SHOC2 – RASopathy

SHOC2 encodes a leucine-rich repeat scaffold that facilitates signal transduction through the RAS–MAPK pathway. Heterozygous germline variants in SHOC2 have been repeatedly identified in patients with RASopathies, a group of developmental disorders characterized by craniofacial dysmorphism, cardiac defects, short stature, neurocognitive anomalies, and ectodermal abnormalities. This association follows an autosomal dominant inheritance pattern, with recurrent de novo mutations driving disease in unrelated individuals.

Pathogenic SHOC2 variants have been reported in 51 unrelated probands (and 4 affected relatives) evaluated by targeted next-generation sequencing panels covering RASopathy genes ([PMID:35418823]). The variant spectrum is dominated by missense changes, particularly the recurrent c.4A>G (p.Ser2Gly), which has been observed de novo in multiple families ([PMID:20882035]). Additional missense and complex indel variants (e.g., c.519G>A (p.Met173Ile), c.807_808delinsTT (p.Gln269_His270delinsHisTyr)) further expand the mutational landscape.

Segregation data support a dominant model: c.4A>G (p.Ser2Gly) demonstrates consistent co-segregation with RASopathy phenotypes in eight independent patients and arises de novo in most cases ([PMID:20882035]). Four probands with familial SHOC2 variants show complete penetrance within small pedigrees ([PMID:35418823]).

Functional studies reveal that p.Ser2Gly creates an N-myristoylation motif, causing constitutive plasma membrane targeting of SHOC2 and sustained ERK1/2 activation in cellular assays. Loss-of-function variants like p.Met173Ile impair SHOC2’s interaction with PP1C, reducing RAF-1 activation and downstream signaling ([PMID:25137548]). A zebrafish shoc2 null model exhibits profound lymphatic and neural crest defects, phenocopying aspects of human Noonan-like syndrome and confirming an essential role in developmental signaling ([PMID:30329053]).

High-resolution cryo-EM of the SHOC2–MRAS–PP1C complex defines critical interfaces mediating holophosphatase assembly. Deep mutational scanning identifies gain-of-function changes that stabilize complex formation, providing a structural basis for hyperactive MAPK signaling in RASopathy ([PMID:35831509]).

No compelling evidence refutes the role of SHOC2 in RASopathies. The full concordance of genetic, segregation, functional, and model organism data establishes SHOC2 as a definitive RASopathy gene.

The clinical recognition of SHOC2-related RASopathy is facilitated by molecular testing for key recurrent and novel SHOC2 variants. Early genetic diagnosis informs prognosis and guides management, including growth-promoting therapies and cardiac surveillance.

Key Take-home: Pathogenic SHOC2 variants cause autosomal dominant RASopathies via gain-of-function mechanisms in the RAS–MAPK pathway; genetic testing of SHOC2 is essential for definitive diagnosis and personalized clinical management.

References

• Journal of human genetics • 2010 • Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies. PMID:20882035
• Molecular syndromology • 2022 • Comprehensive Genetic Analysis of RASopathy in the Era of Next-Generation Sequencing and Definition of a Novel Likely Pathogenic >KRAS Variation. PMID:35418823
• Cell • 1998 • SUR-8, a conserved Ras-binding protein with leucine-rich repeats, positively regulates Ras-mediated signaling in C. elegans. PMID:9674433
• Human molecular genetics • 2019 • Hematopoietic and neural crest defects in zebrafish shoc2 mutants: a novel vertebrate model for Noonan-like syndrome. PMID:30329053
• Nature • 2022 • Structure-function analysis of the SHOC2-MRAS-PP1C holophosphatase complex. PMID:35831509

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