A multidisciplinary study led by Vanja Nagy (LBI-RUD/CeMM/Medical University of Vienna) and Josef Penninger (UBC/IMBA) characterized a new gene, known as FIBCD1, which is likely the cause of a new and rare neurodevelopmental disorder. Using data from two young patients with neurological symptoms, the researchers from both groups found evidence of a new function for the FIBCD1 gene in the brain, and a potentially critical role in diseases such as autism, ADHD, schizophrenia and neurodegenerative disorders, including Alzheimer’s disease. The study makes an important contribution to the understanding of the extracellular matrix in the brain and associated neurological disorders.
The extracellular matrix (ECM) is the tissue in the brain that surrounds cells in a network-like manner to support and direct brain function in that respective area. The ECM provides stability to brain cells to enable proper function, including long-term memory storage, and makes up about one-fifth of the brain’s volume. So far, few cellular receptors for ECM signaling have been identified, but no congenital neurological disorder has been linked. For the first time, researchers from two groups – Vanja Nagy’s group of the Ludwig Boltzmann Institute of Rare and Undiagnosed Diseases (LBI-RUD), the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences (OeAW) and the group of Josef Penninger from the University of British Columbia (UBC) and the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences (OeAW) – characterized FIBCD1 as a receptor of the ECM ‘sugar’ components and linked it to a rare genetic neurological disease .
Until now, we were only aware of FIBCD1 in an immunological context, and it had never been studied in the brain or in relation to our central nervous system function. FIBCD1 is highly expressed in the brain and binds to sugar-based molecules. Since the brain ECM is primarily made up of ‘sugar’, we theorized that the receptor must contribute to brain function through ECM binding and/or signaling.”
Vanja Nagy, principal investigator of the study
Mutated FIBCD1 receptors in patients with neurological disorders
The first authors Christopher Fell (LBI-RUD/CeMM) and Astrid Hagelkruys (IMBA) used knockdown fly and knockout mouse models, as well as a series of in silico and in vitro experiments, to demonstrate that FIBCD1 is indeed a receptor for ECM components in the brain. Their work confirmed that the absence of FIBCD1 can lead to nervous system disorders that affect behavior and cellular dysfunction in animal models. “This allowed us to conclude that harmful variants in FIBCD1 can also cause neurological disorders in humans,” explained Fell and Hagelkruys. This conclusion is also supported by data from two young patients with neurodevelopmental symptoms, one from the United States and one from China, who could not be diagnosed prior to characterization of FIBCD1 expression and function in brain neurons. Both patients suffer from a variety of devastating symptoms that primarily affect their central nervous systems, including Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder (ADHD), delayed developmental milestones, language disorders and structural brain abnormalities. A mutation or variant in FIBCD1 was identified in both patients, reaching an important diagnostic milestone.
The link between FIBCD1 and the brain raises many new questions
“We could already see in the animal models that the inactivation of FIBCD1 leads to enormous neuronal functional disruption,” explains Vanja Nagy. “In the affected patients, we determined that in both cases the identified FIBCD1 variants are functionless – the binding to sugars does not work. We therefore determined that this could be the possible underlying pathological mechanism in the patients’ disease.” Despite this fact, the two patients’ symptoms were remarkably different: while one of the patients had structural abnormalities in the brain, the other patient did not. “To be able to make a more concrete determination about the function of FIBCD1 in the human central nervous system, and what it can cause if it is mutated, a much larger study cohort is needed,” Nagy added.
Intensive collaboration for research into rare diseases
The study represents a major scientific milestone in several respects: on the one hand, the identification and characterization of FIBCD1 in the brain has made an important contribution to our understanding of the ECM. On the other hand, it is an example of the significant level of collaboration needed to investigate rare diseases: a total of 29 experts from 24 institutions in 7 different countries worked together to identify a new gene, FIBCD1, which was found to be likely responsible for neurodevelopmental symptoms in two unrelated patients from different countries. “The diagnosis of patients with rare diseases is not only of enormous importance for the affected individuals themselves. It also contributes crucially to a better understanding of the molecular connections in our bodies, the functions of our genes, and thus development of better therapies for many more common diseases,” says Nagy.