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11 Aug 2022 von lbirud

Receptor FIBCD1 newly identified in neuro-developmental disorders

A multidisciplinary study led by Vanja Nagy (LBI-RUD/CeMM/Medical University of Vienna) and Josef Penninger (UBC/IMBA) characterized a novel gene, known as FIBCD1, to be likely causative 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 novel function for the FIBCD1 gene in the brain, and a potentially pivotal role in diseases such as autism, ADHD, schizophrenia, and neurodegenerative disorders including Alzheimer’s. The study makes an important contribution to the understanding of the extracellular matrix in the brain and its associated neurological diseases.

(Vienna, August 2, 2022) The extracellular matrix (ECM) is the tissue in the brain that surrounds cells in a meshwork-like manner to support and instruct brain function in that respective region. The ECM provides stability to brain cells to enable proper function, including long-term memory storage and makes up around a fifth of the brain volume. Until now, few cellular receptors for ECM signaling have been identified, but no association with a congenital neurological disease was made. For the first time, researchers from two groups – Vanja Nagy’s group from the Ludwig Boltzmann Institute of Rare and Undiagnosed Diseases (LBI-RUD), the CeMM Research Center for Molecular Medicine of the OeAW and the Medical University of Vienna (MedUni Vienna), and Josef Penninger’s group from the University of British Columbia (UBC) and the Institute of Molecular Biotechnology of the OeAW (IMBA) – have characterized FIBCD1, to be 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 connection with our central nervous system function. FIBCD1 is highly expressed in the brain, and it binds to glycosaminoglycans, sugar molecules. Since the brain ECM consists predominantly glycosaminoglycans, we theorized that the receptor must contribute to brain function through ECM binding and/or signaling,” explains Vanja Nagy, the principal investigator of the study.

Mutated FIBCD1 receptors in patients with neurological disorders

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 deleterious variants in FIBCD1 could also cause neurological disorders in humans,” Fell and Hagelkruys explained. This conclusion is also supported by the data from two young patients with neurodevelopmental symptoms, one from the United States and one from China, for whom no diagnosis could be made prior to characterization of FIBCD1’s expression and function in brain neurons. Both patients suffer from a variety of devastating symptoms primarily affecting their central nervous system, including autism spectrum disorder and attention deficit hyperactivity disorder (ADHD), delayed developmental milestones, language impairments, and structural brain anomalies. In both patients, a mutation or variant in FIBCD1 was identified, thereby establishing an important diagnostic milestone.
The link between FIBCD1 and the brain raises many new questions

“We were already able to see in the animal models that the inactivation of FIBCD1 leads to massive neuronal functional perturbance,” Vanja Nagy explains. “In the affected patients, we determined that in both cases, the FIBCD1 variants identified are functionless – the binding to sugars does not work. We have therefore determined that this might be the possible underlining pathological mechanism in the disease of the patients.” Despite this fact, the symptoms of the two patients 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 trigger if mutated, a much larger study cohort is needed,” Nagy added.

Intensive collaboration for research into rare diseases

The study represents an enormous scientific milestone in several ways: on 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 exemplifies the considerable level of collaboration that is needed to research rare diseases: a total of 29 experts from 24 institutions across 7 different countries collaborated 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 to the affected individuals themselves. It also crucially contributes to a better understanding of the molecular connections in our bodies, the functions of our genes, and thus to the development of better therapies for many more common diseases,” says Nagy.

Picture attached: Vanja Nagy, Christopher Fell, Astrid Hagelkruys © Laura Alvarez, CeMM

The Study “FIBCD1 is an endocytic GAG receptor associated with a novel neurodevelopmental disorder“ was published in EMBO Molecular Medicine on August 2, 2022, DOI: 10.15252/emmm.202215829.

Authors: Christopher W Fell*, Astrid Hagelkruys*, Ana Cicvaric, Marion Horrer, Lucy Liu, Joshua Shing Shun Li, Johannes Stadlmann, Anton A Polyansky, Stefan Mereiter, Miguel Angel Tejada, Tomislav Kokotović, Venkat Swaroop Achuta, Angelica Scaramuzza, Kimberly A Twyman, Michelle M Morrow, Jane Juusola, Huifang Yan, Jingmin Wang, Margit Burmeister, Biswa Choudhury, Thomas Levin Andersen, Gerald Wirnsberger, Uffe Holmskov, Norbert Perrimon, Bojan Žagrović, Francisco J Monje, Jesper Bonnet Moeller, Josef M Penninger** and Vanja Nagy***
*shared first authors
**shared last authors

Funding: The study was supported by the Austrian Academy of Sciences, the Damon Runyon Cancer Research Foundation, European Union’s Horizon 2020 research and innovation programme, the Austrian Science Fund (FWF), the Novo Nordisk Foundation, the Austrian Federal Ministry of Education, Science and Research, the City of Vienna, the Zastrow Foundation, and a Canada Research Chairs Program; Vanja Nagy is funded by the Ludwig Boltzmann Gesellschaft core funding, the Austrian Science Fund and TAI 202 1000 Ideas Project.

Vanja Nagy joined the LBI-RUD as Key Researcher and CeMM as Adjunct PI in 2016. She obtained her PhD at the Icahn School of Medicine at Mount Sinai, USA, and received postdoctoral training in the groups of Ivan Dikic and Josef Penninger. Nagy’s lab focuses on the identification and characterization of novel causative genes in rare neurodevelopmental disorders affecting both the central and peripheral nervous systems. Her work is essential in understanding how dysfunctions manifest in neurological pathologies for the development of efficient and personalized therapeutic strategies. In close collaboration with clinicians, Nagy and her team perform whole-exome sequencing of patient samples to prioritize potentially deleterious genetic variants. They then use genetically modified human cell lines, human stem cells, primary mouse cultures, and mouse models to validate and understand the identified genetic defects.

The CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences is an international, independent and interdisciplinary research institution for molecular medicine under the scientific direction of Giulio Superti-Furga. CeMM is oriented towards medical needs and integrates basic research and clinical expertise to develop innovative diagnostic and therapeutic approaches for precision medicine. Research focuses on cancer, inflammation, metabolic and immune disorders, and rare diseases. The Institute’s research building is located on the campus of the Medical University and the Vienna General Hospital.

The Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD)
was founded in April 2016 in a joint effort of Ludwig Boltzmann Gesellschaft, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Medical University of Vienna, and St. Anna Children’s Cancer Research Institute. The three founding partner institutions, and CeRUD Vienna Center for Rare and Undiagnosed Diseases, constitute LBI-RUD’s most important collaboration partners. Research at LBI-RUD focuses on the deciphering of rare immunological, hematopoietic, nervous, dermal, gastro-intestinal, and hepatic diseases. Those studies provide unique insights into human biology and are the basis for the development of tailored therapeutic concepts in the sense of the personalized medicine of the future. The mission of LBI-RUD is – together with its partner institutions – to sustainably develop and maintain research infrastructure integrating scientific, societal, ethical, and economical aspects of rare diseases. rare-diseases.at

IMBA – Institute of Molecular Biotechnology – is one of the leading biomedical research institutes in Europe focusing on cutting-edge stem cell technologies, functional genomics, and RNA biology. IMBA is located at the Vienna BioCenter, the vibrant cluster of universities, research institutes and biotech companies in Austria. IMBA is a subsidiary of the Austrian Academy of Sciences, the leading national sponsor of non-university academic research. The stem cell and organoid research at IMBA is being funded by the Austrian Federal Ministry of Science and the City of Vienna. imba.oeaw.ac.at

Medical University of Vienna (MedUni Vienna) is one of the most traditional medical education and research facilities in Europe. With almost 8,000 students, it is currently the largest medical training center in the German-speaking countries. With 6,000 employees, 30 departments and two clinical institutes, 12 medical theory centers and numerous highly specialized laboratories, it is also one of Europe’s leading research establishments in the biomedical sector. meduniwien.ac.at

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