SHOC2 – Cardiofaciocutaneous Syndrome

Cardiofaciocutaneous (CFC) syndrome is a RASopathy characterized by congenital cardiac anomalies, distinctive facial features, and developmental delay. Heterozygous missense variants in SHOC2 have been identified as a cause of autosomal dominant CFC syndrome. In a cohort of 30 patients, 5 individuals with CFC syndrome harbored the recurrent SHOC2 c.4A>G (p.Ser2Gly) variant, all confirmed de novo (PMID:33452774). A separate study of 17 CFC syndrome patients found SHOC2 mutations in 23.5% (4 probands), predominantly affecting the N-terminal region (PMID:21784453).

Inheritance of SHOC2-related CFC is autosomal dominant with all reported variants arising de novo; there are no reports of transmission or familial segregation. To date, 9 unrelated probands with de novo SHOC2 variants meet criteria for clinical diagnosis of CFC syndrome. The sole recurrent variant, c.4A>G (p.Ser2Gly), defines the prototypical Mazzanti syndrome phenotype within the CFC spectrum.

The mutational spectrum of SHOC2 in CFC syndrome is restricted to missense changes clustering in the N-terminal leucine-rich repeat region. The canonical c.4A>G (p.Ser2Gly) variant accounts for the majority of cases, while additional pathogenic alleles (e.g., p.Met173Ile) broaden the phenotypic severity and age of onset.

Experimental evidence supports a gain-of-function mechanism. The C. elegans ortholog sur-8 modulates Ras-mediated signaling, and reduction of sur-8 suppresses activated ras phenotypes, implicating conserved function (PMID:9674433). A zebrafish shoc2 null model exhibits developmental defects in neural crest and hematopoiesis, recapitulating RASopathy features and demonstrating rescue by wild-type but not mutant Shoc2 (PMID:30329053).

Cellular assays reveal that SHOC2 p.Ser2Gly undergoes aberrant N-myristoylation, driving constitutive plasma membrane localization and sustained ERK1/2 activation, while other variants impair PP1c binding and fail to fully rescue MAPK signaling (PMIDs:27466182; PMID:25137548).

High-resolution cryo-EM of the SHOC2-MRAS-PP1C holophosphatase complex elucidates how SHOC2 missense variants stabilize interactions, enhance phosphatase activity, and potentiate MAPK signaling, providing a structural basis for pathogenesis (PMID:35831509).

Recent studies link SHOC2 variants to lymphatic defects via mTOR-mediated mitochondrial dysfunction in endothelial cells, suggesting broader implications for congenital lymphangiogenesis in RASopathies (PMID:40196569).

No significant conflicting evidence has been reported. Overall, SHOC2 demonstrates a moderate clinical validity for CFC syndrome based on multiple de novo occurrences, consistent functional data, and mechanistic concordance.

Key take-home: Genetic testing for SHOC2 should be included in diagnostic panels for CFC and related RASopathies, as pathogenic SHOC2 variants confer autosomal dominant CFC syndrome through a gain-of-function mechanism of MAPK hyperactivation.

References

• Indian pediatrics • 2021 • Mutation and Phenotypic Spectrum of Patients With RASopathies. PMID:33452774
• The Journal of pediatrics • 2011 • Spectrum of mutations in Noonan syndrome and their correlation with phenotypes. PMID:21784453
• 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
• 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 mutation • 2014 • A Novel SHOC2 Variant in Rasopathy. PMID:25137548
• Nature • 2022 • Structure-function analysis of the SHOC2-MRAS-PP1C holophosphatase complex. PMID:35831509
• bioRxiv : the preprint server for biology • 2025 • Shoc2 Deficiency Disrupts Lymphangiogenesis through mTOR-Mediated Mitochondrial Dysfunction. PMID:40196569

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