The role of serine/threonine phosphatases in human development: Evidence from congenital disorders
Reversible protein phosphorylation is a fundamental regulation mechanism in eukaryotic cell and organismal physiology, and in human health and disease. Until recently, and unlike protein kinases, mutations in serine/threonine protein phosphatases (PSP) had not been commonly associated with disorders...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2022.1030119/full |
| _version_ | 1797995588561666048 |
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| author | Pieter Vaneynde Pieter Vaneynde Iris Verbinnen Iris Verbinnen Veerle Janssens Veerle Janssens |
| author_facet | Pieter Vaneynde Pieter Vaneynde Iris Verbinnen Iris Verbinnen Veerle Janssens Veerle Janssens |
| author_sort | Pieter Vaneynde |
| collection | DOAJ |
| description | Reversible protein phosphorylation is a fundamental regulation mechanism in eukaryotic cell and organismal physiology, and in human health and disease. Until recently, and unlike protein kinases, mutations in serine/threonine protein phosphatases (PSP) had not been commonly associated with disorders of human development. Here, we have summarized the current knowledge on congenital diseases caused by mutations, inherited or de novo, in one of 38 human PSP genes, encoding a monomeric phosphatase or a catalytic subunit of a multimeric phosphatase. In addition, we highlight similar pathogenic mutations in genes encoding a specific regulatory subunit of a multimeric PSP. Overall, we describe 19 affected genes, and find that most pathogenic variants are loss-of-function, with just a few examples of gain-of-function alterations. Moreover, despite their widespread tissue expression, the large majority of congenital PSP disorders are characterised by brain-specific abnormalities, suggesting a generalized, major role for PSPs in brain development and function. However, even if the pathogenic mechanisms are relatively well understood for a small number of PSP disorders, this knowledge is still incomplete for most of them, and the further identification of downstream targets and effectors of the affected PSPs is eagerly awaited through studies in appropriate in vitro and in vivo disease models. Such lacking studies could elucidate the exact mechanisms through which these diseases act, and possibly open up new therapeutic avenues. |
| first_indexed | 2024-04-11T10:03:58Z |
| format | Article |
| id | doaj.art-652110a7a8294a96a5e2363b2d0a43ea |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-04-11T10:03:58Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-652110a7a8294a96a5e2363b2d0a43ea2022-12-22T04:30:17ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2022-10-011010.3389/fcell.2022.10301191030119The role of serine/threonine phosphatases in human development: Evidence from congenital disordersPieter Vaneynde0Pieter Vaneynde1Iris Verbinnen2Iris Verbinnen3Veerle Janssens4Veerle Janssens5Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, University of Leuven (KU Leuven), Leuven, BelgiumLeuven Brain Institute (LBI), Leuven, BelgiumLaboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, University of Leuven (KU Leuven), Leuven, BelgiumLeuven Brain Institute (LBI), Leuven, BelgiumLaboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, University of Leuven (KU Leuven), Leuven, BelgiumLeuven Brain Institute (LBI), Leuven, BelgiumReversible protein phosphorylation is a fundamental regulation mechanism in eukaryotic cell and organismal physiology, and in human health and disease. Until recently, and unlike protein kinases, mutations in serine/threonine protein phosphatases (PSP) had not been commonly associated with disorders of human development. Here, we have summarized the current knowledge on congenital diseases caused by mutations, inherited or de novo, in one of 38 human PSP genes, encoding a monomeric phosphatase or a catalytic subunit of a multimeric phosphatase. In addition, we highlight similar pathogenic mutations in genes encoding a specific regulatory subunit of a multimeric PSP. Overall, we describe 19 affected genes, and find that most pathogenic variants are loss-of-function, with just a few examples of gain-of-function alterations. Moreover, despite their widespread tissue expression, the large majority of congenital PSP disorders are characterised by brain-specific abnormalities, suggesting a generalized, major role for PSPs in brain development and function. However, even if the pathogenic mechanisms are relatively well understood for a small number of PSP disorders, this knowledge is still incomplete for most of them, and the further identification of downstream targets and effectors of the affected PSPs is eagerly awaited through studies in appropriate in vitro and in vivo disease models. Such lacking studies could elucidate the exact mechanisms through which these diseases act, and possibly open up new therapeutic avenues.https://www.frontiersin.org/articles/10.3389/fcell.2022.1030119/fullserine/threonine protein phosphatasede novo mutationcongenital diseaseneurodevelopmental disorderssex development disorder |
| spellingShingle | Pieter Vaneynde Pieter Vaneynde Iris Verbinnen Iris Verbinnen Veerle Janssens Veerle Janssens The role of serine/threonine phosphatases in human development: Evidence from congenital disorders Frontiers in Cell and Developmental Biology serine/threonine protein phosphatase de novo mutation congenital disease neurodevelopmental disorders sex development disorder |
| title | The role of serine/threonine phosphatases in human development: Evidence from congenital disorders |
| title_full | The role of serine/threonine phosphatases in human development: Evidence from congenital disorders |
| title_fullStr | The role of serine/threonine phosphatases in human development: Evidence from congenital disorders |
| title_full_unstemmed | The role of serine/threonine phosphatases in human development: Evidence from congenital disorders |
| title_short | The role of serine/threonine phosphatases in human development: Evidence from congenital disorders |
| title_sort | role of serine threonine phosphatases in human development evidence from congenital disorders |
| topic | serine/threonine protein phosphatase de novo mutation congenital disease neurodevelopmental disorders sex development disorder |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2022.1030119/full |
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