RT Journal Article
SR Electronic
T1 Presynaptic dysfunction in <em>CASK</em>-related neurodevelopmental disorders
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 863308
DO 10.1101/863308
A1 Martin Becker
A1 Francesca Mastropasqua
A1 Jan Philipp Reising
A1 Simon Maier
A1 Mai-Lan Ho
A1 Ielyzaveta Rabkina
A1 Danyang Li
A1 Janina Neufeld
A1 Lea Ballenberger
A1 Lynnea Myers
A1 Viveka Moritz
A1 Malin Kele
A1 Josephine Wincent
A1 Charlotte Willfors
A1 Rouslan Sitnikov
A1 Eric Herlenius
A1 Britt-Marie Anderlid
A1 Anna Falk
A1 Sven Bölte
A1 Kristiina Tammimies
YR 2019
UL http://biorxiv.org/content/early/2019/12/09/863308.abstract
AB CASK-related disorders are a genetically defined group of neurodevelopmental syndromes. There is limited information about the effects of CASK mutations in human neurons. Therefore, we sought to delineate CASK mutation consequences and neuronal level effects using induced pluripotent stem cell-derived neurons from two mutation carriers; one male diagnosed with ASD and a female with MICPCH. We show a reduction of the CASK protein in maturing neurons from the mutation carriers, which leads to significant downregulation of gene sets involved in presynaptic development and CASK protein interactors. Furthermore, CASK-deficient neurons showed decreased inhibitory presynapse size as indicated by VGAT staining, which may alter the excitatory-inhibitory (E/I) balance in developing neural circuitries. Using in vivo magnetic resonance spectroscopy quantification of GABA in the male mutation carrier, we further highlight the possibility to validate in vitro cellular data in brain. Our data shows that future pharmacological and clinical studies on targeting presynapses and E/I imbalance could lead to specific treatments for CASK-related disorders.Highlights Modelling of CASK-related disorders using iPSC-derived human neuronal cellsCASK mutations cause dysregulation of its protein interactor partnersReduced CASK levels primarily affect inhibitory presynapse developmentIn vitro GABAergic phenotype predicts in vivo neurotransmitter levels