FIBCD1 is an endocytic GAG receptor associated with a novel neurodevelopmental disorder
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 fo...
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| Language: | English |
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Springer Nature
2022-08-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202215829 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Christopher W Fell |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-97ff532b47a541dcbc19af3c49df7a36 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2022-08-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-97ff532b47a541dcbc19af3c49df7a362025-08-24T11:43:57ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-08-0114912310.15252/emmm.202215829FIBCD1 is an endocytic GAG receptor associated with a novel neurodevelopmental disorderChristopher W Fell0Astrid Hagelkruys1Ana Cicvaric2Marion Horrer3Lucy Liu4Joshua Shing Shun Li5Johannes Stadlmann6Anton A Polyansky7Stefan Mereiter8Miguel Angel Tejada9Tomislav Kokotović10Venkat Swaroop Achuta11Angelica Scaramuzza12Kimberly A Twyman13Michelle M Morrow14Jane Juusola15Huifang Yan16Jingmin Wang17Margit Burmeister18Biswa Choudhury19Thomas Levin Andersen20Gerald Wirnsberger21Uffe Holmskov22Norbert Perrimon23Bojan Žagrović24Francisco J Monje25Jesper Bonnet Moeller26Josef M Penninger27Vanja Nagy28Ludwig Boltzmann Institute for Rare and Undiagnosed DiseasesVBC – Vienna BioCenter Campus, IMBA, Institute of Molecular Biotechnology of the Austrian Academy of SciencesDepartment of Neurophysiology and Neuropharmacology, Centre for Physiology and Pharmacology, Medical University of ViennaVBC – Vienna BioCenter Campus, IMBA, Institute of Molecular Biotechnology of the Austrian Academy of SciencesDepartment of Genetics, Harvard Medical School, Howard Hughes Medical InstituteDepartment of Genetics, Harvard Medical School, Howard Hughes Medical InstituteVBC – Vienna BioCenter Campus, IMBA, Institute of Molecular Biotechnology of the Austrian Academy of SciencesDepartment of Structural and Computational Biology, Max Perutz Labs, University of ViennaVBC – Vienna BioCenter Campus, IMBA, Institute of Molecular Biotechnology of the Austrian Academy of SciencesVBC – Vienna BioCenter Campus, IMBA, Institute of Molecular Biotechnology of the Austrian Academy of SciencesLudwig Boltzmann Institute for Rare and Undiagnosed DiseasesLudwig Boltzmann Institute for Rare and Undiagnosed DiseasesLudwig Boltzmann Institute for Rare and Undiagnosed DiseasesMercy Kids Autism CenterGeneDxGeneDxDepartment of Pediatrics, Peking University First HospitalDepartment of Pediatrics, Peking University First HospitalMichigan Neuroscience Institute, University of MichiganDepartment of Cellular and Molecular Medicine, UCSDClinical Cell Biology, Department of Pathology, Odense University HospitalVBC – Vienna BioCenter Campus, IMBA, Institute of Molecular Biotechnology of the Austrian Academy of SciencesCancer and Inflammation Research, Department of Molecular Medicine, University of Southern DenmarkDepartment of Genetics, Harvard Medical School, Howard Hughes Medical InstituteDepartment of Structural and Computational Biology, Max Perutz Labs, University of ViennaDepartment of Neurophysiology and Neuropharmacology, Centre for Physiology and Pharmacology, Medical University of ViennaCancer and Inflammation Research, Department of Molecular Medicine, University of Southern DenmarkVBC – Vienna BioCenter Campus, IMBA, Institute of Molecular Biotechnology of the Austrian Academy of SciencesLudwig Boltzmann Institute for Rare and Undiagnosed DiseasesAbstract 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.https://doi.org/10.15252/emmm.202215829extracellular matrixFIBCD1glycosaminoglycansgeneticsneurodevelopmental disorder |
| spellingShingle | 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 FIBCD1 is an endocytic GAG receptor associated with a novel neurodevelopmental disorder EMBO Molecular Medicine extracellular matrix FIBCD1 glycosaminoglycans genetics neurodevelopmental disorder |
| title | FIBCD1 is an endocytic GAG receptor associated with a novel neurodevelopmental disorder |
| title_full | FIBCD1 is an endocytic GAG receptor associated with a novel neurodevelopmental disorder |
| title_fullStr | FIBCD1 is an endocytic GAG receptor associated with a novel neurodevelopmental disorder |
| title_full_unstemmed | FIBCD1 is an endocytic GAG receptor associated with a novel neurodevelopmental disorder |
| title_short | FIBCD1 is an endocytic GAG receptor associated with a novel neurodevelopmental disorder |
| title_sort | fibcd1 is an endocytic gag receptor associated with a novel neurodevelopmental disorder |
| topic | extracellular matrix FIBCD1 glycosaminoglycans genetics neurodevelopmental disorder |
| url | https://doi.org/10.15252/emmm.202215829 |
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