New insights into the molecular basis of spinal neurofibromatosis type 1.
Journal
European journal of human genetics : EJHG
ISSN: 1476-5438
Titre abrégé: Eur J Hum Genet
Pays: England
ID NLM: 9302235
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
received:
13
02
2023
accepted:
27
04
2023
revised:
19
04
2023
pmc-release:
01
08
2024
medline:
7
8
2023
pubmed:
23
5
2023
entrez:
22
5
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37217626
doi: 10.1038/s41431-023-01377-x
pii: 10.1038/s41431-023-01377-x
pmc: PMC10400572
doi:
Substances chimiques
Neurofibromin 1
0
Syndecans
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
931-938Informations de copyright
© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.
Références
Nucleic Acids Res. 2019 Jan 8;47(D1):D941-D947
pubmed: 30371878
BMC Med Genet. 2012 Oct 26;13:98
pubmed: 23101500
Nat Struct Mol Biol. 2021 Dec;28(12):982-988
pubmed: 34887559
Clin Genet. 2015 May;87(5):401-10
pubmed: 25211147
Cells. 2020 Oct 27;9(11):
pubmed: 33121128
J Hum Genet. 2020 Jan;65(2):79-89
pubmed: 31776437
Nature. 2015 Oct 1;526(7571):68-74
pubmed: 26432245
Genes (Basel). 2019 Nov 05;10(11):
pubmed: 31694342
FEBS J. 2013 May;280(10):2477-89
pubmed: 23374223
Nucleic Acids Res. 2018 Jan 4;46(D1):D1062-D1067
pubmed: 29165669
Am J Hum Genet. 2009 Apr;84(4):524-33
pubmed: 19344873
Eur J Hum Genet. 2020 Oct;28(10):1432-1445
pubmed: 32514133
Nucleic Acids Res. 2010 Sep;38(16):e164
pubmed: 20601685
J Biol Chem. 2020 Jan 24;295(4):1105-1119
pubmed: 31836666
Genet Med. 2015 May;17(5):405-24
pubmed: 25741868
Proc Natl Acad Sci U S A. 2023 Jan 31;120(5):e2208960120
pubmed: 36689660
J Med Genet. 2019 Apr;56(4):209-219
pubmed: 30530636
Nucleic Acids Res. 2005 Jan 1;33(Database issue):D514-7
pubmed: 15608251
Neural Plast. 2016;2016:5136286
pubmed: 26819769
Nat Rev Cancer. 2015 May;15(5):290-301
pubmed: 25877329
Front Neurol. 2021 Sep 08;12:704639
pubmed: 34566848
Cancers (Basel). 2019 Nov 21;11(12):
pubmed: 31766501
Cancers (Basel). 2022 Dec 22;15(1):
pubmed: 36612057
Nature. 2021 Nov;599(7884):315-319
pubmed: 34707296
J Neurooncol. 2015 Jan;121(1):209-15
pubmed: 25293439
J Med Genet. 2011 Apr;48(4):256-60
pubmed: 21278392