Clinical variability of neurofibromatosis 1: A modifying role of cooccurring PTPN11 variants and atypical brain MRI findings.
Adolescent
Brain
/ abnormalities
Child
DNA Mutational Analysis
Family
Female
Genes, Neurofibromatosis 1
Genetic Association Studies
Genetic Predisposition to Disease
Humans
Magnetic Resonance Imaging
/ methods
Male
Models, Molecular
Mutation
Mutation, Missense
Neurofibromatosis 1
/ diagnosis
Pedigree
Phenotype
Protein Conformation
Protein Tyrosine Phosphatase, Non-Receptor Type 11
/ chemistry
Structure-Activity Relationship
MRI
NF1
Neurofibromatosis 1
Noonan syndrome
PTPN11
genetic modifiers
Journal
Clinical genetics
ISSN: 1399-0004
Titre abrégé: Clin Genet
Pays: Denmark
ID NLM: 0253664
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
revised:
28
07
2021
received:
26
04
2021
accepted:
30
07
2021
pubmed:
5
8
2021
medline:
19
2
2022
entrez:
4
8
2021
Statut:
ppublish
Résumé
Neurofibromatosis 1 (NF1) is a disorder characterized by variable expressivity caused by loss-of-function variants in NF1, encoding neurofibromin, a protein negatively controlling RAS signaling. We evaluated whether concurrent variation in proteins functionally linked to neurofibromin contribute to the variable expressivity of NF1. Parallel sequencing of a RASopathy gene panel in 138 individuals with molecularly confirmed clinical diagnosis of NF1 identified missense variants in PTPN11, encoding SHP2, a positive regulator of RAS signaling, in four subjects from three unrelated families. Three subjects were heterozygous for a gain-of-function variant and showed a severe expression of NF1 (developmental delay, multiple cerebral neoplasms and peculiar cortical MRI findings), and features resembling Noonan syndrome (a RASopathy caused by activating variants in PTPN11). Conversely, the fourth subject, who showed an attenuated presentation, carried a previously unreported PTPN11 variant that had a hypomorphic behavior in vitro. Our findings document that functionally relevant PTPN11 variants occur in a small but significant proportion of subjects with NF1 modulating disease presentation, suggesting a model in which the clinical expression of pathogenic NF1 variants is modified by concomitant dysregulation of protein(s) functionally linked to neurofibromin. We also suggest targeting of SHP2 function as an approach to treat evolutive complications of NF1.
Substances chimiques
PTPN11 protein, human
EC 3.1.3.48
Protein Tyrosine Phosphatase, Non-Receptor Type 11
EC 3.1.3.48
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
563-572Subventions
Organisme : AIRC (IG 21614), EJP-RD (NSEuroNet) and Italian Ministry of Health (Ricerca Corrente 2020)
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : IG 21614
Informations de copyright
© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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