A CRISPR-Cas9–engineered mouse model for GPI-anchor deficiency mirrors human phenotypes and exhibits hippocampal synaptic dysfunctions

Santos, Miguel Rodríguez de los; Rivalan, Marion; David, Friederike S.; Knaus, Alexej; Stumpf, Alexander; Moreno-Velasquez, Laura; Voigt, Anne; Mattei, Daniele; Long, Melissa; Vogt, Guido; Wittler, Lars; Timmermann, Bernd; Robinson, Peter N.; Horn, Denise; Mundlos, Stefan; Kornak, Uwe; Schmitz, Dietmar; Winter, York; Krawitz, Peter

doi:10.1101/2020.04.20.050591

Cited by 5 publications

(6 citation statements)

References 46 publications

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“…These results suggest that MGAT4B is a tumor-promoting factor and is closely associated with a tumor-suppressive immune state. As for other GT genes belonging to our model, B3GNT8 was associated with malignancy and metastasis of glioma [27], while FUT11 [28], FUT4 [29], GALNT16 [30], GALNT8 [31], MGAT4C [32], and PIGV [33] have been individually studied in various type of tumors previously and are correlated with tumor malignancy, proliferation, cancer stem cells, and immune cell attraction.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis Identified Glycosyltransferase Signature to Predict Glioma Prognosis and TAM Phenotype

Liu

et al. 2023

BioMed Research International

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Glycosylation is the most common posttranslational modification of proteins. Glycosyltransferase gene differential expression dictates the glycosylation model and is epigenetically regulating glioma progression and immunity. This study is aimed at identifying the glycosyltransferase gene signature to predict the prognosis and immune characteristics of glioma. The glycosyltransferase gene signature of glioma was identified in the TCGA database and validated in the CGGA database. Glioma patients were then divided into high- and low-risk groups based on risk scores to compare survival differences and predictive capacity. Subsequently, validation of glycosyltransferase gene signature merits by comparing with other signatures and utility in clinical judgment. The immune cell infiltration, immune pathways, and immune checkpoint expression level were also analyzed and compared in the high- and low-risk groups. Finally, the signature and its gene function were tested in our cohort and in vitro experiments. Eight glycosyltransferase genes were identified to establish the glycosyltransferase signature to predict the prognosis of glioma patients. The survival time was shorter in the high-risk group compared to the low-risk group based on glycosyltransferase signature and was confirmed in an independent external cohort. The glycosyltransferase signature displayed outstanding predictive capacity than other signatures in the TCGA and CGGA database cohorts. Furthermore, patients in the high-risk group were positively correlated with TAM infiltration, immune checkpoint expression level, and protumor immune pathways in TCGA cohorts. Validation of clinical tissue specimens revealed that the high-risk group was closely associated with infiltration of M2 TAMs. High-risk genes in the signature promote glioma proliferation, invasion, and macrophage recruitment in an in vitro validation of U87 and U251 cell lines. This carefully constructed that glycosyltransferase signature can predict the prognosis and immune profile of gliomas and help us evaluate subsequent macrophage-targeted therapies as well as other immune microenvironment modulation therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis Identified Glycosyltransferase Signature to Predict Glioma Prognosis and TAM Phenotype

Liu

et al. 2023

BioMed Research International

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“…PIG-C manipulation has also significantly impacted MSLN surface level (121). Another example is the success of CRISPR-Cas9engineered mouse model for GPI anchor deficiency to resemble human phenotype (134). Additionally, PIG-V knock-out resulted in hippocampal synaptic dysfunctions (134).…”

Section: Overall Insightmentioning

confidence: 99%

“…Another example is the success of CRISPR-Cas9engineered mouse model for GPI anchor deficiency to resemble human phenotype (134). Additionally, PIG-V knock-out resulted in hippocampal synaptic dysfunctions (134). These findings inevitably prompt the utilization of RNA interference therapy to target GPI pathway genes as well as GPI-APs in cancer, whereby blocking GPI pathway can be a promising therapy as multiple signaling pathways will be cut off, causing death of cancer cells.…”

Section: Overall Insightmentioning

confidence: 99%

GPI-AP: Unraveling a New Class of Malignancy Mediators and Potential Immunotherapy Targets

2020

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With millions of cases diagnosed annually and high economic burden to cover expensive costs, cancer is one of the most difficult diseases to treat due to late diagnosis and severe adverse effects from conventional therapy. This creates an urgent need to find new targets for early diagnosis and therapy. Progress in research revealed the key steps of carcinogenesis. They are called cancer hallmarks. Zooming in, cancer hallmarks are characterized by ligands binding to their cognate receptor and so triggering signaling cascade within cell to make response for stimulus. Accordingly, understanding membrane topology is vital. In this review, we shall discuss one type of transmembrane proteins: Glycosylphosphatidylinositol-Anchored Proteins (GPI-APs), with specific emphasis on those involved in tumor cells by evading immune surveillance and future applications for diagnosis and immune targeted therapy.

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“…The progress in neurogenetics, developmental disability genetics and genetic counselling of rare diseases can be illustrated by the fact that the 50th anniversary of the publication by Mabry et al [20] of the case report, 'Familial hyperphosphatasia with mental retardation, seizures, and neurologic deficits (J. Pediatrics. 77 (1), [74][75][76][77][78][79][80][81][82][83][84][85] was marked by the identification of likely pathogenic variants in those index patients [21]. This report of a family with four children who experienced a profound developmental disability provided the prototypic features of a rare disorder [22][23][24][25][26][27] that enabled the discovery of a novel class of glycophosphatidylinositol (GPI) disorders [8].…”

Section: Phenotypingmentioning

confidence: 99%

Rare Genetic Developmental Disabilities: Mabry Syndrome (MIM 239300) Index Cases and Glycophosphatidylinositol (GPI) Disorders

Thompson,

Knaus

2024

Genes

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The case report by Mabry et al. (1970) of a family with four children with elevated tissue non-specific alkaline phosphatase, seizures and profound developmental disability, became the basis for phenotyping children with the features that became known as Mabry syndrome. Aside from improvements in the services available to patients and families, however, the diagnosis and treatment of this, and many other developmental disabilities, did not change significantly until the advent of massively parallel sequencing. As more patients with features of the Mabry syndrome were identified, exome and genome sequencing were used to identify the glycophosphatidylinositol (GPI) biosynthesis disorders (GPIBDs) as a group of congenital disorders of glycosylation (CDG). Biallelic variants of the phosphatidylinositol glycan (PIG) biosynthesis, type V (PIGV) gene identified in Mabry syndrome became evidence of the first in a phenotypic series that is numbered HPMRS1-6 in the order of discovery. HPMRS1 [MIM: 239300] is the phenotype resulting from inheritance of biallelic PIGV variants. Similarly, HPMRS2 (MIM 614749), HPMRS5 (MIM 616025) and HPMRS6 (MIM 616809) result from disruption of the PIGO, PIGW and PIGY genes expressed in the endoplasmic reticulum. By contrast, HPMRS3 (MIM 614207) and HPMRS4 (MIM 615716) result from disruption of post attachment to proteins PGAP2 (HPMRS3) and PGAP3 (HPMRS4). The GPI biosynthesis disorders (GPIBDs) are currently numbered GPIBD1-21. Working with Dr. Mabry, in 2020, we were able to use improved laboratory diagnostics to complete the molecular diagnosis of patients he had originally described in 1970. We identified biallelic variants of the PGAP2 gene in the first reported HPMRS patients. We discuss the longevity of the Mabry syndrome index patients in the context of the utility of pyridoxine treatment of seizures and evidence for putative glycolipid storage in patients with HPMRS3. From the perspective of the laboratory innovations made that enabled the identification of the HPMRS phenotype in Dr. Mabry’s patients, the need for treatment innovations that will benefit patients and families affected by developmental disabilities is clear.

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A CRISPR-Cas9–engineered mouse model for GPI-anchor deficiency mirrors human phenotypes and exhibits hippocampal synaptic dysfunctions

Cited by 5 publications

References 46 publications

Comprehensive Analysis Identified Glycosyltransferase Signature to Predict Glioma Prognosis and TAM Phenotype

Comprehensive Analysis Identified Glycosyltransferase Signature to Predict Glioma Prognosis and TAM Phenotype

GPI-AP: Unraveling a New Class of Malignancy Mediators and Potential Immunotherapy Targets

Rare Genetic Developmental Disabilities: Mabry Syndrome (MIM 239300) Index Cases and Glycophosphatidylinositol (GPI) Disorders

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