New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics
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New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics. / Begemann, Anaïs; Sticht, Heinrich; Begtrup, Amber; Vitobello, Antonio; Faivre, Laurence; Banka, Siddharth; Alhaddad, Bader; Asadollahi, Reza; Becker, Jessica; Bierhals, Tatjana; Brown, Kathleen E; Bruel, Ange-Line; Brunet, Theresa; Carneiro, Maryline; Cremer, Kirsten; Day, Robert; Denommé-Pichon, Anne-Sophie; Dyment, Dave A; Engels, Hartmut; Fisher, Rachel; Goh, Elaine S; Hajianpour, M J; Haertel, Lucia Ribeiro Machado; Hauer, Nadine; Hempel, Maja; Herget, Theresia; Johannsen, Jessika; Kraus, Cornelia; Le Guyader, Gwenaël; Lesca, Gaetan; Mau-Them, Frédéric Tran; McDermott, John Henry; McWalter, Kirsty; Meyer, Pierre; Õunap, Katrin; Popp, Bernt; Reimand, Tiia; Riedhammer, Korbinian M; Russo, Martina; Sadleir, Lynette G; Saenz, Margarita; Schiff, Manuel; Schuler, Elisabeth; Syrbe, Steffen; Van der Ven, Amelie Theresa; Verloes, Alain; Willems, Marjolaine; Zweier, Christiane; Steindl, Katharina; Zweier, Markus; Rauch, Anita.
in: GENET MED, Jahrgang 23, Nr. 3, 03.2021, S. 543-554.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics
AU - Begemann, Anaïs
AU - Sticht, Heinrich
AU - Begtrup, Amber
AU - Vitobello, Antonio
AU - Faivre, Laurence
AU - Banka, Siddharth
AU - Alhaddad, Bader
AU - Asadollahi, Reza
AU - Becker, Jessica
AU - Bierhals, Tatjana
AU - Brown, Kathleen E
AU - Bruel, Ange-Line
AU - Brunet, Theresa
AU - Carneiro, Maryline
AU - Cremer, Kirsten
AU - Day, Robert
AU - Denommé-Pichon, Anne-Sophie
AU - Dyment, Dave A
AU - Engels, Hartmut
AU - Fisher, Rachel
AU - Goh, Elaine S
AU - Hajianpour, M J
AU - Haertel, Lucia Ribeiro Machado
AU - Hauer, Nadine
AU - Hempel, Maja
AU - Herget, Theresia
AU - Johannsen, Jessika
AU - Kraus, Cornelia
AU - Le Guyader, Gwenaël
AU - Lesca, Gaetan
AU - Mau-Them, Frédéric Tran
AU - McDermott, John Henry
AU - McWalter, Kirsty
AU - Meyer, Pierre
AU - Õunap, Katrin
AU - Popp, Bernt
AU - Reimand, Tiia
AU - Riedhammer, Korbinian M
AU - Russo, Martina
AU - Sadleir, Lynette G
AU - Saenz, Margarita
AU - Schiff, Manuel
AU - Schuler, Elisabeth
AU - Syrbe, Steffen
AU - Van der Ven, Amelie Theresa
AU - Verloes, Alain
AU - Willems, Marjolaine
AU - Zweier, Christiane
AU - Steindl, Katharina
AU - Zweier, Markus
AU - Rauch, Anita
PY - 2021/3
Y1 - 2021/3
N2 - PURPOSE: 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.METHODS: 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.RESULTS: 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.CONCLUSION: 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.
AB - PURPOSE: 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.METHODS: 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.RESULTS: 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.CONCLUSION: 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.
U2 - 10.1038/s41436-020-01011-x
DO - 10.1038/s41436-020-01011-x
M3 - SCORING: Journal article
C2 - 33149277
VL - 23
SP - 543
EP - 554
JO - GENET MED
JF - GENET MED
SN - 1098-3600
IS - 3
ER -