Alteration of calcium channel signaling may explain mechanism of autism spectrum disorder

August 03, 2020

Autism spectrum disorder (ASD) is a heterogeneous disorder initiated early in development and characterized by abnormal social communication. Accumulating evidence supports the idea that specific mutations affect regulatory proteins that control arrays of cellular pathways.

A special case of autism is known as the Timothy Syndrome (TS) caused by a point mutation in the alternatively spliced exon 8A of the calcium channel Cav1.2. TS is a multisystem disorder characterized also by cardiac dysfunction, causing sudden death from cardiac arrhythmias.

There are two Timothy mutations, G406R and G402S that occur at the calcium channel Cav1.2. These two mutations modify the inactivation kinetics of the channel and by reducing voltage-dependent inactivation, causing an abnormal calcium overload leading to heart problems such as prolonged QT interval and cardiac arrhythmia. Surprisingly, only the G406R mutation is associated with ASD in 4 out of 5 patients carrying the mutation, while the G402S mutation fails to express the autistic phenotype.

The study sought to answer the question: How does the G406R single point mutation of the Cav1.2 channel affect cellular processes that could lead to a multifactorial disease such as autism? It is known that Cav1.2 and other calcium channels induce gene activation, which is responsible for long-term processes, such as neurodevelopmental disorders, cognitive setbacks, and psychiatric disorders including schizophrenia, bipolar disorder and autism.

The researchers, led by Professor Daphne Atlas at the Hebrew University of Jerusalem's Alexander Silberman Institute of Life Sciences, found that both the Cav1.2 Timothy channel mutants G406R and G402S, activate gene programs (transcriptional activity) via the Ras/ERK/CREB cellular pathway, similar to the native (non-mutated) calcium channel Cav1.2. "We were surprised and thrilled to discover that the autistic mutant G406R exhibits a constitutive (spontaneous) transcriptional activation and the G402S mutation does not." This difference might clarify a mechanism that could explain why G406R mutation confers autism whereas G402S does not "shared Atlas.

It is known that in addition to modifying channel inactivation, the two variants of the Timothy channel differ in their activation kinetics. The G406R mutation causes specific gain-of-function changes in Cav1.2 channel gating, exhibiting a "leftward shift" of voltage-dependent activation and G402S does not. This leftward shift facilitates channel activity even at resting potentials, which means that the channel is spontaneously active, as opposed to the G402S mutant.

The research findings of facilitated spontaneous activity of the G406R channel correlates with a constitutive gene activation. This uncontrolled spontaneous gene activation, imposed by a leftward voltage-shift in the activation kinetics of the channel, implies a mechanism of conferring autism. The induction of uncontrolled long-term dysregulations such as autism by facilitated spontaneous activity of the channel and subsequently spontaneous gene activation can be compared to a dripping faucet.

These results were further supported through screening the literature for channel mutants that are associated with long-term abnormalities. All mutated channels that display a leftward-shift in channel activation are associated with long-term dysregulations. These findings imply that channel mutants that exhibit a facilitated channel activity at rest--with no stimulation--imposed by a negative shift in channel gating, are likely to exhibit a spontaneous and uncontrolled gene activation, similar to the Timothy mutant.

"Further studies are required to establish whether the uncontrolled activity of the channel at rest, which is associated with uncontrolled activation of gene programs in Timothy G406R mutant, is the underlying a mechanism by which other mutated channels confer a high risk for neurodevelopmental disorders in humans," explained Atlas.

Based on altering calcium channel kinetics and gene activation exhibited by the Timothy mutant, these results provide insight into the cellular mechanism that allows predicting disease risk, and genetic diagnosis of individuals with neurodevelopmental disorders.
The study was published in Progress in Neurobiology. It is part of a PhD thesis by Evrim Servili and was done in collaboration with fellow HU colleagues, Drs. Michael Trus, Eilon Sherman and Julia Sajman.

The Hebrew University of Jerusalem

Related Autism Articles from Brightsurf:

Autism-cholesterol link
Study identifies genetic link between cholesterol alterations and autism.

National Autism Indicators Report: the connection between autism and financial hardship
A.J. Drexel Autism Institute released the 2020 National Autism Indicators Report highlighting the financial challenges facing households of children with autism spectrum disorder (ASD), including higher levels of poverty, material hardship and medical expenses.

Autism risk estimated at 3 to 5% for children whose parents have a sibling with autism
Roughly 3 to 5% of children with an aunt or uncle with autism spectrum disorder (ASD) can also be expected to have ASD, compared to about 1.5% of children in the general population, according to a study funded by the National Institutes of Health.

Adulthood with autism
The independence that comes with growing up can be scary for any teenager, but for young adults with autism spectrum disorder and their caregivers, the transition from adolescence to adulthood can seem particularly daunting.

Brain protein mutation from child with autism causes autism-like behavioral change in mice
A de novo gene mutation that encodes a brain protein in a child with autism has been placed into the brains of mice.

Autism and theory of mind
Theory of mind, or the ability to represent other people's minds as distinct from one's own, can be difficult for people with autism.

Potential biomarker for autism
A study of young children with autism spectrum disorder published in JNeurosci reveals altered brain waves compared to typically developing children during a motor control task.

Autism often associated with multiple new mutations
Most autism cases are in families with no previous history of the disorder.

State laws requiring autism coverage by private insurers led to increases in autism care
A new study led by researchers at the Johns Hopkins Bloomberg School of Public Health has found that the enactment of state laws mandating coverage of autism spectrum disorder (ASD) was followed by sizable increases in insurer-covered ASD care and associated spending.

Autism's gender patterns
Having one child with autism is a well-known risk factor for having another one with the same disorder, but whether and how a sibling's gender influences this risk has remained largely unknown.

Read More: Autism News and Autism Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to