Researchers in Spain are working to unravel the molecular origins of CTNNB1 syndrome, an ultra-rare neurodevelopmental disorder, on the occasion of Rare Disease Day. The project, led by the Biofisika Institute (CSIC, EHU) in Leioa, aims to understand how mutations in the beta-catenin protein disrupt brain development.
Sonia Bañuelos, a researcher at the Biofisika Institute and lecturer at the University of the Basque Country (EHU), explained that the goal is to determine how these mutations interfere with proper brain formation. “Understanding the mechanisms at the molecular level is essential so that specific therapies can be developed in the future,” she said.
Despite being exceedingly rare – fewer than 50 cases diagnosed in Spain – the research underscores the broader impact of rare diseases, which collectively affect nearly three million people, according to the Biofisika Institute.
The collaborative effort involves a neuropsychology team from the University of Deusto, molecular geneticists from the Biobizkaia Institute at Cruces University Hospital, and the brain organoid platform at the Achucarro Neuroscience Center. The Spanish Association of CTNNB1 Patients, based in Bizkaia, is also actively involved in the research.
Beta-catenin plays a critical role in both embryonic development and ongoing brain function. It is involved in cell adhesion, providing structural integrity to tissues, and is fundamental to the formation and plasticity of synapses – the connections essential for learning, and memory.
CTNNB1 syndrome typically arises from mutations that result in incomplete or misfolded beta-catenin proteins, hindering their ability to function correctly. This disruption impacts crucial processes during brain development, according to researchers.
The Biofisika Institute team is employing a combination of computational modeling, biophysical techniques, and brain organoids to study the syndrome. They utilize three-dimensional protein structures to predict how mutations affect the interaction between beta-catenin and cadherin, components of cell adhesion complexes. These predictions are then validated through laboratory experiments, producing mutated protein versions in bacteria and observing their impact on nervous tissue development using brain organoids.
A recent study published in PubMed compared the cognitive and adaptive functioning of 25 patients with CTNNB1 syndrome to those with Autism Spectrum Disorder (ASD) and Cerebral Palsy (CP). The study found that CTNNB1 patients exhibited lower scores in visuospatial and logical tasks compared to the other groups, and also displayed more externalizing problems. However, cognitive and adaptive functioning appeared to improve over time for CTNNB1 patients.
Although the research is currently focused on basic science, Bañuelos suggests the findings “could help in a future development of rational designed therapies.” The Biofisika Institute emphasized the necessity of research into rare diseases, stating that understanding the underlying mechanisms is the first step toward finding effective treatments.