A Novel SHOC2 Variant in Rasopathy.

Authors:
Vickie Hannig
Vickie Hannig
University of Washington
United States
Myoungkun Jeoung
Myoungkun Jeoung
University of Kentucky
United States
Eun Ryoung Jang
Eun Ryoung Jang
University of Kentucky
United States
John A Phillips
John A Phillips
Vanderbilt University School of Medicine
United States
Emilia Galperin
Emilia Galperin
University of Colorado Health Sciences Center
United States

Hum Mutat 2014 Nov 11;35(11):1290-4. Epub 2014 Sep 11.

Division of Medical Genetics and Genomic Medicine, Vanderbilt University, Nashville, Tennessee.

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.

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http://dx.doi.org/10.1002/humu.22634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4213265PMC
November 2014
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