New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
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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
Аннотация
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.