Clinical and functional characterization of a novel RASopathy-causing SHOC2 mutation associated with prenatal-onset hypertrophic cardiomyopathy.
Hum Mutat
; 40(8): 1046-1056, 2019 08.
Article
em En
| MEDLINE
| ID: mdl-31059601
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Cardiomiopatia Hipertrófica
/
Peptídeos e Proteínas de Sinalização Intracelular
/
Mutação
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
/
Risk_factors_studies
Limite:
Adult
/
Animals
/
Female
/
Humans
/
Male
/
Pregnancy
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article