title: 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.
authors: Unidad de Genética Molecular, Hospital Universitario Ramón y Cajal, Instituto de Investigación Sanitaria, Ctra Colmenar km 9.1, 28034 Madrid, Spain.
authors: German
authors: G
authors: Melean
authors: Ana
authors: A
authors: Velasco
authors: Elisabete
authors: E
authors: Hernández-Imaz
authors: Francisco Javier
authors: FJ
authors: Rodríguez-Álvarez
authors: Yolanda
authors: Y
authors: Martín
authors: Ana
authors: A
authors: Valero
authors: Concepción
authors: C
authors: Hernández-Chico
mesh_terms: D000328:Adult; D002648:Child; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008577:Meningeal Neoplasms / Q000235:genetics*; D008579:Meningioma / Q000235:genetics*; D008957:Models, Genetic; D009154:Mutation; D009442:Neurilemmoma / Q000235:genetics*; D017253:Neurofibromatoses / Q000235:genetics*; D010375:Pedigree; D020033:Protein Isoforms; D012313:RNA / Q000378:metabolism; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D000071796:SMARCB1 Protein; D012878:Skin Neoplasms / Q000235:genetics*; D014057:Tomography, X-Ray Computed / Q000379:methods; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors; D012313:RNA