New Insights into the Molecular Basis of Spinal Neurofibromatosis Type 1

Overview

Journal Eur J Hum Genet

Specialty Genetics

Date 2023 May 22

PMID 37217626

Authors

Paola Bettinaglio

Eleonora Mangano

Viviana Tritto

Roberta Bordoni

Rosina Paterra

Arianna Borghi

Marinella Volonte

Cristina Battaglia

Veronica Saletti

Claudia Cesaretti

Federica Natacci

Mariarosa A B Melone

Marica Eoli

Paola Riva

Affiliations

Soon will be listed here.

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.

Citing Articles

Genetic/epigenetic effects in NF1 microdeletion syndrome: beyond the haploinsufficiency, looking at the contribution of not deleted genes.

Tritto V, Bettinaglio P, Mangano E, Cesaretti C, Marasca F, Castronovo C Hum Genet. 2024; 143(6):775-795.

PMID: 38874808 PMC: 11186880. DOI: 10.1007/s00439-024-02683-0.

References

Tate J, Bamford S, Jubb H, Sondka Z, Beare D, Bindal N . COSMIC: the Catalogue Of Somatic Mutations In Cancer. Nucleic Acids Res. 2018; 47(D1):D941-D947. PMC: 6323903. DOI: 10.1093/nar/gky1015. View

Mussotter T, Kluwe L, Hogel J, Nguyen R, Cooper D, Mautner V . Non-coding RNA ANRIL and the number of plexiform neurofibromas in patients with NF1 microdeletions. BMC Med Genet. 2012; 13:98. PMC: 3500256. DOI: 10.1186/1471-2350-13-98. View

Lupton C, Bayly-Jones C, DAndrea L, Huang C, Schittenhelm R, Venugopal H . The cryo-EM structure of the human neurofibromin dimer reveals the molecular basis for neurofibromatosis type 1. Nat Struct Mol Biol. 2021; 28(12):982-988. DOI: 10.1038/s41594-021-00687-2. View

Ruggieri M, Polizzi A, Spalice A, Salpietro V, Caltabiano R, DOrazi V . The natural history of spinal neurofibromatosis: a critical review of clinical and genetic features. Clin Genet. 2014; 87(5):401-10. DOI: 10.1111/cge.12498. View

Bergoug M, Doudeau M, Godin F, Mosrin C, Vallee B, Benedetti H . Neurofibromin Structure, Functions and Regulation. Cells. 2020; 9(11). PMC: 7692384. DOI: 10.3390/cells9112365. View

Kang E, Kim Y, Seo G, Oh A, Yoon H, Ra Y . Phenotype categorization of neurofibromatosis type I and correlation to NF1 mutation types. J Hum Genet. 2019; 65(2):79-89. DOI: 10.1038/s10038-019-0695-0. View

Auton A, Brooks L, Durbin R, Garrison E, Kang H, Korbel J . A global reference for human genetic variation. Nature. 2015; 526(7571):68-74. PMC: 4750478. DOI: 10.1038/nature15393. View

Tritto V, Ferrari L, Esposito S, Zuccotti P, Bianchessi D, Natacci F . Non-Coding RNA and Tumor Development in Neurofibromatosis Type 1: Rs2151280 Is Associated with Optic Glioma Development and a Mild Phenotype in Neurofibromatosis Type 1 Patients. Genes (Basel). 2019; 10(11). PMC: 6895873. DOI: 10.3390/genes10110892. View

Malavaki C, Roussidis A, Gialeli C, Kletsas D, Tsegenidis T, Theocharis A . Imatinib as a key inhibitor of the platelet-derived growth factor receptor mediated expression of cell surface heparan sulfate proteoglycans and functional properties of breast cancer cells. FEBS J. 2013; 280(10):2477-89. DOI: 10.1111/febs.12163. View

10.

Landrum M, Lee J, Benson M, Brown G, Chao C, Chitipiralla S . ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 2017; 46(D1):D1062-D1067. PMC: 5753237. DOI: 10.1093/nar/gkx1153. View

11.

Firth H, Richards S, Bevan A, Clayton S, Corpas M, Rajan D . DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genet. 2009; 84(4):524-33. PMC: 2667985. DOI: 10.1016/j.ajhg.2009.03.010. View

12.

Ferrari L, Mangano E, Bonati M, Monterosso I, Capitanio D, Chiappori F . Digenic inheritance of subclinical variants in Noonan Syndrome patients: an alternative pathogenic model?. Eur J Hum Genet. 2020; 28(10):1432-1445. PMC: 7608271. DOI: 10.1038/s41431-020-0658-0. View

13.

Wang K, Li M, Hakonarson H . ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010; 38(16):e164. PMC: 2938201. DOI: 10.1093/nar/gkq603. View

14.

Sherekar M, Han S, Ghirlando R, Messing S, Drew M, Rabara D . Biochemical and structural analyses reveal that the tumor suppressor neurofibromin (NF1) forms a high-affinity dimer. J Biol Chem. 2019; 295(4):1105-1119. PMC: 6983858. DOI: 10.1074/jbc.RA119.010934. View

15.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17(5):405-24. PMC: 4544753. DOI: 10.1038/gim.2015.30. View

16.

Young L, Goldstein de Salazar R, Han S, Huang Z, Merk A, Drew M . Destabilizing NF1 variants act in a dominant negative manner through neurofibromin dimerization. Proc Natl Acad Sci U S A. 2023; 120(5):e2208960120. PMC: 9945959. DOI: 10.1073/pnas.2208960120. View

17.

Frayling I, Mautner V, van Minkelen R, Kallionpaa R, Aktas S, Baralle D . Breast cancer risk in neurofibromatosis type 1 is a function of the type of gene mutation: a new genotype-phenotype correlation. J Med Genet. 2018; 56(4):209-219. DOI: 10.1136/jmedgenet-2018-105599. View

18.

Hamosh A, Scott A, Amberger J, Bocchini C, McKusick V . Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders. Nucleic Acids Res. 2004; 33(Database issue):D514-7. PMC: 539987. DOI: 10.1093/nar/gki033. View

19.

Hu H, Shih P, Shih Y, Hsueh Y . The Involvement of Neuron-Specific Factors in Dendritic Spinogenesis: Molecular Regulation and Association with Neurological Disorders. Neural Plast. 2016; 2016:5136286. PMC: 4706964. DOI: 10.1155/2016/5136286. View

20.

Ratner N, Miller S . A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. Nat Rev Cancer. 2015; 15(5):290-301. PMC: 4822336. DOI: 10.1038/nrc3911. View