Frequency of SMARCB1 mutations in familial and sporadic schwannomatosis

Department of Genetic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9WL, UK.
Neurogenetics (Impact Factor: 2.88). 03/2012; 13(2):141-5. DOI: 10.1007/s10048-012-0319-8
Source: PubMed


Mutations of the SMARCB1 gene have been implicated in several human tumour predisposing syndromes. They have recently been identified as an underlying cause of the tumour suppressor syndrome schwannomatosis. There is a much higher rate of mutation detection in familial disease than in sporadic disease. We have carried out extensive genetic testing on a cohort of familial and sporadic patients who fulfilled clinical diagnostic criteria for schwannomatosis. In our current cohort, we identified novel mutations within the SMARCB1 gene and detected several mutations that have been previously identified in other schwannomatosis cohorts. Of the schwannomatosis screens reported to date, including our current dataset, SMARCB1 mutations have been found in 45 % of familial probands and 7 % of sporadic patients. The exon 1 mutation, c.41C >A, and the 3' untranslated region mutation, c.*82C >T, are the most common changes reported in schwannomatosis disease so far, indicating mutation hotspots at both 5' and 3' portions of the gene. SMARCB1 mutations are found in a significant proportion of schwannomatosis patients, but there remains the possibility that further causative genes remain to be found.

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    • "These residues are at the N terminus of helix 1, and their deletion would be expected to be highly destabilizing. Missense mutations have also been identified in sporadic schwannomatosis; it is not clear whether a particular substitution is pathogenic (Smith et al., 2012b). One of these mutations also affects Pro14, in this case replacing it with a serine. "
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    ABSTRACT: SWI/SNF complexes use the energy of ATP hydrolysis to remodel chromatin. In mammals they play a central role in regulating gene expression during differentiation and proliferation. Mutations in SWI/SNF subunits are among the most frequent gene alterations in cancer. The INI1/hSNF5/SMARCB1 subunit is mutated in both malignant rhabdoid tumor, a highly aggressive childhood cancer, and schwannomatosis, a tumor-predisposing syndrome characterized by mostly benign tumors of the CNS. Here, we show that mutations in INI1 that cause schwannomatosis target a hitherto unidentified N-terminal winged helix DNA binding domain that is also present in the BAF45a/PHF10 subunit of the SWI/SNF complex. The domain is structurally related to the SKI/SNO/DAC domain, which is found in a number of metazoan chromatin-associated proteins. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
    Structure 06/2015; 25(7). DOI:10.1016/j.str.2015.04.021 · 5.62 Impact Factor
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    • "In contrast, inherited mutations found in familial schwannomatosis are more likely to be non-truncating (missense or splice-site) mutations [Boyd et al., 2008; Hadfield et al., 2008], which might account for the milder phenotype as these are potentially hypomorphic. However, sporadic schwannomatosis patients may carry truncating (frameshift or nonsense) or non-truncating (missense/splice-site) mutations [Rousseau et al., 2011; Smith et al., 2012], which are predicted to knock out the protein product. "
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    ABSTRACT: Germline mutations in the SMARCB1 gene cause familial schwannomatosis, a condition characterized by the presence of multiple schwannomas, although mutations in SMARCB1 have also been associated with rhadboid tumor predisposition syndrome 1 (RTPS1). Both schwannomatosis and RTPS1 are autosomal dominant conditions that predispose individuals to develop distinct types of tumors. We clinically and genetically characterized two families with schwannomatosis associated with SMARCB1 mutations. Eight affected members of these families developed different numbers of schwannomas and/or meningiomas at distinct ages, evidence that meningiomas are variably expressed in this condition. We identified two germline mutations in SMARCB1 associated with the familial disease, c.233-1G>A and the novel c.207_208dupTA mutation, which both proved to affect the main SMARCB1 isoforms at the RNA level distinctly. Interestingly, the c.207_208dupTA mutation had no effect on the coding sequence, pre-mRNA splicing or the level of expression of the SMARCB1 isoform 2. Furthermore, SMARCB1 isoforms harboring a premature termination codon were largely eliminated via the nonsense-mediated mRNA decay pathway. Our results highlight the importance of RNA-based studies to characterize SMARCB1 germline mutations in order to determine their impact on protein expression and gain further insight into the genetic basis of conditions associated with SMARCB1 mutations.
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