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Changes of RAS Pathway Phosphorylation in Lymphoblastoid Cell Lines from Noonan Syndrome Patients Carrying Hypomorphic Variants in Two NS Genes

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 th...

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Detalles Bibliográficos
Autores principales: Tritto, Viviana, Capitanio, Daniele, Gelfi, Cecilia, Riva, Paola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9959625/
https://www.ncbi.nlm.nih.gov/pubmed/36835447
http://dx.doi.org/10.3390/ijms24044035
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author Tritto, Viviana
Capitanio, Daniele
Gelfi, Cecilia
Riva, Paola
author_facet Tritto, Viviana
Capitanio, Daniele
Gelfi, Cecilia
Riva, Paola
author_sort Tritto, Viviana
collection PubMed
description 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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spelling pubmed-99596252023-02-26 Changes of RAS Pathway Phosphorylation in Lymphoblastoid Cell Lines from Noonan Syndrome Patients Carrying Hypomorphic Variants in Two NS Genes Tritto, Viviana Capitanio, Daniele Gelfi, Cecilia Riva, Paola Int J Mol Sci Article 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. MDPI 2023-02-17 /pmc/articles/PMC9959625/ /pubmed/36835447 http://dx.doi.org/10.3390/ijms24044035 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tritto, Viviana
Capitanio, Daniele
Gelfi, Cecilia
Riva, Paola
Changes of RAS Pathway Phosphorylation in Lymphoblastoid Cell Lines from Noonan Syndrome Patients Carrying Hypomorphic Variants in Two NS Genes
title Changes of RAS Pathway Phosphorylation in Lymphoblastoid Cell Lines from Noonan Syndrome Patients Carrying Hypomorphic Variants in Two NS Genes
title_full Changes of RAS Pathway Phosphorylation in Lymphoblastoid Cell Lines from Noonan Syndrome Patients Carrying Hypomorphic Variants in Two NS Genes
title_fullStr Changes of RAS Pathway Phosphorylation in Lymphoblastoid Cell Lines from Noonan Syndrome Patients Carrying Hypomorphic Variants in Two NS Genes
title_full_unstemmed Changes of RAS Pathway Phosphorylation in Lymphoblastoid Cell Lines from Noonan Syndrome Patients Carrying Hypomorphic Variants in Two NS Genes
title_short Changes of RAS Pathway Phosphorylation in Lymphoblastoid Cell Lines from Noonan Syndrome Patients Carrying Hypomorphic Variants in Two NS Genes
title_sort changes of ras pathway phosphorylation in lymphoblastoid cell lines from noonan syndrome patients carrying hypomorphic variants in two ns genes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9959625/
https://www.ncbi.nlm.nih.gov/pubmed/36835447
http://dx.doi.org/10.3390/ijms24044035
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