Changes of RAS Pathway Phosphorylation in Lymphoblastoid Cell Lines from Noonan Syndrome Patients Carrying Hypomorphic Variants in Two NS Genes.
Int J Mol Sci
; 24(4)2023 Feb 17.
Article
em En
| MEDLINE
| ID: mdl-36835447
ABSTRACT
Noonan syndrome (NS) is an autosomal dominant multisystem disorder, characterized by variable expressivity and locus heterogeneity, being caused by mutations in one of a subset of RAS pathway genes. Nevertheless, for 20-30% of patients it is not possible to provide molecular diagnosis, suggesting that further unknown genes or mechanisms are involved in NS pathogenesis. Recently, we proposed a digenic inheritance of subclinical variants as an alternative NS pathogenic model in two NS patients negative for molecular diagnosis. They showed hypomorphic variants of RAS pathway genes co-inherited from both their healthy parents that we hypothesized to generate an additive effect. Here, we report on the phosphoproteome and proteome analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS) performed on the immortalized peripheral blood mononuclear cells (PBMCs) from the two above trios. Our results indicate that the two unrelated patients show overlapped profiles in both protein abundances and their phosphorylation levels not reached by their parents. IPA software predicted RAS-related pathways as significantly activated in the two patients. Interestingly, they remained unchanged or only slightly activated in both patients' parents. These findings suggest that the presence of one subclinical variant can activate the RAS pathway below the pathological threshold, which can instead be exceeded by the additive effect due to the co-presence of two subclinical variants causing NS, supporting our digenic inheritance hypothesis.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas ras
/
Síndrome de Noonan
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article