Abstract
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 language | English |
|---|---|
| Journal | Human Mutation |
| DOIs | |
| Publication status | E-pub ahead of print - May 6 2019 |
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Clinical and functional characterization of a novel RASopathy-causing SHOC2 mutation associated with prenatal-onset hypertrophic cardiomyopathy. / Motta, Marialetizia; Giancotti, Antonella; Mastromoro, Gioia; Chandramouli, Balasubramanian; Pinna, Valentina; Pantaleoni, Francesca; Di Giosaffatte, Niccolò; Petrini, Stefania; Mazza, Tommaso; D'Ambrosio, Valentina; Versacci, Paolo; Ventriglia, Flavia; Chillemi, Giovanni; Pizzuti, Antonio; Tartaglia, Marco; De Luca, Alessandro.
In: Human Mutation, 06.05.2019.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Clinical and functional characterization of a novel RASopathy-causing SHOC2 mutation associated with prenatal-onset hypertrophic cardiomyopathy
AU - Motta, Marialetizia
AU - Giancotti, Antonella
AU - Mastromoro, Gioia
AU - Chandramouli, Balasubramanian
AU - Pinna, Valentina
AU - Pantaleoni, Francesca
AU - Di Giosaffatte, Niccolò
AU - Petrini, Stefania
AU - Mazza, Tommaso
AU - D'Ambrosio, Valentina
AU - Versacci, Paolo
AU - Ventriglia, Flavia
AU - Chillemi, Giovanni
AU - Pizzuti, Antonio
AU - Tartaglia, Marco
AU - De Luca, Alessandro
N1 - © 2019 Wiley Periodicals, Inc.
PY - 2019/5/6
Y1 - 2019/5/6
N2 - 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.
AB - 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.
U2 - 10.1002/humu.23767
DO - 10.1002/humu.23767
M3 - Article
C2 - 31059601
JO - Human Mutation
JF - Human Mutation
SN - 1059-7794
ER -