Scientists have helped to explain a genetic form of microcephaly by uncovering a molecular cause for the rare disease.
Microcephaly is a condition where babies’ heads are small and grow more slowly than their peers. The team from Virginia Tech have demonstrated how a non-functioning version of an ordinary gene – called CASK – impairs brain structure and function, impacting on the molecular activity within brain cells and the connections between brain cells.
The CASK gene lies on the X chromosome and contains instructions for producing the CASK protein molecule, which is necessary for brain growth and function. Males without a functional CASK gene develop a severe encephalopathy and may not survive, and females with one mutated copy express this mutation in half of their cells and the non-mutated copy in the other half.
The study has been published in Experimental Neurology.
The CASK gene
CASK is found across the animal kingdom, including in worms, fruit flies, mice, and people, but dysfunctional variants of the CASK gene in children result in microcephaly with pontine and cerebellar hypoplasia, or impaired growth, which may contribute to intellectual disability, microcephaly, abnormal brain and optic nerve development, and seizures in girls. The new research indicates that seizures are not a likely cause for the smaller brain size.
Paras Patel, a student in Virginia Tech’s translational biology, medicine, and health graduate programme and lead author on the published study, said: “There are drastic changes in brain development in these children, and whenever that happens, the prospect of seizures and cellular toxicity due to epileptic activity becomes a concern.”
To understand the functional changes caused by CASK-related disorder, the researchers studied a mouse model where half of the cells did not have mouse CASK and the other half had normal mouse CASK, which is a genetically similar profile to the majority of human cases to understand the functional changes caused by CASK-related disorder. The scientists discovered abnormalities that would affect communication between brain cells, as well as molecular changes that affect processes cells use to make protein.
In addition, the findings point to an unexpected role for CASK in the regulation of energy production in cells, including the mitochondria, which are structures that convert nutrients into energy.
Corresponding author, Mukherjee, commented: “Strikingly, significant numbers of molecular changes that we observed occur in proteins related to cellular energy production and other aspects of mitochondrial function. The role for CASK at the mitochondria provides interesting future directions into how this function could explain diminished brain size and dysregulated function in cases of CASK mutation in humans.”
“The interest from parents whose children are affected by CASK gene mutations is very inspiring,” said Patel. “They search the web for all the new studies and read extremely complex papers, so it is exciting to provide a step forward for them which comes from an extensive, unbiased investigation relevant to the disorder.”