Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2067/45993
Titolo: SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype
Autori: Motta, Marialetizia
Fasano, Giulia
Gredy, Sina
Brinkmann, Julia
Bonnard, Adeline Alice
Simsek-Kiper, Pelin Ozlem
Gulec, Elif Yilmaz
Essaddam, Leila
Utine, Gulen Eda
Guarnetti Prandi, Ingrid
Venditti, Martina
Pantaleoni, Francesca
Radio, Francesca Clementina
Ciolfi, Andrea
Petrini, Stefania
Consoli, Federica
Vignal, Cédric
Hepbasli, Denis
Ullrich, Melanie
de Boer, Elke
Vissers, Lisenka E L M
Gritli, Sami
Rossi, Cesare
De Luca, Alessandro
Ben Becher, Saayda
Gelb, Bruce D
Dallapiccola, Bruno
Lauri, Antonella
Chillemi, Giovanni 
Schuh, Kai
Cavé, Hélène
Zenker, Martin
Tartaglia, Marco
Rivista: AMERICAN JOURNAL OF HUMAN GENETICS 
Data pubblicazione: 2021
Abstract: 
Upregulated signal flow through RAS and the mitogen-associated protein kinase (MAPK) cascade is the unifying mechanistic theme of the RASopathies, a family of disorders affecting development and growth. Pathogenic variants in more than 20 genes have been causally linked to RASopathies, the majority having a dominant role in promoting enhanced signaling. Here, we report that SPRED2 loss of function is causally linked to a recessive phenotype evocative of Noonan syndrome. Homozygosity for three different variants-c.187C>T (p.Arg63∗), c.299T>C (p.Leu100Pro), and c.1142_1143delTT (p.Leu381Hisfs∗95)-were identified in four subjects from three families. All variants severely affected protein stability, causing accelerated degradation, and variably perturbed SPRED2 functional behavior. When overexpressed in cells, all variants were unable to negatively modulate EGF-promoted RAF1, MEK, and ERK phosphorylation, and time-course experiments in primary fibroblasts (p.Leu100Pro and p.Leu381Hisfs∗95) documented an increased and prolonged activation of the MAPK cascade in response to EGF stimulation. Morpholino-mediated knockdown of spred2a and spred2b in zebrafish induced defects in convergence and extension cell movements indicating upregulated RAS-MAPK signaling, which were rescued by expressing wild-type SPRED2 but not the SPRED2Leu381Hisfs∗95 protein. The clinical phenotype of the four affected individuals included developmental delay, intellectual disability, cardiac defects, short stature, skeletal anomalies, and a typical facial gestalt as major features, without the occurrence of the distinctive skin signs characterizing Legius syndrome. These features, in part, characterize the phenotype of Spred2-/- mice. Our findings identify the second recessive form of Noonan syndrome and document pleiotropic consequences of SPRED2 loss of function in development.
URI: http://hdl.handle.net/2067/45993
ISSN: 0002-9297
DOI: 10.1016/j.ajhg.2021.09.007
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