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Acta Neuropathol. 2020 Jan;139(1):157-174. doi: 10.1007/s00401-019-02086-w. Epub 2019 Oct 29.

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

Author information

1
Department of Experimental Hematology and Cancer Biology, Cincinati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinanti School of Medicine, Cincinnati, OH, USA.
2
Graduate Program in Cancer and Cell Biology, University of Cincinnati, Cincinnati, OH, USA.
3
Division of Biomedical Informatics, Cincinnati Children's Hospital, Cincinnati, OH, USA.
4
Division of Human Genetics, Cincinnati Children's Hospital Medical Center and the Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH, USA.
5
Department of Human Genetics, KU Leuven, Leuven, Belgium.
6
Department of Neurological Surgery, Mayo Clinic, Rochester, MN, USA.
7
Hoxworth Blood Center, University of Cincinnati, Cincinnati, OH, USA.
8
Department of Molecular Genetics and Microbiology, UF Genetics Institute, UF Health Cancer Center, University of Florida, Gainesville, FL, USA.
9
Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA.
10
Department of Experimental Hematology and Cancer Biology, Cincinati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinanti School of Medicine, Cincinnati, OH, USA. Nancy.Ratner@cchmc.org.

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.

KEYWORDS:

ATM; DNA damage; Genomics; Modifier genes; Mutation; Neurofibroma; Neurofibromatosis type 1

PMID:
31664505
DOI:
10.1007/s00401-019-02086-w

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