Somatic Instability of the NF2 Gene in Schwannomatosis

Kaufman, David L.; Heinrich, Bianca; Willett, C; Perry, Arie; Finseth, Frederick; Sobel, Raymond A.; MacCollin, Mia

doi:10.1001/archneur.60.9.1317

Cited by 48 publications

(25 citation statements)

References 17 publications

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“…Familial schwannomatosis is caused by alteration at an as yet uncloned locus on proximal chromosome 22q . Tumors from both familial and sporadic schwannomatosis patients are biallelically inactivated at NF2, but each tumor from a single patient carries an unrelated mutation [Kaufman et al, 2003]. This pattern of ''somatic instability'' is thus far unique amongst human genetic disorders and its relationship to the underlying constitutional cause of schwannomatosis remains unknown.…”

Section: The Nf2 Gene and Tumor Suppressor Genetheorymentioning

confidence: 99%

Mutational spectrum of theNF2gene: a meta-analysis of 12 years of research and diagnostic laboratory findings

et al. 2007

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The NF2 tumor suppressor gene on chromosome 22 is a member of the protein 4.1 family of cytoskeletal elements. A number of single- and multiple-tumor phenotypes have been linked to alterations of NF2 since its characterization in 1993. We present a meta-analysis of 967 constitutional and somatic NF2 alterations from 93 published reports, along with 59 additional unpublished events identified in our laboratory and 115 alterations identified in clinical samples submitted to the Massachusetts General Hospital (MGH) Neurogenetics DNA Diagnostic Laboratory. In total, these sources defined 1,070 small genetic changes detected primarily by exon scanning, 42 intragenic changes of one whole exon or larger, and 29 whole gene deletions and gross chromosomal rearrangements. Constitutional single-exon events (N=422) were significantly more likely to be nonsense or splice site changes than somatic events (N=533), which favored frameshift changes (chi(2) test; P<0.001). Somatic events also differed markedly between tumors of different pathology, most significantly in the tendency of somatic events in meningiomas to lie within the 5' FERM domain of the transcript (Fisher's exact test; P<0.01 in comparison to schwannomas) with a complete absence of mutations in exons 14 and 15. There was no statistically significant difference in mutation type or exon distribution between published constitutional events and those found by the clinical laboratory. Less than 10% of all published and unpublished small alterations are nontruncating (N=63) and these changes are clustered in exons 2 and 3, suggesting that this region may be especially crucial to tumor suppressor activity in the protein.

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Section: The Nf2 Gene and Tumor Suppressor Genetheorymentioning

confidence: 99%

Mutational spectrum of theNF2gene: a meta-analysis of 12 years of research and diagnostic laboratory findings

et al. 2007

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“…Molecular analysis of the NF2 gene (MIM] 607379) in schwannomatosis patients has demonstrated the presence of inactivating mutations in the tumor tissues, but no evidence of germline mutations as found in NF2 patients Kaufman et al, 2003].…”

Section: Introductionmentioning

confidence: 99%

Evidence of a four-hit mechanism involvingSMARCB1andNF2in schwannomatosis-associated schwannomas

et al. 2008

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Schwannomatosis is characterized by the onset of multiple intracranial, spinal, or peripheral schwannomas, without involvement of the vestibular nerve, which is instead pathognomonic of neurofibromatosis type 2 (NF2). Recently, a schwannomatosis family with a germline mutation of the SMARCB1 gene on chromosome 22 has been described. We report on the molecular analysis of the SMARCB1 and NF2 genes in a series of 21 patients with schwannomatosis and in eight schwannomatosis-associated tumors from four different patients. A novel germline SMARCB1 mutation was found in one patient; inactivating somatic mutations of NF2, associated with loss of heterozygosity (LOH) of 22q, were found in two schwannomas of this patient. This is the second report of a germline SMARCB1 mutation in patients affected by schwannomatosis and the first report of SMARCB1 mutations associated with somatic NF2 mutations in schwannomatosis-associated tumors. The latter observation suggests that a four-hit mechanism involving the SMARCB1 and NF2 genes may be implicated in schwannomatosis-related tumorigenesis.

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“…A fourth recently described form, Schwannomatosis, consists of multiple deep painful schwannomas and is thought to represent a mosaic form of NF2. 1 This review will focus on NF1, the most common form of NF with a prevalence of 1/3500, and the one most likely to be encountered by the orthopedist.…”

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Neurofibromatosis Update

Crawford

Schorry

2006

Journal of Pediatric Orthopaedics

123

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Type 1 neurofibromatosis (NF-1), also known as von Recklinghausen disease, is one of the most common human single-gene disorders, affecting at least 1 million persons throughout the world. It encompasses a spectrum of multifacted disorders and may present with a wide range of clinical manifestations, including abnormalities of the skin, nervous tissue, bones, and soft tissues. The condition can be conclusively diagnosed when 2 of 7 criteria established by the National Institutes of Health Consensus Development Conference are met. Most children with NF-1 have no major orthopedic problems. For those with musculoskeletal involvement, the most important issue is early recognition. Spinal deformity, congenital tibial dysplasia (congenital bowing and pseudarthrosis), and disorders of excessive bone and soft-tissue growth are the three types of musculoskeletal manifestitations that require evaluation. Statistics gathered from the Cincinnati Children's Hospital Neurofibromatosis Center database of 588 patients show the incidence of spinal deformity in children with NF-1 to be 21%; pectus deformity, 4.3%; limb-length inequality, 7.1%; congenital tibial dysplasia, 5%; hemihypertrophy, 1.4%; and plexiform neurofibromas, 25%. The orthopedic complications can be managed, but only rarely are they cured. Current developments in molecular genetics are exciting and give hope to more positive outcomes.

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Somatic Instability of the NF2 Gene in Schwannomatosis

Abstract: Molecular analysis of tumor specimens distinguishes schwannomatosis from other forms of neurofibromatosis. Further work is needed to understand the natural history and molecular biology of this condition.

Cited by 48 publications

References 17 publications

Mutational spectrum of theNF2gene: a meta-analysis of 12 years of research and diagnostic laboratory findings

Mutational spectrum of theNF2gene: a meta-analysis of 12 years of research and diagnostic laboratory findings

Evidence of a four-hit mechanism involvingSMARCB1andNF2in schwannomatosis-associated schwannomas

Neurofibromatosis Update

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