Modeling (not so) rare developmental disorders associated with mutations in the protein-tyrosine phosphatase SHP2

Šolman, Maja; Woutersen, Daniëlle T. J.; Hertog, Jeroen den

doi:10.3389/fcell.2022.1046415

Cited by 7 publications

(2 citation statements)

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“…For instance, pathogenic gain-of-function mutations in the constrained PTPN11 gene (LOEUF 0.14) are a known cause of Noonan’s Syndrome. On the other hand, loss-of-function PTPN11 mutations give rise to an allelic disorder (Noonan’s Syndrome with Multiple Lentigines), with overlapping clinical features ( Solman et al, 2022 ). Similarly, variants in genes that are not predicted to be haploinsufficient, can nevertheless be pathogenic, for instance by acting in a dominant-negative fashion, as is the case for C-terminally truncating mutations in PPM1D (LOEUF 1.1) ( Jansen et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

A retrospective analysis of phosphatase catalytic subunit gene variants in patients with rare disorders identifies novel candidate neurodevelopmental disease genes

Lyulcheva-Bennett

Consortium

Bennett

2023

Front. Cell Dev. Biol.

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Rare genetic disorders represent some of the most severe and life-limiting conditions that constitute a considerable burden on global healthcare systems and societies. Most individuals affected by rare disorders remain undiagnosed, highlighting the unmet need for improved disease gene discovery and novel variant interpretation. Aberrant (de) phosphorylation can have profound pathological consequences underpinning many disease processes. Numerous phosphatases and associated proteins have been identified as disease genes, with many more likely to have gone undiscovered thus far. To begin to address these issues, we have performed a systematic survey of de novo variants amongst 189 genes encoding phosphatase catalytic subunits found in rare disease patients recruited to the 100,000 Genomes Project (100 kGP), the largest national sequencing project of its kind in the United Kingdom. We found that 49% of phosphatases were found to carry de novo mutation(s) in this cohort. Only 25% of these phosphatases have been previously linked to genetic disorders. A gene-to-patient approach matching variants to phenotypic data identified 9 novel candidate rare-disease genes: PTPRD, PTPRG, PTPRT, PTPRU, PTPRZ1, MTMR3, GAK, TPTE2, PTPN18. As the number of patients undergoing whole genome sequencing increases and information sharing improves, we anticipate that reiterative analysis of genomic and phenotypic data will continue to identify candidate phosphatase disease genes for functional validation. This is the first step towards delineating the aetiology of rare genetic disorders associated with altered phosphatase function, leading to new biological insights and improved clinical outcomes for the affected individuals and their families.

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Section: Discussionmentioning

confidence: 99%

A retrospective analysis of phosphatase catalytic subunit gene variants in patients with rare disorders identifies novel candidate neurodevelopmental disease genes

Lyulcheva-Bennett

Consortium

Bennett

2023

Front. Cell Dev. Biol.

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“…In humans, mutations in SHP2 are linked to developmental disorders like Noonan Syndrome (NS) and Noonan Syndrome with multiple lentigines (formerly known as Leopard Syndrome), as well as acute myeloid leukemia. SHP2 is also associated with many other types of cancer (Solman, Woutersen, et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Protein tyrosine phosphatases in zebrafish development and regeneration

Allers

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Protein tyrosine phosphatases (PTPs) have a central role in cell signaling, by dephosphorylating other proteins. PTPs are highly susceptible to oxidation, due to the low pKa of their active sites. Their reactive cysteine gets oxidized, which leads to the temporary inactivation of the PTP. It has been shown in many different species that a burst of Reactive Oxygen Species (ROS) is produced upon injury. This burst of ROS plays an important role in wound healing and regeneration. We hypothesized that the ROS could start a signaling cascade by oxidizing PTPs. Previously, eight PTPs were identified that were specifically oxidized in response to amputation of the tail fin of adult zebrafish. One of these PTPs, Shp2a, was shown to be essential for regeneration. In chapter 2 we describe how we generated zebrafish knockouts of 6 PTPs that were shown previously to be oxidized upon amputation of the caudal fin and their paralogs. We show that these PTPs were not essential for regeneration. In addition, we did not recapitulate all the phenotypes we expected. We hypothesize that this is due to genetic compensation. In chapter 3 we describe our investigation of zebrafish with a knockout of ptpn4a. We show that the majority of the mutant zebrafish died at the juvenile stage and suffered from epileptic seizures. This corresponds to human patients who suffer from intellectual disability and epileptic seizures due to nonsense mutations in PTPN4. We show that a minority of the mutant zebrafish compensated for the loss of Ptpn4a and survived, but also that a separate knockout line lost its compensation ability over time and showed enhanced lethality at the juvenile stage. In chapter 4 we describe our investigation of zebrafish with a knockout of ptpn6. We show that these mutant zebrafish displayed fully penetrant mortality at the larval stage and died from lethal hyperinflammation. This corresponds to the phenotype of the motheaten mice lacking SHP1 and human patients suffering from neutrophilic dermatoses and emphysema. We show that loss of Shp1 led to a reduced number of emerging HSPCs, increased HSPC proliferation, an increased number of macrophages and a decreased number of neutrophils. In addition, we show that loss of Shp1 affected the behavior of neutrophils and macrophages and led to reduced directional migration upon wounding. In chapter 5 we describe how we investigated the role of oxidation of Shp2a during regeneration, by creating a fusion protein consisting of Shp2a linked with Catalase. Due to the close vicinity, the Catalase protected Shp2a from oxidation. We show that by inhibiting oxidation of Shp2a, we inhibited regeneration. This indicates that transient oxidation of Shp2a is an essential step in the signaling cascade that results in regeneration. This research puts an end to the apparent paradox that Shp2a is oxidized during regeneration, but that catalytic activity of Shp2a is essential for regeneration to proceed. We hypothesize that transient oxidation of Shp2a leads to a reduction of a negative feedback loop, resulting in increased signaling activity once Shp2a is reduced again.

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