaculty Centre, University of Münster, Germany
Lecture "Mechanistic insights into the basis of disease – harnessing the power of quantitative cell biology"
Mutations in the inverted formin 2 gene (INF2) represent the most common cause of autosomal dominant focal segmental glomerulosclerosis (FSGS), a kidney disease driven by structural and functional impairment of podocytes. While there is an urgent need for targeted therapeutics for INF2-related FSGS, the pathomechanism by which INF2 mutations disrupt podocyte function is still unknown. The function of INF2 in actin regulation depends on the relief of an autoinhibitory interaction between its N-terminal diaphanous inhibitory domain (DID) and C-terminal diaphanous autoregulatory domain (DAD). We have used cell-based assays to characterize over 50 autosomal dominant INF2 mutants that map to the N-terminal DID domain. We found that all these mutations lead to deregulated activation of the formin and a constitutive stress response. I will show how quantitative cellular profiling allowed us to distinguish INF2 mutations that were linked exclusively to FSGS from those that caused a combination of FSGS and the Charcot–Marie–Tooth neuropathy. I will also discuss recent results where our study of INF2 disease mutants uncovered a novel type of formin regulation and the first case of substrate inhibition in an actin regulator.
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