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

Irena J J Muffels; Theodore Carter; Holger Rehmann; Sebastiaan J Vastert; Annemarie A Verrijn Stuart; Andreas C Blank; Aurore Garde; Bert van der Zwaag; Iris M De Lange; Jacques C Giltay; Koen L I van Gassen; Klaas Koop; Cedric S Asensio; Peter M van Hasselt

doi:10.1016/j.isci.2025.112585

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

iScience. 2025 May 5;28(6):112585. doi: 10.1016/j.isci.2025.112585. eCollection 2025 Jun 20.

Affiliations

¹ Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands.
² Department of Biological Sciences, College of Natural Sciences and Mathematics, Denver, CO, USA.
³ Department of Energy and Biotechnology, Flensburg University of Applied Sciences, Flensburg, Germany.
⁴ Department of Pediatric Rheumatology and Immunology and Center for Translational Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands.
⁵ Department of Pediatric Endocrinology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands.
⁶ Department of Pediatric Cardiology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands.
⁷ Centre de Génétique et Centre de Référence Maladies Rares, Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (FHU TRANSLAD), Hôpital d'Enfants, Centre Hospitalier Universitaire de Dijon, Dijon, France.
⁸ Department of Medical Genetics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands.

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.

Keywords: Biological sciences; Endocrinology; Functional aspects of cell biology.