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New insights into the molecular basis of spinal neurofibromatosis type 1

European Journal of Human Genetics volume 31, pages 931–938 (2023)Cite this article

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Abstract

Spinal neurofibromatosis (SNF) is a form of neurofibromatosis type 1 (NF1) characterized by bilateral neurofibromas involving all spinal roots. The pathogenic mechanisms determining the SNF form are currently unknown. To verify the presence of genetic variants possibly related to SNF or classic NF1, we studied 106 sporadic NF1 and 75 SNF patients using an NGS panel of 286 genes encoding RAS pathway effectors and neurofibromin interactors and evaluated the expression of syndecans (SDC1, SDC2, SDC3, SDC4), the NF1 3’ tertile interactors, by quantitative real-time PCR. We previously identified 75 and 106 NF1 variants in SNF and NF1 cohorts, respectively. The analysis of the distribution of pathogenic NF1 variants in the three NF1 tertiles showed a significantly higher prevalence of NF1 3’ tertile mutations in SNF than in the NF1 cohort. We hypothesized a potential pathogenic significance of the 3’ tertile NF1 variants in SNF. The analysis of syndecan expression on PBMCs RNAs from 16 SNF, 16 classic NF1 patients and 16 healthy controls showed that the expression levels of SDC2 and SDC3 were higher in SNF and NF1 patients than in controls; moreover, SDC2, SDC3 and SDC4 were significantly over expressed in patients mutated in the 3’ tertile compared to controls. Two different mutational NF1 spectra seem to characterize SNF and classic NF1, suggesting a pathogenic role of NF1 3’ tertile and its interactors, syndecans, in SNF. Our study, providing new insights on a possible role of neurofibromin C-terminal in SNF, could address effective personalized patient management and treatments.

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Fig. 1: Distribution of different classes of variants within the NF1 tertiles.
Fig. 2: Syndecans expression in patients and controls.
Fig. 3: Syndecans’ expression in different NF1 mutated tertiles in patients and controls.

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Data availability

The raw reads of panel NGStr3 are available in NCBI Short-read Archive (SRA, https://www.ncbi.nlm.nih.gov/sra) under the accession number PRJNA8509016 and the raw reads of panel NGStr2 under the accession number PRJNA688415.

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Acknowledgements

The authors are grateful to patients for their cooperation and support. The authors thank Simona Curti for English language revision. This research is supported (not financially) by the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS). The authors ME, VS, CC and FN are members of ERN GENTURIS. ERN GENTURIS is funded by the European Union.

Funding

Funding

This research was funded by the Italian Ministry of Health, grant number RF-2016-02361293 (to PR, ME, FN), by ANF ODV (to PR), and by University of Campania “Luigi Vanvitelli”—project V:ALERE 2019 Id343-TRANSITION “Nutri-epigenetics and physical activity: a natural help for Neurofibromatosis type 1” (to MABM).

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Author notes

  1. These authors contributed equally: Paola Bettinaglio, Eleonora Mangano.

Authors and Affiliations

  1. Department of Medical Biotechnology and Translational Medicine (BIOMETRA), University of Milan, 20054, Segrate, Milan, Italy

    Paola Bettinaglio, Viviana Tritto, Marinella Volontè, Cristina Battaglia & Paola Riva

  2. Institute of Biomedical Technologies (ITB) National Research Center (CNR), ITB-CNR, 20054, Segrate, Milan, Italy

    Eleonora Mangano, Roberta Bordoni & Cristina Battaglia

  3. Molecular Neuro-Oncology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133, Milan, Italy

    Rosina Paterra, Arianna Borghi & Marica Eoli

  4. Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Mariani Foundation Center for Complex Disabilities, 20054, Milan, Italy

    Veronica Saletti

  5. Medical Genetics Unit, Woman-Child-Newborn Department, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, 20122, Milan, Italy

    Claudia Cesaretti & Federica Natacci

  6. Department of Advanced Medical and Surgical Sciences, 2nd Division of Neurology, Center for Rare Diseases and InterUniversity Center for Research in Neurosciences, University of Campania Luigi Vanvitelli, 80131, Naples, Italy

    Mariarosa A. B. Melone

  7. Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, PA, 19122-6078, USA

    Mariarosa A. B. Melone

Authors
  1. Paola Bettinaglio
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Contributions

Conceptualization: PR, ME, and PB; methodology: PB, VT, RB, RP, AB, and EM; software: EM; validation: VT, PB, EM, CC, and MABM; investigation: PB, EM, and PR; resources: ME, PR, and FN; data curation: FN, PB, and ME; writing—original draft preparation: PR, PB, and EM; writing—review and editing: PR and PB; supervision: PR, ME, and FN; project administration: PR; funding acquisition: ME, PR, FN, and MABM. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Marica Eoli or Paola Riva.

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The authors declare no competing interests.

Ethical approval

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Fondazione IRCCS Istituto Neurologico Carlo Besta Ethical Committee and Scientific Board (N°50-19/3/2018).

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Informed consent was obtained from all subjects involved in the study.

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Bettinaglio, P., Mangano, E., Tritto, V. et al. New insights into the molecular basis of spinal neurofibromatosis type 1. Eur J Hum Genet 31, 931–938 (2023). https://doi.org/10.1038/s41431-023-01377-x

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