RNA-based analysis of two SMARCB1 mutations associated with familial schwannomatosis with meningiomas

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.

Loss of SMARCE1 expression is a specific diagnostic marker of clear cell meningioma: a comprehensive immunophenotypical and molecular analysis

“…This is consistent with the low mean (30.9 years) and median (26 years) age of patients with CCM (from 8 months to 88 years) relative to the median age of meningioma in general (65 years) . In the literature, the female‐to‐male ratio of patients with CCM was 1.1 (124 females and 110 males) (, cf. review in ).…”

“…Based on our extensive literature review of 234 CCMs (cf. Table S1 Supporting Information), we estimate that 45% of patients with CCM had tumor recurrence (local in 84%, local and other distant locations in 11%, and only distant location in 5% of reported cases) during the mean follow‐up of 45 months (, cf. review in ).…”

“…In the literature, SMARCE1 ‐deficient CCMs have been particularly described in children (approximately 36% of reported CCMs, from 8 months to 17 years of age) (, cf. review in ) and young adults (approximately 21% of reported CCMs, from 18 to 30 years of age) (, cf. review in ).…”

The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis

“…Meningiomas occur in 5% of schwannomatosis patients (Merker et al 2012) and appear to be located predominantly in the cerebral falx (van den Munckhof et al 2012). Three different families have been identified in which some members harboured germline SMARCB1 mutations and exhibited multiple schwannomas and meningiomas (Bacci et al 2010; Christiaans et al 2011; van den Munckhof et al 2012; Melean et al 2012) (Supp. Table S3).…”

SMARCB1 Involvement in the Development of Leiomyoma in a Patient With Schwannomatosis

“…The occurrence of meningioma in schwannomatosis patients has been noted in SMARCB1 mutation-positive familial and sporadic cases. [7][8][9][10][11][12][13] By directly analyzing the genetic events in the tumors of a large family with schwannomatosis and multiple meningiomas we could demonstrate that the mutated SMARCB1 gene segregating in this family was not only involved in the development of the schwannomas but in that of the meningiomas as well. 12,13 In this study, we report the occurrence of a leiomyoma of the uterine cervix in a familial schwannomatosis patient.…”