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Nat Genet. 2014 Feb;46(2):182-7. doi: 10.1038/ng.2855. Epub 2013 Dec 22.

Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas.

Author information

1
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].
2
1] Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA. [2].
3
Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
4
Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.
5
Heflin Center for Genomic Sciences, University of Alabama at Birmingham, Birmingham, Alabama, USA.
6
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
7
Department of Medical Genetics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
8
Johns Hopkins Comprehensive Neurofibromatosis Center, Baltimore, Maryland, USA.
9
Lakeridge Health Corporation, Oshawa, Ontario, Canada.
10
Clinical Cancer Genetics Program, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA.
11
Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA.
12
Department of Neurology, Veterans Administration Hospital of Pittsburgh and University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
13
Kaiser Permanente Genetics Northern California, San Francisco, California, USA.
14
Department of Pediatrics, Division of Medical Genetics, University of California, San Francisco, San Francisco, California, USA.
15
Department of Internal Medicine, Division of Human Genetics, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
16
Department of Neuro-Oncology, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA.
17
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.

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.

PMID:
24362817
PMCID:
PMC4352302
DOI:
10.1038/ng.2855
[Indexed for MEDLINE]
Free PMC Article
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