X-Chromosome Inactivation Reveals Cause Of Rare Brain Disease

Scientists have found that the CASK gene is responsible for a rare brain disorder called MICPCH.

AsianScientist (Feb. 26, 2019) – A team of scientists in Japan and Egypt has identified a molecular pathway underlying a rare brain disorder called MICPCH (microcephaly, disproportionate pontine and cerebellar hypoplasia) syndrome. Their findings are published in the journal Molecular Psychiatry.

MICPCH is an extremely rare disorder diagnosed in only 53 females and seven males worldwide so far. It is characterized by several developmental symptoms, including small head size, slowed growth, cognitive delays, epilepsy, seizures, vision and hearing problems, as well as decreased muscle tone and autism. MICPCH is linked to irregularities, or mutations, on the X-chromosome that eventually lead to the chromosome’s inactivation.

In the present study, researchers led by Professor Katsuhiko Tabuchi of Shinshu University, Japan, in collaboration with colleagues from Kafr Elsheikh University, used genetic manipulation techniques to shut off a gene encoding calcium/calmodulin-dependent serine protein kinase (CASK) gene through X-chromosome inactivation in female mice, without lethal consequences.

“The aim of the study was to understand the pathophysiology of CASK-deficiency disorders in females, such as MICPCH syndrome, which are supposed to be influenced by X-chromosome inactivation,” said Tabuchi.

CASK is a protein found within the outer membrane of neurons and is one of the most important molecules that maintains the balance between excitation and inhibition in neurons, akin to a thermostat that is used to maintain a balanced temperature in a home. Mutations in the gene that produce CASK lead to several neurodevelopmental disorders such as mental retardation.

The researchers found that neurons lacking CASK have a disrupted excitation and inhibition balance. They also found that the loss of balance resulted from a decrease in the concentration of a specific receptor—the N-methyl-D-aspartate receptor—on the membrane that receives signals from other neurons. When the receptor concentration was increased, the excitatory and inhibitory balance was restored, indicating that the receptor plays a central role in the mechanism in CASK-deficient neurons.

In the future, the researchers hope to address the effects of a CASK-deficiency in even greater detail by looking at its effects on the neural circuitry.

“We hope to highlight the effect of two different types of neurons in one brain as well as the pathophysiology of CASK-deficiency disorders at neural circuit levels,” Tabuchi concluded.

The article can be found at: Mori et al. (2019) Deficiency of Calcium/calmodulin-dependent Serine Protein Kinase Disrupts the Excitatory-inhibitory Balance of Synapses by Down-regulating GluN2B.


Source: Shinshu University; Photo: Shutterstock.
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