SMO – Curry-Jones syndrome

Curry-Jones syndrome (CJS) is a multisystem malformation syndrome characterized by craniosynostosis, pre-axial polysyndactyly, agenesis of the corpus callosum, cutaneous stigmata, and gastrointestinal abnormalities. The major genetic cause is a recurrent, somatic mosaic variant in SMO (c.1234C>T (p.Leu412Phe)) leading to constitutive Hedgehog pathway activation. Initial multi-patient studies identified eight mutation-positive individuals with highly similar asymmetric clinical features and variable mutant allele burdens across tissues (PMID:27236920).

A subsequent case report described a newborn with classic CJS features—craniosynostosis, pre-axial polysyndactyly, skin findings, intestinal malrotation, and smooth muscle hamartomas—harboring the same SMO c.1234C>T mosaic mutation at up to 35% allele fraction in skin and 26% in gut (PMID:28386950). These nine unrelated mosaic probands underscore the specificity and recurrence of this variant in CJS.

Inheritance is through postzygotic somatic mosaicism, with no evidence of germline transmission or segregation in families; all cases were sporadic with zero affected relatives. The variant spectrum is narrow: a single missense change c.1234C>T (p.Leu412Phe) is recurrent across all reported patients.

Functional studies demonstrate that p.Leu412Phe constitutively activates SMO in the absence of Hedgehog ligands, explaining both developmental malformations and the predisposition to tumorigenesis observed in some CJS cases. This activation is concordant across cell assays and suggests potential responsiveness to Smoothened inhibitors.

No conflicting evidence has been reported. Integration of genetic and experimental data provides strong support for SMO c.1234C>T mosaicism as the definitive cause of CJS. Detection of this variant informs diagnosis, enables molecular confirmation, and raises the possibility of targeted Hedgehog-pathway therapies in affected individuals.

Key Take-home: SMO c.1234C>T (p.Leu412Phe) somatic mosaicism is the recurrent, diagnostic, and mechanistic driver of Curry-Jones syndrome.

References

• American Journal of Human Genetics • 2016 • A Recurrent Mosaic Mutation in SMO, Encoding the Hedgehog Signal Transducer Smoothened, Is the Major Cause of Curry-Jones Syndrome. PMID:27236920
• American Journal of Medical Genetics Part A • 2017 • Gastrointestinal disorders in Curry-Jones syndrome: Clinical and molecular insights from an affected newborn. PMID:28386950

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