Clinical and functional characterization of a novel RASopathy-causing SHOC2 mutation associated with prenatal-onset hypertrophic cardiomyopathy

Marialetizia Motta, Antonella Giancotti, Gioia Mastromoro, Balasubramanian Chandramouli, Valentina Pinna, Francesca Pantaleoni, Niccolò Di Giosaffatte, Stefania Petrini, Tommaso Mazza, Valentina D'Ambrosio, Paolo Versacci, Flavia Ventriglia, Giovanni Chillemi, Antonio Pizzuti, Marco Tartaglia, Alessandro De Luca

Research output: Contribution to journalArticle


SHOC2 is a scaffold protein mediating RAS-promoted activation of mitogen-activated protein kinase (MAPK) signaling in response to extracellular stimuli. A recurrent activating mutation in SHOC2 (p.Ser2Gly) causes Mazzanti syndrome, a RASopathy characterized by features resembling Noonan syndrome and distinctive ectodermal abnormalities. A second mutation (p.Met173Ile) supposed to cause loss-of-function was more recently identified in two individuals with milder phenotypes. Here, we report on the third RASopathy-causing SHOC2 mutation (c.807_808delinsTT, p.Gln269_His270delinsHisTyr), which was found associated with prenatal-onset hypertrophic cardiomyopathy. Structural analyses indicated a possible impact of the mutation on the relative orientation of the two SHOC2's leucine-rich repeat domains. Functional studies provided evidence of its activating role, revealing enhanced binding of the mutant protein to MRAS and PPP1CB, and increased signaling through the MAPK cascade. Differing from SHOC2 S2G , SHOC2 Q269_H270delinsHY is not constitutively targeted to the plasma membrane. These data document that diverse mechanisms in SHOC2 functional dysregulation converge toward MAPK signaling upregulation.

Original languageEnglish
JournalHuman Mutation
Publication statusE-pub ahead of print - May 6 2019


Cite this