Expression of SMARCB1 (INI1) mutations in familial schwannomatosis

Miriam Smith, Miriam J. Smith, James A. Walker, Yiping Shen, Anat Stemmer-Rachamimov, James F. Gusella, Scott R. Plotkin

    Research output: Contribution to journalArticlepeer-review


    Genetic changes in the SMARCB1 tumor suppressor gene have recently been reported in tumors and blood from families with schwannomatosis. Exon scanning of all nine SMARCB1 exons in genomic DNA from our cohort of families meeting the criteria for 'definite' or 'presumptive' schwannomatosis previously revealed constitutional alterations in 13 of 19 families (68%). Screening of four new familial schwannomatosis probands identified one additional constitutional alteration. We confirmed the presence of mRNA transcripts for two missense alterations, four mutations of conserved splice motifs and two additional mutations, in less conserved sequences, which also affect splicing. Furthermore, we found that transcripts for a rare 3'-untranslated region (c.*82C > T) alteration shared by four unrelated families did not produce splice variants but did show unequal allelic expression, suggesting that the alteration is either causative itself or linked to an unidentified causative mutation. Overexpression studies in cells lacking SMARCB1 suggest that mutant SMARCB1 proteins, like wild-type SMARCB1 protein, retain the ability to suppress cyclin D1 activity. These data, together with the expression of SMARCB1 protein in a proportion of cells from schwannomatosis-related schwannomas, suggest that these tumors develop through a mechanism that is distinct from that of rhabdoid tumors in which SMARCB1 protein is completely absent in tumor cells. © The Author 2012.
    Original languageEnglish
    Article numberdds370
    Pages (from-to)5239-5245
    Number of pages6
    JournalHuman Molecular Genetics
    Issue number24
    Publication statusPublished - Dec 2012


    • 3' Untranslated Regions/genetics
    • Alleles
    • Chromosomal Proteins, Non-Histone/genetics/*metabolism
    • Cyclin D1/genetics/metabolism
    • DNA, Complementary
    • DNA-Binding Proteins/genetics/*metabolism
    • Germ-Line Mutation/genetics
    • Humans
    • Immunohistochemistry
    • Mutation
    • Mutation, Missense/genetics
    • Neurilemmoma/genetics/*metabolism
    • Neurofibromatoses/genetics/*metabolism
    • RNA Splicing/genetics
    • RNA Stability/genetics
    • Skin Neoplasms/genetics/*metabolism
    • Transcription Factors/genetics/*metabolism


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