Compound heterozygosity for PTPN11 variants in a subject with Noonan syndrome provides insights into the mechanism of SHP2-related disorders.
Alleles
Amino Acid Substitution
Genetic Association Studies
Genetic Variation
Heterozygote
Humans
LEOPARD Syndrome
/ genetics
Male
Middle Aged
Models, Molecular
Mutation
Mutation, Missense
Noonan Syndrome
/ genetics
Pedigree
Protein Conformation
Protein Tyrosine Phosphatase, Non-Receptor Type 11
/ chemistry
LEOPARD syndrome
Noonan syndrome
PTPN11
SHP2
phosphatase assay
Journal
Clinical genetics
ISSN: 1399-0004
Titre abrégé: Clin Genet
Pays: Denmark
ID NLM: 0253664
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
28
09
2020
revised:
26
11
2020
accepted:
19
12
2020
pubmed:
24
12
2020
medline:
1
1
2022
entrez:
23
12
2020
Statut:
ppublish
Résumé
The RASopathies are a family of clinically related disorders caused by mutations affecting genes participating in the RAS-MAPK signaling cascade. Among them, Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) are allelic conditions principally associated with dominant mutations in PTPN11, which encodes the nonreceptor SH2 domain-containing protein tyrosine phosphatase SHP2. Individual PTPN11 mutations are specific to each syndrome and have opposite consequences on catalysis, but all favor SHP2's interaction with signaling partners. Here, we report on a subject with NS harboring biallelic variants in PTPN11. While the former (p.Leu261Phe) had previously been reported in NS, the latter (p.Thr357Met) is a novel change impairing catalysis. Members of the family carrying p.Thr357Met, however, did not show any obvious feature fitting NSML or within the RASopathy phenotypic spectrum. A major impact of this change on transcript processing and protein stability was excluded. These findings further support the view that NSML cannot be ascribed merely to impaired SHP2's catalytic activity and suggest that PTPN11 mutations causing this condition act through an alternative dominant mechanism.
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
457-461Informations de copyright
© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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