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

## TL;DR

This study reports two patients with different LIMK1 gene variants causing distinct health issues, linked to altered insulin release and actin dynamics.

## Contribution

First report of LIMK1 variants with opposing effects on actin and exocytosis, explaining divergent clinical outcomes.

## Key findings

- One LIMK1 variant increased actin polymerization and rapid exocytosis, linked to immune and glucose issues.
- Another LIMK1 variant decreased actin polymerization and slowed exocytosis, associated with seizures and developmental delay.
- Both variants increased overall insulin secretion despite differing exocytosis dynamics.

## Abstract

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.

•We found two disease-causing LIMK1 missense variants in patients with divergent symptoms•One patient shows seizures while the other shows immune- and glucose dysregulation•The A43T variant boosts actin polymerization, while G511A stimulates depolymerization•These opposing changes align with exocytosis dynamics and divergent clinical phenotypes

We found two disease-causing LIMK1 missense variants in patients with divergent symptoms

One patient shows seizures while the other shows immune- and glucose dysregulation

The A43T variant boosts actin polymerization, while G511A stimulates depolymerization

These opposing changes align with exocytosis dynamics and divergent clinical phenotypes

Endocrinology; Biological sciences; Functional aspects of cell biology.