A Deregulated Stress Response Underlies Distinct INF2-Associated Disease Profiles
Inverted formin 2 (INF2) is the key regulator of a stress response—calcium-mediated actin reset, or CaAR—that reorganizes the actin cytoskeleton of mammalian cells in response to calcium influx. INF2 has been linked to the podocytic kidney disease focal segemental glomerulosclerosis (FSGS) and to cases of the neurologic disorder Charcot–Marie–Tooth disease that are accompanied by FSGS. The authors show that >50 disease-associated INF2 variants lead to deregulation of CaAR in cell lines, in Drosophila nephrocytes, and in cells from patient cells with these disorders. Their findings suggest that CaAR can be used as a sensitive assay for INF2 function and for robust evaluation of disease-linked variants of this formin. This work also highlights the use of quantitative cellular assays in assessing effects of disease-associated mutations to better understand complex disease phenotypes.
