title: Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas.
abstract: Constitutional SMARCB1 mutations at 22q11.23 have been found in ∼50% of familial and <10% of sporadic schwannomatosis cases. We sequenced highly conserved regions along 22q from eight individuals with schwannomatosis whose schwannomas involved somatic loss of one copy of 22q, encompassing SMARCB1 and NF2, with a different somatic mutation of the other NF2 allele in every schwannoma but no mutation of the remaining SMARCB1 allele in blood and tumor samples. LZTR1 germline mutations were identified in seven of the eight cases. LZTR1 sequencing in 12 further cases with the same molecular signature identified 9 additional germline mutations. Loss of heterozygosity with retention of an LZTR1 mutation was present in all 25 schwannomas studied. Mutations segregated with disease in all available affected first-degree relatives, although four asymptomatic parents also carried an LZTR1 mutation. Our findings identify LZTR1 as a gene predisposing to an autosomal dominant inherited disorder of multiple schwannomas in ∼80% of 22q-related schwannomatosis cases lacking mutation in SMARCB1.
authors.affiliation: 1] Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA. [2] Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland. [3].
authors.forename: Arkadiusz
authors.initials: A
authors.lastname: Piotrowski
authors.affiliation: 1] Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA. [2].
authors.forename: Jing
authors.initials: J
authors.lastname: Xie
authors.affiliation: Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Ying F
authors.initials: YF
authors.lastname: Liu
authors.affiliation: Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Andrzej B
authors.initials: AB
authors.lastname: Poplawski
authors.affiliation: Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Alicia R
authors.initials: AR
authors.lastname: Gomes
authors.affiliation: Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Madanecki
authors.affiliation: Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Chuanhua
authors.initials: C
authors.lastname: Fu
authors.affiliation: Heflin Center for Genomic Sciences, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Crowley
authors.affiliation: Heflin Center for Genomic Sciences, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: David K
authors.initials: DK
authors.lastname: Crossman
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Linlea
authors.initials: L
authors.lastname: Armstrong
authors.affiliation: Department of Medical Genetics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Dusica
authors.initials: D
authors.lastname: Babovic-Vuksanovic
authors.affiliation: Johns Hopkins Comprehensive Neurofibromatosis Center, Baltimore, Maryland, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Bergner
authors.affiliation: Johns Hopkins Comprehensive Neurofibromatosis Center, Baltimore, Maryland, USA.
authors.forename: Jaishri O
authors.initials: JO
authors.lastname: Blakeley
authors.affiliation: Lakeridge Health Corporation, Oshawa, Ontario, Canada.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Blumenthal
authors.affiliation: Clinical Cancer Genetics Program, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA.
authors.forename: Molly S
authors.initials: MS
authors.lastname: Daniels
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Feit
authors.affiliation: Department of Neurology, Veterans Administration Hospital of Pittsburgh and University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Kathy
authors.initials: K
authors.lastname: Gardner
authors.affiliation: Lakeridge Health Corporation, Oshawa, Ontario, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hurst
authors.affiliation: Kaiser Permanente Genetics Northern California, San Francisco, California, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Kobelka
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Chung
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Division of Human Genetics, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Nagy
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Rauen
authors.affiliation: Department of Neuro-Oncology, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Slopis
authors.affiliation: Kaiser Permanente Genetics Northern California, San Francisco, California, USA.
authors.forename: Pim
authors.initials: P
authors.lastname: Suwannarat
authors.affiliation: Department of Internal Medicine, Division of Human Genetics, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Westman
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Zanko
authors.affiliation: 1] Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA. [2] Heflin Center for Genomic Sciences, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Korf
authors.affiliation: Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Ludwine M
authors.initials: LM
authors.lastname: Messiaen
mesh_terms: D001483:Base Sequence; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D040461:Gene Components; D005799:Genes, Dominant / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009442:Neurilemmoma / Q000235:genetics*; D016518:Neurofibromatosis 2 / Q000235:genetics; D010375:Pedigree; D011487:Protein Conformation; D000071796:SMARCB1 Protein; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C509917:LZTR1 protein, human; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors