SHOC2 – Noonan syndrome

1. Noonan syndrome is an autosomal dominant RASopathy characterized by short stature, congenital heart defects, distinctive facial features, and ectodermal anomalies. Heterozygous gain-of-function variants in SHOC2, a scaffold protein in the RAS-MAPK signaling cascade, underlie a Noonan-like syndrome with loose anagen hair and overlapping NS features ([PMID:20882035]).

2. The recurrent SHOC2 c.4A>G (p.Ser2Gly) variant has been reported in at least 13 unrelated probands across multiple cohorts, occurring de novo in the majority and absent in controls ([PMID:20882035]; [PMID:23918763]). No other SHOC2 variants have been recurrently associated with classic NS, indicating a narrow variant spectrum.

3. Phenotypically, individuals with SHOC2 p.Ser2Gly exhibit short stature (HP:0004322), sparse and easily pluckable loose anagen hair (HP:0040169), hyperpigmented skin, and variable cardiac anomalies including pulmonic stenosis and hypertrophic cardiomyopathy (HP:0001627) ([PMID:20882035]; [PMID:23918763]). Neurodevelopmental delay and structural brain anomalies have been documented in a subset of cases ([PMID:23918763]).

4. Functional studies demonstrate that p.Ser2Gly introduces an N-myristoylation site driving constitutive plasma membrane localization of SHOC2, enhances MRAS–PP1C binding, and upregulates ERK1/2 signaling. Zebrafish shoc2 null mutants exhibit lymphatic and neural crest defects that are rescued by human SHOC2 expression, confirming in vivo requirement and mechanism ([PMID:27466182]; [PMID:30329053]).

5. Taken together, genetic and experimental data define SHOC2 as a definitive NS gene acting via a gain-of-function mechanism. Clinical genetic testing for the SHOC2 c.4A>G variant is warranted in patients with NS-like features, especially loose anagen hair, to guide diagnosis and management.

Key Take-home: SHOC2 c.4A>G (p.Ser2Gly) causes an autosomal dominant Noonan syndrome phenotype with loose anagen hair through enhanced MAPK signaling, supporting its clinical testing and potential targeted therapies.

References

• Journal of human genetics • 2010 • Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies. PMID:20882035
• American journal of medical genetics. Part A • 2013 • Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis. PMID:23918763
• Human molecular genetics • 2016 • SHOC2 subcellular shuttling requires the KEKE motif-rich region and N-terminal leucine-rich repeat domain and impacts on ERK signalling. PMID:27466182
• Human molecular genetics • 2019 • Hematopoietic and neural crest defects in zebrafish shoc2 mutants: a novel vertebrate model for Noonan-like syndrome. PMID:30329053

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