Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Presynaptic dysfunction in CASK-related neurodevelopmental disorders

Becker, Martin ; Mastropasqua, Francesca ; Reising, Jan Philipp ; Maier, Simon ; Ho, Mai-Lan ; Rabkina, Ielyzaveta ; Li, Danyang ; Neufeld, Janina ; Ballenberger, Lea and Myers, Lynnea , et al. (2020) In Translational Psychiatry 10(1).
Abstract

CASK-related disorders are genetically defined 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 effects using induced pluripotent stem cell-derived neurons from two mutation carriers. One male case with autism spectrum disorder carried a novel splice-site mutation and a female case with intellectual disability carried an intragenic tandem duplication. We show reduction of CASK protein in maturing neurons from the mutation carriers, which leads to significant downregulation of genes involved in presynaptic development and of CASK protein interactors. Furthermore, CASK-deficient neurons showed decreased... (More)

CASK-related disorders are genetically defined 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 effects using induced pluripotent stem cell-derived neurons from two mutation carriers. One male case with autism spectrum disorder carried a novel splice-site mutation and a female case with intellectual disability carried an intragenic tandem duplication. We show reduction of CASK protein in maturing neurons from the mutation carriers, which leads to significant downregulation of genes involved in presynaptic development and of 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 the brain. Our data show that future pharmacological and clinical studies on targeting presynapses and E/I imbalance could lead to specific treatments for CASK-related disorders.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Autism Spectrum Disorder/genetics, Brain/diagnostic imaging, Female, Guanylate Kinases/genetics, Humans, Intellectual Disability/genetics, Male, Mutation
in
Translational Psychiatry
volume
10
issue
1
article number
312
publisher
Nature Publishing Group
external identifiers
  • pmid:32929080
  • scopus:85090933511
ISSN
2158-3188
DOI
10.1038/s41398-020-00994-0
language
English
LU publication?
no
id
ef1e5c44-1841-414b-89a6-3c5b67145f58
date added to LUP
2021-08-09 13:49:32
date last changed
2024-06-01 13:12:41
@article{ef1e5c44-1841-414b-89a6-3c5b67145f58,
  abstract     = {{<p>CASK-related disorders are genetically defined 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 effects using induced pluripotent stem cell-derived neurons from two mutation carriers. One male case with autism spectrum disorder carried a novel splice-site mutation and a female case with intellectual disability carried an intragenic tandem duplication. We show reduction of CASK protein in maturing neurons from the mutation carriers, which leads to significant downregulation of genes involved in presynaptic development and of 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 the brain. Our data show that future pharmacological and clinical studies on targeting presynapses and E/I imbalance could lead to specific treatments for CASK-related disorders.</p>}},
  author       = {{Becker, Martin and Mastropasqua, Francesca and Reising, Jan Philipp and Maier, Simon and Ho, Mai-Lan and Rabkina, Ielyzaveta and Li, Danyang and Neufeld, Janina and Ballenberger, Lea and Myers, Lynnea and Moritz, Viveka and Kele, Malin and Wincent, Josephine and Willfors, Charlotte and Sitnikov, Rouslan and Herlenius, Eric and Anderlid, Britt-Marie and Falk, Anna and Bölte, Sven and Tammimies, Kristiina}},
  issn         = {{2158-3188}},
  keywords     = {{Autism Spectrum Disorder/genetics; Brain/diagnostic imaging; Female; Guanylate Kinases/genetics; Humans; Intellectual Disability/genetics; Male; Mutation}},
  language     = {{eng}},
  month        = {{09}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Translational Psychiatry}},
  title        = {{Presynaptic dysfunction in CASK-related neurodevelopmental disorders}},
  url          = {{http://dx.doi.org/10.1038/s41398-020-00994-0}},
  doi          = {{10.1038/s41398-020-00994-0}},
  volume       = {{10}},
  year         = {{2020}},
}