Variant Synonymizer: Platform to identify mutations defined in different ways is available now!

VarSy

Over 2,000 gene–disease validation summaries are now available—no login required!

Browse Summaries

SMO – Medulloblastoma

A somatic mutation in the Hedgehog receptor Smoothened (SMO) has been implicated in acquired resistance to pathway inhibition in medulloblastoma. A relapsed patient treated with the SMO inhibitor GDC-0449 harbored a c.1417G>C (p.Asp473His) mutation in SMO that preserved Hedgehog signaling but abrogated drug binding, leading to therapeutic failure (PMID:19726788). The identical p.Asp473His variant also emerged in a GDC-0449-resistant mouse medulloblastoma model, confirming its role in drug resistance and maintenance of pathway activation. No germline SMO variants or familial segregation have been reported in medulloblastoma predisposition.

Overall, genetic evidence for SMO in medulloblastoma is limited to this single somatic case, but functional studies provide moderate support for its role in resistance mechanisms. These findings highlight the need for alternative therapeutic strategies targeting downstream Hedgehog effectors in SMO-mutant medulloblastoma.

References

  • Science (New York, N.Y.) • 2009 • Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma PMID:19726788

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Single somatic case report of SMO mutation in medulloblastoma without germline or familial segregation

Genetic Evidence

Limited

One acquired SMO variant in a relapsed medulloblastoma patient; no inherited cases reported ([PMID:19726788])

Functional Evidence

Moderate

In vitro binding assays and resistant mouse model demonstrate p.Asp473His disrupts inhibitor binding while preserving Hedgehog signaling ([PMID:19726788])