Published: 16-09-2020 15:34 | Updated: 16-09-2020 17:33

Problems in synapse connection sites found in rare neurodevelopmental disorders

Assistant Professor Kristiina Tammimies, corresponding author, and Dr. Martin Becker, the first author of the study. Photo: N/A

Researchers at Karolinska Institutet describe molecular and cellular consequences of unique genetic mutations affecting the CASK gene which has been implicated in various neurodevelopmental disorders. Notably, the results indicate differences in the development of presynapses of inhibitory neurons in individuals with specific mutations. The findings elucidate key mechanisms during early neuronal maturation and may help to define targets for future drug discoveries for these disorders.

CASK-related neurodevelopmental disorders are caused by mutations affecting the CASK gene and result in a variety of symptoms ranging from brain abnormalities to severe intellectual disability or autism spectrum disorder. Currently, there are no specific treatments for CASK-related disorders.  

In the published study, the researchers used genetic, molecular, cellular, and functional methods to investigate neuronal mechanisms related to CASK-related neurodevelopmental disorders in the patient-specific neurons.

Assistant Professor Kristiina Tammimies, corresponding author of the study. Photo: Ulf Sirborn

”There are hundreds of genes implicated in neurodevelopmental disorders through genetic studies; however, we know very little about what is happening during early human brain development when the involved genes do not work as they should", says Assistant Professor Kristiina Tammimies, the corresponding author of the study from the Center of Neurodevelopmental Disorders at Karolinska Institutet (KIND), Department of Women's and Children’s Health.

Downregulation of genes

"In this study, we wanted to have a deeper understanding of the molecular consequences of specific mutations in CASK gene using a relevant cellular model. Thus, we used cells from the individuals that carried these unique genetic changes and were diagnosed with neurodevelopmental disorders. The collected skin cells were turned into induced pluripotent stem cells and further differentiated to neuronal cells", Dr. Tammimies explains. 

By studying cells derived from individuals carrying CASK genetic alternations, the study demonstrates downregulation of genes that are needed for the functional development of the presynapse. This part of the neuron is crucial to propagate neuronal signals. Furthermore, the results showed that the downregulation was specific for inhibitory neuronal cells.

Photo: Ulf Sirborn

“We now have an in vitro model for CASK disorders in which we see effects that could be linked to the affected individuals,” says Dr. Martin Becker, the first author of the study. ”On a cellular level, this opens a range of possibilities to try and rescue the observed neuronal aberrations. Initially, this approach will be limited to the patient’s genetic variant, but the results will eventually aid the development of treatment options for related genetic variants.”

In vivo proof-of-concept validation

The study also provides a proof-of-concept of how molecular investigation in a dish for brain disorders could be validated in the future using non-invasive imaging methods. For this, the researchers explored data collected within the EU-financed study EU-AIMS and the ongoing RATSS- study at KIND led by Professor Sven Bölte. With the help of in vivo measurements of neurotransmitters using magnetic resonance spectroscopy quantification, the researchers were able to demonstrate persistent low levels of inhibitory neurotransmitter GABA in brain regions of one of the CASK mutation carriers.

“Our proof-of-concept findings on validating iPSC-derived neuronal data using magnetic resonance spectroscopy indicate the possibility to confirm in vitro iPSC-derived neuronal level data in the living persons and open avenues how we can verify and translate in vitro findings back to the affected individuals.” says Dr. Tammimies.

The study was financed by several bodies, including the Swedish Foundation for Strategic Research, the Swedish Research Council, the Swedish Brain Foundation, the Åke Wiberg Foundation, the Jeansson Foundations, the Thuring Foundation, StratNeuro, and the European Union’s Seventh Framework Programme (FP7/2007–2013) and in-kind contributions from companies belonging to the European Federation of Pharmaceutical Industries and Associations (EU-AIMS).


Presynaptic dysfunction in CASK-related neurodevelopmental disorders.
Becker M, Mastropasqua F, Reising JP, Maier S, Ho ML, Rabkina I, et al
Transl Psychiatry 2020 Sep;10(1):312