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FIBCD1 is an endocytic GAG receptor associated with a novel neurodevelopmental disorder
EMBO Molecular Medicine ( IF 11.1 ) Pub Date : 2022-08-02 , DOI: 10.15252/emmm.202215829
Christopher W Fell 1, 2, 3 , Astrid Hagelkruys 4 , Ana Cicvaric 5, 6 , Marion Horrer 4 , Lucy Liu 7 , Joshua Shing Shun Li 7 , Johannes Stadlmann 4, 8 , Anton A Polyansky 9, 10 , Stefan Mereiter 4 , Miguel Angel Tejada 4, 11 , Tomislav Kokotović 1, 2, 3 , Venkat Swaroop Achuta 1, 3 , Angelica Scaramuzza 1, 3 , Kimberly A Twyman 12 , Michelle M Morrow 13 , Jane Juusola 13 , Huifang Yan 14, 15 , Jingmin Wang 14, 15 , Margit Burmeister 16, 17 , Biswa Choudhury 18 , Thomas Levin Andersen 19, 20 , Gerald Wirnsberger 4, 21 , Uffe Holmskov 22 , Norbert Perrimon 7 , Bojan Žagrović 9 , Francisco J Monje 5 , Jesper Bonnet Moeller 22, 23 , Josef M Penninger 4, 24 , Vanja Nagy 1, 2, 3
Affiliation  

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.

中文翻译:

FIBCD1 是一种与新型神经发育障碍相关的内吞 GAG 受体

对两名特发性复杂神经发育障碍 (NDD) 患者进行全外显子组测序,发现FIBCD1内具有未知意义的双等位基因变异,编码一种内吞乙酰基结合跨膜受体,在中枢神经系统中的功能尚不清楚。我们发现FIBCD1优先结合并内吞糖胺聚糖(GAG)硫酸软骨素-4S(CS-4S)并调节脑细胞外基质(ECM)的GAG含量。在计算机分子模拟研究和患者变体的 GAG 结合分析中,确定这些变体通过破坏 FIBCD1-CS-4S 关联而丧失功能。果蝇中的基因敲低导致神经肌肉接头的形态破坏和运动相关的行为缺陷。在人类和小鼠中,FIBCD1 在离散的大脑区域表达,包括海马体。Fibcd1 KO 小鼠表现出正常的海马神经元形态,但海马依赖性学习受损。此外, Fibcd1 KO 小鼠急性切片中的海马突触重塑存在缺陷,但在酶调节 ECM 后恢复。我们共同确定 FIBCD1 是大脑 ECM 中 GAG 的内吞受体,也是与 NDD 相关的新基因,揭示了在神经系统结构、功能和可塑性中的关键作用。
更新日期:2022-08-02
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