LIMK1 variants are associated with divergent endocrinological phenotypes and altered exocytosis dynamics

LIM kinase 1 (LIMK1) plays a pivotal role in dynamic actin remodeling through phosphorylation of cofilin, thereby regulating exocytosis. We report two individuals harboring LIMK1 de novo variants with dissimilar phenotypes: one exhibited epileptic encephalopathy and developmental delay, while the other showed common variable immune deficiency and glucose dysregulation. We suspected that the divergent phenotypic features arose from opposing effects on LIMK1 activity. Indeed, actin polymerization was significantly decreased in individual 1, whereas it was increased in individual 2. Insulin-secreting cell lines expressing the LIMK1 variant of individual 1 exhibited significantly slower exocytosis, contrasting the rapid and uncontrolled exocytosis in individual 2. Intriguingly, both variants led to increased overall insulin secretion. This first report of two individuals with LIMK1 variants with divergent effects on cofilin phosphorylation and actin polymerization, reveals that LIMK1 has an important role in tuned insulin exocytosis. These distinct exocytosis defects may underlie the glucose dysregulation observed.