ECE2024 Poster Presentations Late-Breaking (77 abstracts)
LIMK1 variants are associated with divergent endocrinological phenotypes aligning with divergently altered exocytosis dynamics.
Irena Muffels 1 , Theodore Carter 2 , Holger Rehmann 3 , Bas Vastert 4 , Annemarie Verrijn Stuart 5 , Andreas Blank 6 , Aurore Garde 7 , Bert Van Der Zwaag 8 , Iris De Lange 8 , Jaques Giltay 8 , Koen Van Gassen 8 , Klaas Koop 1 , Cedric Asensio 2 & Peter Van Hasselt 1
1Wilhelmina Children’s Hospital, University Medical Center Utrecht, Metabolic Diseases; 2College of Natural Sciences and Mathematics, Department of Biological Sciences, Denver, United States; 3Flensburg University of Applied Sciences, Department of Energy and Biotechnology, Flennsburg, Germany; 4Wilhelmina Children’s Hospital, University Medical Center Utrecht, Center for Translational Immunology (CTI), Utrecht, Netherlands; 5Wilhelmina Children’s Hospital, University Medical Center Utrecht, Pediatric Endocrinology, Utrecht, Netherlands; 6Wilhelmina Children’s Hospital, University Medical Center Utrecht, Department of Pediatric Cardiology; 7Centre 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; 8Wilhelmina Children’s Hospital, University Medical Center Utrecht, Department of Medical Genetics, Utrecht, Netherlands
Background: LIM kinase 1 (LIMK1) plays a pivotal role in dynamic actin remodeling through phosphorylation of cofilin. In turn, the dynamic remodeling of the actin cytoskeleton is involved in exocytosis, thereby contributing to tuned secretion of hormones and neurotransmitters, although the exact role of actin in these processes is still debated.
Results: We report two individuals with de novo variants in LIMK1 with dissimilar clinical phenotypes: one individual exhibited epileptic encephalopathy and developmental delay, the other showed common variable immune deficiency, glucose dysregulation, and episodic sinus tachycardia. Given the intragenic localization of these variants, one impacting the highly conserved kinase domain, the other variant located in the auto-inhibitory LIM domain, we suspected that the phenotypic features could be explained by opposite effects of the LIMK1 variants on LIMK1-mediated exocytosis dynamics. Indeed, we found significantly decreased actin polymerization in individual 1, contrasting with increased LIMK1 availability, cofilin phosphorylation, and actin polymerization in fibroblasts of individual 2. As compared to wildtype, significantly slower and decreased insulin exocytosis was observed in insulin-secreting cell lines expressing the LIMK1 variant of individual 1 (harboring the catalytically dead variant), which contrasted with rapid and uncontrolled insulin exocytosis in case of a lack of auto-inhibition for individual 2.
Conclusion: This first report of two individuals with LIMK1 variants harboring divergent effects on cofilin phosphorylation and actin polymerization, reveals novel and important roles for LIMK1 in tuned exocytosis. These distinct exocytosis defects may underlie the epileptic encephalopathy and glucose dysregulation observed in these individuals.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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