title: Loss-of-function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas.
abstract: One-third of all primary central nervous system tumors in adults are meningiomas. Rarely, meningiomas occur at multiple sites, usually occurring in individuals with type 2 neurofibromatosis (NF2). We sequenced the exomes of three unrelated individuals with familial multiple spinal meningiomas without NF2 mutations. We identified two individuals with heterozygous loss-of-function mutations in the SWI/SNF chromatin-remodeling complex subunit gene SMARCE1. Sequencing of SMARCE1 in six further individuals with spinal meningiomas identified two additional heterozygous loss-of-function mutations. Tumors from individuals with SMARCE1 mutations were of clear-cell histological subtype, and all had loss of SMARCE1 protein, consistent with a tumor suppressor mechanism. Our findings identify multiple-spinal-meningioma disease as a new discrete entity and establish a key role for the SWI/SNF complex in the pathogenesis of both meningiomas and tumors with clear-cell histology.
authors: Genetic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St. Mary's Hospital, University of Manchester, Manchester, UK.
authors: Miriam J
authors: MJ
authors: Smith
authors: James
authors: J
authors: O'Sullivan
authors: Sanjeev S
authors: SS
authors: Bhaskar
authors: Kristen D
authors: KD
authors: Hadfield
authors: Gemma
authors: G
authors: Poke
authors: John
authors: J
authors: Caird
authors: Saba
authors: S
authors: Sharif
authors: Diana
authors: D
authors: Eccles
authors: David
authors: D
authors: Fitzpatrick
authors: Daniel
authors: D
authors: Rawluk
authors: Daniel
authors: D
authors: du Plessis
authors: William G
authors: WG
authors: Newman
authors: D Gareth
authors: DG
authors: Evans
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D002872:Chromosome Deletion; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008577:Meningeal Neoplasms / Q000235:genetics / Q000473:pathology; D008579:Meningioma / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D016518:Neurofibromatosis 2 / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C504738:SMARCE1 protein, human
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