Summary: A study of patients with polymicrogyria provides new insight into how mutations in the ATP1A3 gene affect early human brain development.
Source: Boston Children’s Hospital
Polymicrogyria is a developmental brain disorder in which the cerebral cortex develops many small, irregular folds (gyria) and shows disrupted layering. Children with this condition often experience significant developmental delays, intellectual disability, and epilepsy, and many require mobility support. Various genes have been implicated in causing this abnormal overfolding of the cortex.
While studying four patients with polymicrogyria, Richard Smith, PhD, discovered mutations in an unexpected gene: ATP1A3. That finding prompted a focused investigation into when and where ATP1A3 is active during early human brain development and how disruption of this gene could lead to cortical malformation.
“ATP1A3 is central to many cellular processes,” says Smith, an investigator in the Division of Genetics and Genomics at Boston Children’s Hospital. “It’s one of the most important genes in the brain.”
Bioelectric mechanisms in brain formation
ATP1A3 encodes a subunit of the sodium-potassium pump, a membrane protein complex that transports sodium and potassium ions across the cell membrane. By maintaining different concentrations of charged ions inside and outside cells, this pump establishes the electrical gradients that underlie cellular excitability. Those gradients are essential both for action potentials in neurons and for many other cellular functions that guide development.
Smith, trained in electrophysiology, wanted to understand how these ion pumps and the resulting ionic flows contribute to the cellular events that build the cortex. Studying the four patients with ATP1A3 mutations revealed biological clues that suggested a wider role for this gene in shaping brain structure.
A spatial and temporal atlas of ATP1A3 expression
To map ATP1A3 activity across developmental time and cortical regions, Smith and colleagues including senior investigator Christopher Walsh, MD, PhD, assembled donated human tissues from hospital tissue banks and the NIH NeuroBiobank. They examined samples from two developmental stages: around 20 weeks’ gestation, when the initially smooth fetal cortex begins to fold, and in early infancy, soon after birth.
Using single-cell RNA sequencing (DropSeq) in collaboration with Marta Florio, PhD, at Harvard Medical School, the team profiled gene expression in approximately 125,000 individual prenatal cortical cells sampled from 11 distinct cortical regions, and about 52,000 cells from infant cortex across four regions. This single-cell approach allowed the researchers to determine precisely which cell types and cortical layers express ATP1A3 at each stage.
They found that ATP1A3 expression was highest in the prefrontal cortex at both prenatal and early postnatal stages and was particularly enriched in neurons that are highly active or fire frequently. In the fetal brain, ATP1A3 expression stood out in the subplate, a transient layer that plays a pivotal role in early cortical circuit formation. The subplate is known to coordinate electrical signaling that promotes synapse formation, neuronal migration, and other developmental processes that lay down cortical architecture.
In infant samples, ATP1A3 expression was increased in interneurons, the inhibitory neuron class that helps balance cortical excitation. “We think ATP1A3 mutations may disrupt the balance between excitation and inhibition in the developing brain,” Smith says, “which could contribute to epilepsy seen in ATP1A3-related conditions.”
Implications for ATP1A3-related disorders and future research
Published in PNAS, this research highlights how detailed study of rare genetic disorders can reveal basic principles of human brain development. The spatial and temporal atlas of ATP1A3 expression provides a framework for future work to connect specific mutations with disrupted developmental processes that produce cortical malformations such as polymicrogyria.
When the team first shared preliminary results as a preprint, they received many responses from clinicians and families reporting patients with overlapping clinical features. That response reinforced the significance of ATP1A3 in a broader spectrum of neurologic conditions.
The study also informs understanding of other diseases already linked to ATP1A3. In the patients with polymicrogyria, the identified mutations produced severe loss of function, consistent with a developmental malformation occurring early in life. By contrast, milder ATP1A3 mutations are associated with later-onset neurological syndromes such as alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism, and some cases of childhood-onset psychiatric illness. Those conditions, which manifest after development, might present more opportunities for therapeutic intervention.
“Polymicrogyria represents an extreme outcome in the spectrum of ATP1A3-related disorders,” Smith notes. “But we suspect many disorders in the middle of that spectrum have early pathogenic roots. If we can identify them early, there may be a window for intervention before symptoms become severe.” He adds that routine newborn DNA screening, if it becomes widespread, could help detect pathogenic ATP1A3 variants before clinical symptoms appear and open the possibility of early treatment.
Although structural malformations like polymicrogyria are challenging to reverse, the infant brain is highly plastic. Reducing seizure-related injury or modifying early pathogenic processes could still improve outcomes and quality of life for affected children.
Funding: Smith’s work is supported by the NIH National Institute of Neurological Disorders and Stroke and the Tommy Fuss Foundation. Walsh is an HHMI Investigator and receives support from the Paul G. Allen Frontiers Group and the NIH.
About this genetics and brain development research news
Source: Boston Children’s Hospital
Contact: Bethany Tripp – Boston Children’s Hospital
Image: The image is credited to Richard Smith/Sebastian Stankiewicz, Boston Children’s Hospital
Original Research: The research is published in PNAS