New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics.
CYFIP2
WASF
WAVE-regulatory complex (WRC)
epilepsy
intellectual disability
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
18
05
2020
accepted:
06
10
2020
revised:
01
10
2020
pubmed:
6
11
2020
medline:
4
6
2021
entrez:
5
11
2020
Statut:
ppublish
Résumé
A few de novo missense variants in the cytoplasmic FMRP-interacting protein 2 (CYFIP2) gene have recently been described as a novel cause of severe intellectual disability, seizures, and hypotonia in 18 individuals, with p.Arg87 substitutions in the majority. We assembled data from 19 newly identified and all 18 previously published individuals with CYFIP2 variants. By structural modeling and investigation of WAVE-regulatory complex (WRC)-mediated actin polymerization in six patient fibroblast lines we assessed the impact of CYFIP2 variants on the WRC. Sixteen of 19 individuals harbor two previously described and 11 novel (likely) disease-associated missense variants. We report p.Asp724 as second mutational hotspot (4/19 cases). Genotype-phenotype correlation confirms a consistently severe phenotype in p.Arg87 patients but a more variable phenotype in p.Asp724 and other substitutions. Three individuals with milder phenotypes carry putative loss-of-function variants, which remain of unclear pathogenicity. Structural modeling predicted missense variants to disturb interactions within the WRC or impair CYFIP2 stability. Consistent with its role in WRC-mediated actin polymerization we substantiate aberrant regulation of the actin cytoskeleton in patient fibroblasts. Our study expands the clinical and molecular spectrum of CYFIP2-related neurodevelopmental disorder and provides evidence for aberrant WRC-mediated actin dynamics as contributing cellular pathomechanism.
Identifiants
pubmed: 33149277
doi: 10.1038/s41436-020-01011-x
pii: S1098-3600(21)04951-0
pmc: PMC7935717
doi:
Substances chimiques
Actins
0
Adaptor Proteins, Signal Transducing
0
CYFIP2 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
543-554Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 098051
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Références
Schenck A, Bardoni B, Langmann C, et al. CYFIP/Sra-1 controls neuronal connectivity in Drosophila and links the Rac1 GTPase pathway to the fragile X protein. Neuron. 2003;38:887–898.
doi: 10.1016/S0896-6273(03)00354-4
Chen Z, Borek D, Padrick SB, et al. Structure and control of the actin regulatory WAVE complex. Nature. 2010;468:533–538.
doi: 10.1038/nature09623
Schenck A, Qurashi A, Carrera P, et al. WAVE/SCAR, a multifunctional complex coordinating different aspects of neuronal connectivity. Dev Biol. 2004;274:260–270.
doi: 10.1016/j.ydbio.2004.07.009
Nakashima M, Kato M, Aoto K, et al. De novo hotspot variants in CYFIP2 cause early-onset epileptic encephalopathy. Ann Neurol. 2018;83:794–806.
doi: 10.1002/ana.25208
Zweier M, Begemann A, McWalter K, et al. Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein 2, cause intellectual disability and seizures. Eur J Hum Genet. 2019;27:747–759.
doi: 10.1038/s41431-018-0331-z
Peng J, Wang Y, He F, et al. Novel West syndrome candidate genes in a Chinese cohort. CNS Neurosci Ther. 2018;24:1196–1206.
doi: 10.1111/cns.12860
Zhong M, Liao S, Li T, et al. Early diagnosis improving the outcome of an infant with epileptic encephalopathy with cytoplasmic FMRP interacting protein 2 mutation: case report and literature review. Medicine (Baltimore). 2019;98:e17749.
doi: 10.1097/MD.0000000000017749
Sobreira N, Schiettecatte F, Valle D, Hamosh A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat. 2015;36:928–930.
doi: 10.1002/humu.22844
Sayle RA, Milner-White EJ. RASMOL: biomolecular graphics for all. Trends Biochem Sci. 1995;20:374.
doi: 10.1016/S0968-0004(00)89080-5
Xiong P, Zhang C, Zheng W, Zhang Y. BindProfX: assessing mutation-induced binding affinity change by protein interface profiles with pseudo-counts. J Mol Biol. 2017;429:426–434.
doi: 10.1016/j.jmb.2016.11.022
Delgado J, Radusky LG, Cianferoni D, Serrano L. FoldX 5.0: working with RNA, small molecules and a new graphical interface. Bioinformatics. 2019;35:4168–4169.
doi: 10.1093/bioinformatics/btz184
Berg S, Kutra D, Kroeger T, et al. ilastik: interactive machine learning for (bio)image analysis. Nat Methods. 2019;16:1226–1232.
doi: 10.1038/s41592-019-0582-9
McQuin C, Goodman A, Chernyshev V, et al. CellProfiler 3.0: next-generation image processing for biology. PLoS Biol. 2018;16:e2005970.
doi: 10.1371/journal.pbio.2005970
Chen B, Chou HT, Brautigam CA, et al. Rac1 GTPase activates the WAVE regulatory complex through two distinct binding sites. eLife. 2017;6:e29795.
doi: 10.7554/eLife.29795
Suetsugu S, Yamazaki D, Kurisu S, Takenawa T. Differential roles of WAVE1 and WAVE2 in dorsal and peripheral ruffle formation for fibroblast cell migration. Dev Cell. 2003;5:595–609.
doi: 10.1016/S1534-5807(03)00297-1
Lee Y, Zhang Y, Ryu JR, et al. Reduced CYFIP2 stability by Arg87 variants Causing Human Neurological Disorders. Ann Neurol. 2019;86:803–805.
doi: 10.1002/ana.25598
Pathania M, Davenport EC, Muir J, et al. The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines. Transl Psychiatry. 2014;4:e374.
doi: 10.1038/tp.2014.16
Davenport EC, Szulc BR, Drew J, et al. Autism and schizophrenia-associated CYFIP1 regulates the balance of synaptic excitation and inhibition. Cell Rep. 2019;26:2037–2051.
doi: 10.1016/j.celrep.2019.01.092
Schaks M, Singh SP, Kage F, et al. Distinct interaction sites of Rac GTPase with WAVE regulatory complex have non-redundant functions in vivo. Curr Biol. 2018;28:3674–3684.
doi: 10.1016/j.cub.2018.10.002
Hoon JL, Wong WK, Koh CG. Functions and regulation of circular dorsal ruffles. Mol Cell Biol. 2012;32:4246–4257.
doi: 10.1128/MCB.00551-12
Innocenti M. New insights into the formation and the function of lamellipodia and ruffles in mesenchymal cell migration. Cell Adh Migr. 2018;12:401–416.
pubmed: 29513145
pmcid: 6363039
Hornbeck PV, Zhang B, Murray B, et al. PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res. 2015;43:D512–D520.
doi: 10.1093/nar/gku1267
Kim Y, Sung JY, Ceglia I, et al. Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology. Nature. 2006;442:814–817.
doi: 10.1038/nature04976
Mendoza MC. Phosphoregulation of the WAVE regulatory complex and signal integration. Semin Cell Dev Biol. 2013;24:272–279.
doi: 10.1016/j.semcdb.2013.01.007
Lee Y, Kim D, Ryu JR, et al. Phosphorylation of CYFIP2, a component of the WAVE-regulatory complex, regulates dendritic spine density and neurite outgrowth in cultured hippocampal neurons potentially by affecting the complex assembly. Neuroreport. 2017;28:749–754.
doi: 10.1097/WNR.0000000000000838
Sossey-Alaoui K, Head K, Nowak N, Cowell JK. Genomic organization and expression profile of the human and mouse WAVE gene family. Mamm Genome. 2003;14:314–322.
doi: 10.1007/s00335-002-2247-7
Zhang Y, Kang HR, Han K. Differential cell-type-expression of CYFIP1 and CYFIP2 in the adult mouse hippocampus. Anim Cells Syst (Seoul). 2019;23:380–383.
doi: 10.1080/19768354.2019.1696406
Zallen JA, Cohen Y, Hudson AM, et al. SCAR is a primary regulator of Arp2/3-dependent morphological events in Drosophila. J Cell Biol. 2002;156:689–701.
doi: 10.1083/jcb.200109057
Han K, Chen H, Gennarino VA, et al. Fragile X-like behaviors and abnormal cortical dendritic spines in cytoplasmic FMR1-interacting protein 2-mutant mice. Hum Mol Genet. 2015;24:1813–1823.
doi: 10.1093/hmg/ddu595
Pittman AJ, Gaynes JA, Chien CB. nev (cyfip2) is required for retinal lamination and axon guidance in the zebrafish retinotectal system. Dev Biol. 2010;344:784–794.
doi: 10.1016/j.ydbio.2010.05.512
Cioni JM, Wong HH, Bressan D, et al. Axon-axon interactions regulate topographic optic tract sorting via CYFIP2-dependent WAVE complex function. Neuron. 2018;97:1078–1093.
doi: 10.1016/j.neuron.2018.01.027
Shakir MA, Jiang K, Struckhoff EC, et al. The Arp2/3 activators WAVE and WASP have distinct genetic interactions with Rac GTPases in Caenorhabditis elegans axon guidance. Genetics. 2008;179:1957–1971.
doi: 10.1534/genetics.108.088963
Ito Y, Carss KJ, Duarte ST, et al. De novo truncating mutations in WASF1 cause intellectual disability with seizures. Am J Hum Genet. 2018;103:144–153.
doi: 10.1016/j.ajhg.2018.06.001
Reijnders MRF, Ansor NM, Kousi M, et al. RAC1 missense mutations in developmental disorders with diverse phenotypes. Am J Hum Genet. 2017;101:466–477.
doi: 10.1016/j.ajhg.2017.08.007
Cuvertino S, Stuart HM, Chandler KE, et al. ACTB loss-of-function mutations result in a pleiotropic developmental disorder. Am J Hum Genet. 2017;101:1021–1033.
doi: 10.1016/j.ajhg.2017.11.006
Riviere JB, van Bon BW, Hoischen A, et al. De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome. Nat Genet. 2012;44:440–444.
doi: 10.1038/ng.1091
Zhang Y, Kang H, Lee Y, et al. Smaller body size, early postnatal lethality, and cortical extracellular matrix-related gene expression changes of Cyfip2-null embryonic mice. Front Mol Neurosci. 2018;11:482.
doi: 10.3389/fnmol.2018.00482
Kumar V, Kim K, Joseph C, et al. C57BL/6N mutation in cytoplasmic FMRP interacting protein 2 regulates cocaine response. Science. 2013;342:1508–1512.
doi: 10.1126/science.1245503
Chung L, Wang X, Zhu L, et al. Parental origin impairment of synaptic functions and behaviors in cytoplasmic FMRP interacting protein 1 (Cyfip1) deficient mice. Brain Res. 2015;1629:340–350.
doi: 10.1016/j.brainres.2015.10.015
Bozdagi O, Sakurai T, Dorr N, et al. Haploinsufficiency of Cyfip1 produces fragile X-like phenotypes in mice. PLoS One. 2012;7:e42422.
doi: 10.1371/journal.pone.0042422