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A Novel SHOC2 Variant in Rasopathy.
- Source :
-
Human mutation [Hum Mutat] 2014 Nov; Vol. 35 (11), pp. 1290-4. Date of Electronic Publication: 2014 Sep 11. - Publication Year :
- 2014
-
Abstract
- Rasopathies are a group of genetic disorders caused by germline mutations in multiple genes of the Extracellular signal-Regulated Kinases 1 and 2 (ERK1/2) pathway. The only previously identified missense mutation in SHOC2, a scaffold protein of the ERK1/2 pathway, led to Noonan-like syndrome with loose anagen hair. Here, we report a novel mutation in SHOC2(c.519G>A; p.M173I) that leads to a Rasopathy with clinical features partially overlapping those occurring in Noonan and cardiofaciocutaneous syndromes. Studies to clarify the significance of this SHOC2 variant revealed that the mutant protein has impaired capacity to interact with protein phosphatase 1c (PP1c), leading to insufficient activation of RAF-1 kinase. This SHOC2 variant thus is unable to fully rescue ERK1/2 activity in cells depleted of endogenous SHOC2. We conclude that SHOC2 mutations can cause a spectrum of Rasopathy phenotypes in heterozygous individuals. Importantly, our work suggests that individuals with mild Rasopathy symptoms may be underdiagnosed.<br /> (© 2014 WILEY PERIODICALS, INC.)
- Subjects :
- Abnormalities, Multiple metabolism
Child, Preschool
Facies
Female
Gene Expression
Humans
Intracellular Signaling Peptides and Proteins chemistry
Intracellular Signaling Peptides and Proteins metabolism
MAP Kinase Signaling System
Mutation
Phenotype
Protein Binding
Abnormalities, Multiple diagnosis
Abnormalities, Multiple genetics
Genetic Variation
Intracellular Signaling Peptides and Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1098-1004
- Volume :
- 35
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Human mutation
- Publication Type :
- Academic Journal
- Accession number :
- 25137548
- Full Text :
- https://doi.org/10.1002/humu.22634