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000266342 037__ $$aDZNE-2023-01127
000266342 041__ $$aEnglish
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000266342 1001_ $$aMariano, Vittoria$$b0
000266342 245__ $$aIntellectual Disability and Behavioral Deficits Linked to CYFIP1 Missense Variants Disrupting Actin Polymerization
000266342 260__ $$aAmsterdam [u.a.]$$bElsevier Science$$c2024
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000266342 520__ $$a15q11.2 deletions and duplications have been linked to autism spectrum disorder, schizophrenia, and intellectual disability. Recent evidence suggests that dysfunctional CYFIP1 (cytoplasmic FMR1 interacting protein 1) contributes to the clinical phenotypes observed in individuals with 15q11.2 deletion/duplication syndrome. CYFIP1 plays crucial roles in neuronal development and brain connectivity, promoting actin polymerization and regulating local protein synthesis. However, information about the impact of single nucleotide variants in CYFIP1 on neurodevelopmental disorders is limited.Here, we report a family with 2 probands exhibiting intellectual disability, autism spectrum disorder, spastic tetraparesis, and brain morphology defects and who carry biallelic missense point mutations in the CYFIP1 gene. We used skin fibroblasts from one of the probands, the parents, and typically developing individuals to investigate the effect of the variants on the functionality of CYFIP1. In addition, we generated Drosophila knockin mutants to address the effect of the variants in vivo and gain insight into the molecular mechanism that underlies the clinical phenotype.Our study revealed that the 2 missense variants are in protein domains responsible for maintaining the interaction within the wave regulatory complex. Molecular and cellular analyses in skin fibroblasts from one proband showed deficits in actin polymerization. The fly model for these mutations exhibited abnormal brain morphology and F-actin loss and recapitulated the core behavioral symptoms, such as deficits in social interaction and motor coordination.Our findings suggest that the 2 CYFIP1 variants contribute to the clinical phenotype in the probands that reflects deficits in actin-mediated brain development processes.
000266342 536__ $$0G:(DE-HGF)POF4-351$$a351 - Brain Function (POF4-351)$$cPOF4-351$$fPOF IV$$x0
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000266342 650_7 $$2NLM Chemicals$$aActins
000266342 650_7 $$2Other$$aActin remodeling
000266342 650_7 $$2Other$$aAutism spectrum disorder
000266342 650_7 $$2Other$$aCYFIP1
000266342 650_7 $$2Other$$aDrosophila
000266342 650_7 $$2Other$$aMotor impairment
000266342 650_7 $$2Other$$aSocial deficits
000266342 650_7 $$2NLM Chemicals$$aAdaptor Proteins, Signal Transducing
000266342 650_7 $$2NLM Chemicals$$aCYFIP1 protein, human
000266342 650_7 $$2NLM Chemicals$$aFMR1 protein, human
000266342 650_7 $$0139135-51-6$$2NLM Chemicals$$aFragile X Mental Retardation Protein
000266342 650_2 $$2MeSH$$aHumans
000266342 650_2 $$2MeSH$$aIntellectual Disability: genetics
000266342 650_2 $$2MeSH$$aActins: genetics
000266342 650_2 $$2MeSH$$aActins: metabolism
000266342 650_2 $$2MeSH$$aAutism Spectrum Disorder: genetics
000266342 650_2 $$2MeSH$$aAutism Spectrum Disorder: metabolism
000266342 650_2 $$2MeSH$$aPolymerization
000266342 650_2 $$2MeSH$$aAdaptor Proteins, Signal Transducing: genetics
000266342 650_2 $$2MeSH$$aFragile X Mental Retardation Protein: metabolism
000266342 7001_ $$aKanellopoulos, Alexandros K.$$b1
000266342 7001_ $$aRicci, Carlotta$$b2
000266342 7001_ $$aDi Marino, Daniele$$b3
000266342 7001_ $$aBorrie, Sarah C.$$b4
000266342 7001_ $$0P:(DE-2719)2810386$$aDupraz, Sebastian$$b5$$udzne
000266342 7001_ $$0P:(DE-2719)2810270$$aBradke, Frank$$b6$$udzne
000266342 7001_ $$aAchsel, Tilmann$$b7
000266342 7001_ $$aLegius, Eric$$b8
000266342 7001_ $$aOdent, Sylvie$$b9
000266342 7001_ $$aBilluart, Pierre$$b10
000266342 7001_ $$aBienvenu, Thierry$$b11
000266342 7001_ $$00000-0002-4419-210X$$aBagni, Claudia$$b12
000266342 773__ $$0PERI:(DE-600)1499907-9$$a10.1016/j.biopsych.2023.08.027$$gp. S0006322323015639$$n2$$p161 - 174$$tBiological psychiatry$$v95$$x0006-3223$$y2024
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