EMBO Molecular Medicine (Sep 2022)
FIBCD1 is an endocytic GAG receptor associated with a novel neurodevelopmental disorder
- 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,
- Vanja Nagy
Affiliations
- Christopher W Fell
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases Vienna Austria
- Astrid Hagelkruys
- VBC – Vienna BioCenter Campus IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences Vienna Austria
- Ana Cicvaric
- Department of Neurophysiology and Neuropharmacology, Centre for Physiology and Pharmacology Medical University of Vienna Vienna Austria
- Marion Horrer
- VBC – Vienna BioCenter Campus IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences Vienna Austria
- Lucy Liu
- Department of Genetics, Harvard Medical School Howard Hughes Medical Institute Boston MA USA
- Joshua Shing Shun Li
- Department of Genetics, Harvard Medical School Howard Hughes Medical Institute Boston MA USA
- Johannes Stadlmann
- VBC – Vienna BioCenter Campus IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences Vienna Austria
- Anton A Polyansky
- Department of Structural and Computational Biology, Max Perutz Labs University of Vienna Vienna Austria
- Stefan Mereiter
- VBC – Vienna BioCenter Campus IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences Vienna Austria
- Miguel Angel Tejada
- VBC – Vienna BioCenter Campus IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences Vienna Austria
- Tomislav Kokotović
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases Vienna Austria
- Venkat Swaroop Achuta
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases Vienna Austria
- Angelica Scaramuzza
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases Vienna Austria
- Kimberly A Twyman
- Mercy Kids Autism Center Saint Louis MO USA
- Michelle M Morrow
- GeneDx Gaithersburg MD USA
- Jane Juusola
- GeneDx Gaithersburg MD USA
- Huifang Yan
- Department of Pediatrics Peking University First Hospital Beijing China
- Jingmin Wang
- Department of Pediatrics Peking University First Hospital Beijing China
- Margit Burmeister
- Michigan Neuroscience Institute University of Michigan Ann Arbor MI USA
- Biswa Choudhury
- Department of Cellular and Molecular Medicine UCSD La Jolla CA USA
- Thomas Levin Andersen
- Clinical Cell Biology, Department of Pathology Odense University Hospital Odense Denmark
- Gerald Wirnsberger
- VBC – Vienna BioCenter Campus IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences Vienna Austria
- Uffe Holmskov
- Cancer and Inflammation Research, Department of Molecular Medicine University of Southern Denmark Odense Denmark
- Norbert Perrimon
- Department of Genetics, Harvard Medical School Howard Hughes Medical Institute Boston MA USA
- Bojan Žagrović
- Department of Structural and Computational Biology, Max Perutz Labs University of Vienna Vienna Austria
- Francisco J Monje
- Department of Neurophysiology and Neuropharmacology, Centre for Physiology and Pharmacology Medical University of Vienna Vienna Austria
- Jesper Bonnet Moeller
- Cancer and Inflammation Research, Department of Molecular Medicine University of Southern Denmark Odense Denmark
- Josef M Penninger
- VBC – Vienna BioCenter Campus IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences Vienna Austria
- Vanja Nagy
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases Vienna Austria
- DOI
- https://doi.org/10.15252/emmm.202215829
- Journal volume & issue
-
Vol. 14,
no. 9
pp. n/a – n/a
Abstract
Abstract Whole‐exome sequencing of two patients with idiopathic complex neurodevelopmental disorder (NDD) identified biallelic variants of unknown significance within FIBCD1, encoding an endocytic acetyl group‐binding transmembrane receptor with no known function in the central nervous system. We found that FIBCD1 preferentially binds and endocytoses glycosaminoglycan (GAG) chondroitin sulphate‐4S (CS‐4S) and regulates GAG content of the brain extracellular matrix (ECM). In silico molecular simulation studies and GAG binding analyses of patient variants determined that such variants are loss‐of‐function by disrupting FIBCD1‐CS‐4S association. Gene knockdown in flies resulted in morphological disruption of the neuromuscular junction and motor‐related behavioural deficits. In humans and mice, FIBCD1 is expressed in discrete brain regions, including the hippocampus. Fibcd1 KO mice exhibited normal hippocampal neuronal morphology but impaired hippocampal‐dependent learning. Further, hippocampal synaptic remodelling in acute slices from Fibcd1 KO mice was deficient but restored upon enzymatically modulating the ECM. Together, we identified FIBCD1 as an endocytic receptor for GAGs in the brain ECM and a novel gene associated with an NDD, revealing a critical role in nervous system structure, function and plasticity.
Keywords