Loss of SUFU function in familial multiple meningioma

Mervi Aavikko, Song Ping Li, Silva Saarinen, Pia Alhopuro, Eevi Kaasinen, Ekaterina Morgunova, Yilong Li, Kari Vesanen, Miriam J. Smith, D. Gareth R Evans, Minna Pöyhönen, Anne Kiuru, Anssi Auvinen, Lauri A. Aaltonen, Jussi Taipale, Pia Vahteristo

    Research output: Contribution to journalArticlepeer-review


    Meningiomas are the most common primary tumors of the CNS and account for up to 30% of all CNS tumors. An increased risk of meningiomas has been associated with certain tumor-susceptibility syndromes, especially neurofibromatosis type II, but no gene defects predisposing to isolated familial meningiomas have thus far been identified. Here, we report on a family of five meningioma-affected siblings, four of whom have multiple tumors. No NF2 mutations were identified in the germline or tumors. We combined genome-wide linkage analysis and exome sequencing, and we identified in suppressor of fused homolog (Drosophila), SUFU, a c.367C>T (p.Arg123Cys) mutation segregating with the meningiomas in the family. The variation was not present in healthy controls, and all seven meningiomas analyzed displayed loss of the wild-type allele according to the classic two-hit model for tumor-suppressor genes. In silico modeling predicted the variant to affect the tertiary structure of the protein, and functional analyses showed that the activity of the altered SUFU was significantly reduced and therefore led to dysregulated hedgehog (Hh) signaling. SUFU is a known tumor-suppressor gene previously associated with childhood medulloblastoma predisposition. Our genetic and functional analyses indicate that germline mutations in SUFU also predispose to meningiomas, particularly to multiple meningiomas. It is possible that other genic mutations resulting in aberrant activation of the Hh pathway might underlie meningioma predisposition in families with an unknown etiology. © 2012 The American Society of Human Genetics.
    Original languageEnglish
    Pages (from-to)520-526
    Number of pages6
    JournalAmerican Journal of Human Genetics
    Issue number3
    Publication statusPublished - 7 Sep 2012


    • Adult
    • Aged
    • Female
    • Genes, Neurofibromatosis 2
    • Humans
    • Male
    • Meningeal Neoplasms/genetics
    • Meningioma/genetics
    • Middle Aged
    • Models, Molecular
    • Mutation
    • Pedigree
    • Repressor Proteins/*genetics


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