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December 2023 - Christopher Fell

Dr. Christopher Fell

MedUni Wien RESEARCHER OF THE MONTH December 2023

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.

Selected Literature

  1. Fell CW, Nagy V (2021) Cellular models and high‐throughput screening for genetic causality of intellectual disability. Trends Mol Med 27: 220–230

  2. Moeller JB, Leonardi I, Schlosser A, Flamar AL, Bessman NJ, Putzel GG, Thomsen T, Hammond M, Jepsen CS, Skjodt K et al (2019) Modulation of the fungal mycobiome is regulated by the chitin‐binding receptor FIBCD1. J Exp Med 216: 2689–2700

  3. Schlosser A, Thomsen T, Moeller JB, Nielsen O, Tornoe I, Mollenhauer J, Moestrup SK, Holmskov U (2009) Characterization of FIBCD1 as an acetyl group‐binding receptor that binds chitin. J Immunol 183: 3800–3809

  4. Thomsen T, Schlosser A, Holmskov U, Sorensen GL (2011) Ficolins and FIBCD1: soluble and membrane bound pattern recognition molecules with acetyl group selectivity. Mol Immunol 48: 369–381

Dr. Christopher Fell

Dr. Christopher Fell
MIT McGovern Institute
43 Vassar St
Cambridge, MA 02139