期刊
EMBO MOLECULAR MEDICINE
卷 14, 期 9, 页码 -出版社
WILEY
DOI: 10.15252/emmm.202215829
关键词
extracellular matrix; FIBCD1; glycosaminoglycans; genetics; neurodevelopmental disorder
资金
- DOC fellowship of the Austrian Academy of Sciences (OeAW) [25525, 25408]
- European Union [841319]
- Austrian Science Fund (FWF) [P 32924, Z 271-B19, TAI 202 1000]
- Novo Nordisk foundation
- Federal Ministry of Education, Science and Research
- Austrian Academy of Sciences
- City of Vienna
- T. von Zastrow foundation
- Canada 150 Research Chairs Program [F18-01336]
- Ludwig Boltzmann Gesellschaft core funding
- [DRG-2319-18]
- Marie Curie Actions (MSCA) [841319] Funding Source: Marie Curie Actions (MSCA)
This study identified FIBCD1 as a novel gene associated with neurodevelopmental disorders through whole-exome sequencing. Functional analyses in fly and mouse models revealed the critical role of FIBCD1 in the nervous system.
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.
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