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Erschienen in: Acta Neuropathologica 1/2020

29.10.2019 | Original Paper

NF1 patient missense variants predict a role for ATM in modifying neurofibroma initiation

verfasst von: Yanan Yu, Kwangmin Choi, Jianqiang Wu, Paul R. Andreassen, Phillip J. Dexheimer, Mehdi Keddache, Hilde Brems, Robert J. Spinner, Jose A. Cancelas, Lisa J. Martin, Margaret R. Wallace, Eric Legius, Kristine S. Vogel, Nancy Ratner

Erschienen in: Acta Neuropathologica | Ausgabe 1/2020

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Abstract

In Neurofibromatosis type 1, NF1 gene mutations in Schwann cells (SC) drive benign plexiform neurofibroma (PNF), and no additional SC changes explain patient-to-patient variability in tumor number. Evidence from twin studies suggests that variable expressivity might be caused by unidentified modifier genes. Whole exome sequencing of SC and fibroblast DNA from the same resected PNFs confirmed biallelic SC NF1 mutations; non-NF1 somatic SC variants were variable and present at low read number. We identified frequent germline variants as possible neurofibroma modifier genes. Genes harboring variants were validated in two additional cohorts of NF1 patients and by variant burden test. Genes including CUBN, CELSR2, COL14A1, ATR and ATM also showed decreased gene expression in some neurofibromas. ATM-relevant DNA repair defects were also present in a subset of neurofibromas with ATM variants, and in some neurofibroma SC. Heterozygous ATM G2023R or homozygous S707P variants reduced ATM protein expression in heterologous cells. In mice, genetic Atm heterozygosity promoted Schwann cell precursor self-renewal and increased tumor formation in vivo, suggesting that ATM variants contribute to neurofibroma initiation. We identify germline variants, rare in the general population, overrepresented in NF1 patients with neurofibromas. ATM and other identified genes are candidate modifiers of PNF pathogenesis.
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Metadaten
Titel
NF1 patient missense variants predict a role for ATM in modifying neurofibroma initiation
verfasst von
Yanan Yu
Kwangmin Choi
Jianqiang Wu
Paul R. Andreassen
Phillip J. Dexheimer
Mehdi Keddache
Hilde Brems
Robert J. Spinner
Jose A. Cancelas
Lisa J. Martin
Margaret R. Wallace
Eric Legius
Kristine S. Vogel
Nancy Ratner
Publikationsdatum
29.10.2019
Verlag
Springer Berlin Heidelberg
Erschienen in
Acta Neuropathologica / Ausgabe 1/2020
Print ISSN: 0001-6322
Elektronische ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-019-02086-w

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