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Yardena Samuels - One of the best experts on this subject based on the ideXlab platform.
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Genetic and Functional Analysis of GRIN2A in Tumor Samples.
Methods in molecular biology (Clifton N.J.), 2017Co-Authors: Todd D. Prickett, Jared J. Gartner, Yardena SamuelsAbstract:Ionotropic glutamate receptors (iGluRs) are large integral membrane multi-protein complexes that create ion channels in plasma membranes. Upon binding of receptor specific ligands (e.g., glutamate), increased efflux or influx of mono- or divalent cations (e.g., Ca2+) promotes synaptic transmission, cellular migration, and survival. Three classes of iGluRs were originally defined after their respective agonists: AMPA, kainate, and NMDA receptors (NMDARs). Recently, we examined iGluR families at the genetic level using Next-Generation Sequencing (NGS) (whole-exome sequencing (WES)) and discovered a high prevalence of somatic mutations within the gene for one of the NMDAR subunits, GRIN2A, specifically in malignant melanoma. Following confirmation of the somatic mutations, we focused on functional characterization of a subset of the GRIN2A mutants that demonstrated a loss of NMDAR functionality. We used gene expression and protein biochemistry to examine complex formation between GluN1 subunit (encoded by GRIN1) and GluN2A subunit (encoded by GRIN2A), anchorage-independent growth in soft agar and cellular migration. Furthermore, we used shRNA depletion of endogenous GRIN2A in melanoma cells expressing either wild-type GRIN2A or mutant GRIN2A and measured cellular proliferation compared to negative controls. Our data show that somatic mutation of certain residues in GluN2A results in increased survival and is the first such report to demonstrate the functional importance of GRIN2A mutations in melanoma and the significance ionotropic glutamate receptor signaling plays in malignant melanoma.
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Abstract LB-48: Somatic mutation of the NMDAR subunit GRIN2A in malignant melanoma results in loss of tumor suppressor activity.
Molecular and Cellular Biology, 2013Co-Authors: Todd D. Prickett, Brad Zerlanko, Victoria Hill, Jared J. Gartner, Jiji Jiang, John R. Wunderlich, J. Silvio Gutkind, Steven A. Rosenberg, May Samaan, Yardena SamuelsAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Glutamate receptors regulate many different cellular processes such as; homeostasis, growth, neurotransmission, proliferation, survival and cell death. These receptors are composed of two different major types; the ionotropic and the metabotropic family. The ionotropic glutamate receptors are composed of large complexes of multi-protein subunits creating ion channels in the cell plasma membranes that allow for influx or efflux of mono- or divalent cations (e.g., Ca2+)1. Upon binding of glutamate, these ligand gated-ion channels change their conformation giving rise to ion permeability and oscillations that in many neuronal cells (cerebellar granule cells, neurons, astrocytes, and glial cells) are important for synaptic transmissions, cellular migration and survival. We recently discovered the high prevalence of somatic mutations within one of the ionotropic glutamate receptors, GRIN2A, in malignant melanoma (1). Whole-exome sequencing of 14 tumor and matched normal samples from treatment naive melanoma patients revealed that GRIN2A harbored 34 somatic mutations across 125 melanoma samples (25.2%). The mutations were distributed throughout the gene, with clustering of mutations within important functional domains. We also observed three recurrent alterations (S278F, E371K, and E1175K) as well as 5 nonsense mutations. Recently, additional groups have since observed high mutation frequencies of GRIN2A within separate melanoma cohorts, suggesting that genetic alteration of this gene is important (2-3). Functional characterization of a subset of GRIN2A mutants demonstrated loss of complex formation between GRIN1 and GRIN2A, decreased cell death, increased anchorage-independent growth in soft agar, increased migration and decreased Ca2+-channel influx promoting cell survival whilst expression of GRIN1:GRIN2A wild-type complexes resulted in decreased cell proliferation via Ca2+ -mediated programmed cell death. Depletion of endogenous GRIN2A in melanoma cells expressing wild-type GRIN2A resulted in increased proliferation compared to control. In contrast, shRNA depletion of GRIN2A in mutant cell lines had little to no effect. Our data shows that somatic mutation of GRIN2A results in decreased Ca2+-mediated apoptosis in melanoma cells causing increased survival and is the first to demonstrate the functional implications of GRIN2A mutations in melanoma. Importantly, our whole-exome study was the first to demonstrate that the glutamate signaling pathway is significantly altered in melanoma. Citation Format: Todd D. Prickett, Victoria Hill, Jared Gartner, Brad Zerlanko, Jiji Jiang, May Samaan, John Wunderlich, Silvio Gutkind, Steven A. Rosenberg, Yardena Samuels. Somatic mutation of the NMDAR subunit GRIN2A in malignant melanoma results in loss of tumor suppressor activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-48. doi:10.1158/1538-7445.AM2013-LB-48
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Towards Deciphering the Genetic Landscape in Melanoma
Annals of Oncology, 2012Co-Authors: Yardena Samuels, Todd D. Prickett, Xiaomu Wei, Jimmy C. Lin, Jamie K. Teer, Steven A. RosenbergAbstract:ABSTRACT Melanoma is the deadliest form of human skin cancer, accounting for 70% of skin-cancer related deaths although it comprises only 4% of skin cancer cases. As opposed to the steady decrease in overall rate of other cancers, the incidence of melanoma continues to rise worldwide. The median patient survival is six months following diagnosis. There is a clear need to develop improved therapy for this disease. Melanoma develops through acquired mutations in cancer genes. Cancer genome sequencing can identify recurring genetic alterations that will generate new approaches to the treatment of melanoma, enabling a more personalized approach, based on gene mutation profiles of each patient's tumor. To systematically survey mutations in melanoma, we performed whole-exome sequencing of 14 matched normal and metastatic tumor DNAs. This allowed us to discover GRIN2A, a member of the ionotropic glutamate receptor family (iGluR), to be a significantly mutated gene that had not previously been identified as playing a role in melanoma. The comprehensive nature of the acquired data in this study allowed the identification of the glutamate signaling pathway to be significantly mutated, which includes GRIN2A, GRM3 and ERBB4, found to be mutated at 25, 16 and 19 percent of melanomas, respectively GRIN2A and GRM3, a metabotropic glutamate receptor (mGluR) are regulated by glutamate. GRIN2A, which is a ligand-gated ion channel, allows cations such as calcium to pass through the plasma membrane of the cell after the binding of glutamate to the receptor. GRM3 activates pathways such as the MEK pathway upon glutamate binding. The functional interplay between GRIN2A, GRM3 and ERBB4 in melanoma will be discussed and preliminary data presented. Our findings have potential therapeutic implications, as glutamate pathway modification has previously been shown to limit tumor growth. Further investigation of the glutamate pathway in melanoma a development of glutamate pathway inhibitors is therefore warranted. Disclosure All authors have declared no conflicts of interest.
Todd D. Prickett - One of the best experts on this subject based on the ideXlab platform.
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Genetic and Functional Analysis of GRIN2A in Tumor Samples.
Methods in molecular biology (Clifton N.J.), 2017Co-Authors: Todd D. Prickett, Jared J. Gartner, Yardena SamuelsAbstract:Ionotropic glutamate receptors (iGluRs) are large integral membrane multi-protein complexes that create ion channels in plasma membranes. Upon binding of receptor specific ligands (e.g., glutamate), increased efflux or influx of mono- or divalent cations (e.g., Ca2+) promotes synaptic transmission, cellular migration, and survival. Three classes of iGluRs were originally defined after their respective agonists: AMPA, kainate, and NMDA receptors (NMDARs). Recently, we examined iGluR families at the genetic level using Next-Generation Sequencing (NGS) (whole-exome sequencing (WES)) and discovered a high prevalence of somatic mutations within the gene for one of the NMDAR subunits, GRIN2A, specifically in malignant melanoma. Following confirmation of the somatic mutations, we focused on functional characterization of a subset of the GRIN2A mutants that demonstrated a loss of NMDAR functionality. We used gene expression and protein biochemistry to examine complex formation between GluN1 subunit (encoded by GRIN1) and GluN2A subunit (encoded by GRIN2A), anchorage-independent growth in soft agar and cellular migration. Furthermore, we used shRNA depletion of endogenous GRIN2A in melanoma cells expressing either wild-type GRIN2A or mutant GRIN2A and measured cellular proliferation compared to negative controls. Our data show that somatic mutation of certain residues in GluN2A results in increased survival and is the first such report to demonstrate the functional importance of GRIN2A mutations in melanoma and the significance ionotropic glutamate receptor signaling plays in malignant melanoma.
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Somatic Mutation of GRIN2A in Malignant Melanoma Results in Loss of Tumor Suppressor Activity via Aberrant NMDAR Complex Formation
The Journal of investigative dermatology, 2014Co-Authors: Todd D. Prickett, Brad Zerlanko, Victoria Hill, Jared J. Gartner, Nouar Qutob, Jiji Jiang, May Simaan, John R. Wunderlich, J. Silvio Gutkind, Steven A. RosenbergAbstract:The ionotropic glutamate receptors (N-methyl-D-aspartate receptors (NMDARs)) are composed of large complexes of multi-protein subunits creating ion channels in the cell plasma membranes that allow for influx or efflux of mono- or divalent cations (e.g., Ca2+) important for synaptic transmissions, cellular migration, and survival. Recently, we discovered the high prevalence of somatic mutations within one of the ionotropic glutamate receptors, GRIN2A, in malignant melanoma. Functional characterization of a subset of GRIN2A mutants demonstrated a loss of NMDAR complex formation between GRIN1 and GRIN2A, increased anchorage-independent growth in soft agar, and increased migration. Somatic mutation of GRIN2A results in a dominant negative effect inhibiting the tumor-suppressive phenotype of wild-type (WT) GRIN2A in melanoma. Depletion of endogenous GRIN2A in melanoma cells expressing WT GRIN2A resulted in increased proliferation compared with control. In contrast, short-hairpin RNA depletion of GRIN2A in mutant cell lines slightly reduced proliferation. Our data show that somatic mutation of GRIN2A results in increased survival, and we demonstrate the functional importance of GRIN2A mutations in melanoma and the significance that ionotropic glutamate receptor signaling has in malignant melanoma.
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Abstract LB-48: Somatic mutation of the NMDAR subunit GRIN2A in malignant melanoma results in loss of tumor suppressor activity.
Molecular and Cellular Biology, 2013Co-Authors: Todd D. Prickett, Brad Zerlanko, Victoria Hill, Jared J. Gartner, Jiji Jiang, John R. Wunderlich, J. Silvio Gutkind, Steven A. Rosenberg, May Samaan, Yardena SamuelsAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Glutamate receptors regulate many different cellular processes such as; homeostasis, growth, neurotransmission, proliferation, survival and cell death. These receptors are composed of two different major types; the ionotropic and the metabotropic family. The ionotropic glutamate receptors are composed of large complexes of multi-protein subunits creating ion channels in the cell plasma membranes that allow for influx or efflux of mono- or divalent cations (e.g., Ca2+)1. Upon binding of glutamate, these ligand gated-ion channels change their conformation giving rise to ion permeability and oscillations that in many neuronal cells (cerebellar granule cells, neurons, astrocytes, and glial cells) are important for synaptic transmissions, cellular migration and survival. We recently discovered the high prevalence of somatic mutations within one of the ionotropic glutamate receptors, GRIN2A, in malignant melanoma (1). Whole-exome sequencing of 14 tumor and matched normal samples from treatment naive melanoma patients revealed that GRIN2A harbored 34 somatic mutations across 125 melanoma samples (25.2%). The mutations were distributed throughout the gene, with clustering of mutations within important functional domains. We also observed three recurrent alterations (S278F, E371K, and E1175K) as well as 5 nonsense mutations. Recently, additional groups have since observed high mutation frequencies of GRIN2A within separate melanoma cohorts, suggesting that genetic alteration of this gene is important (2-3). Functional characterization of a subset of GRIN2A mutants demonstrated loss of complex formation between GRIN1 and GRIN2A, decreased cell death, increased anchorage-independent growth in soft agar, increased migration and decreased Ca2+-channel influx promoting cell survival whilst expression of GRIN1:GRIN2A wild-type complexes resulted in decreased cell proliferation via Ca2+ -mediated programmed cell death. Depletion of endogenous GRIN2A in melanoma cells expressing wild-type GRIN2A resulted in increased proliferation compared to control. In contrast, shRNA depletion of GRIN2A in mutant cell lines had little to no effect. Our data shows that somatic mutation of GRIN2A results in decreased Ca2+-mediated apoptosis in melanoma cells causing increased survival and is the first to demonstrate the functional implications of GRIN2A mutations in melanoma. Importantly, our whole-exome study was the first to demonstrate that the glutamate signaling pathway is significantly altered in melanoma. Citation Format: Todd D. Prickett, Victoria Hill, Jared Gartner, Brad Zerlanko, Jiji Jiang, May Samaan, John Wunderlich, Silvio Gutkind, Steven A. Rosenberg, Yardena Samuels. Somatic mutation of the NMDAR subunit GRIN2A in malignant melanoma results in loss of tumor suppressor activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-48. doi:10.1158/1538-7445.AM2013-LB-48
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Towards Deciphering the Genetic Landscape in Melanoma
Annals of Oncology, 2012Co-Authors: Yardena Samuels, Todd D. Prickett, Xiaomu Wei, Jimmy C. Lin, Jamie K. Teer, Steven A. RosenbergAbstract:ABSTRACT Melanoma is the deadliest form of human skin cancer, accounting for 70% of skin-cancer related deaths although it comprises only 4% of skin cancer cases. As opposed to the steady decrease in overall rate of other cancers, the incidence of melanoma continues to rise worldwide. The median patient survival is six months following diagnosis. There is a clear need to develop improved therapy for this disease. Melanoma develops through acquired mutations in cancer genes. Cancer genome sequencing can identify recurring genetic alterations that will generate new approaches to the treatment of melanoma, enabling a more personalized approach, based on gene mutation profiles of each patient's tumor. To systematically survey mutations in melanoma, we performed whole-exome sequencing of 14 matched normal and metastatic tumor DNAs. This allowed us to discover GRIN2A, a member of the ionotropic glutamate receptor family (iGluR), to be a significantly mutated gene that had not previously been identified as playing a role in melanoma. The comprehensive nature of the acquired data in this study allowed the identification of the glutamate signaling pathway to be significantly mutated, which includes GRIN2A, GRM3 and ERBB4, found to be mutated at 25, 16 and 19 percent of melanomas, respectively GRIN2A and GRM3, a metabotropic glutamate receptor (mGluR) are regulated by glutamate. GRIN2A, which is a ligand-gated ion channel, allows cations such as calcium to pass through the plasma membrane of the cell after the binding of glutamate to the receptor. GRM3 activates pathways such as the MEK pathway upon glutamate binding. The functional interplay between GRIN2A, GRM3 and ERBB4 in melanoma will be discussed and preliminary data presented. Our findings have potential therapeutic implications, as glutamate pathway modification has previously been shown to limit tumor growth. Further investigation of the glutamate pathway in melanoma a development of glutamate pathway inhibitors is therefore warranted. Disclosure All authors have declared no conflicts of interest.
Steven A. Rosenberg - One of the best experts on this subject based on the ideXlab platform.
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Somatic Mutation of GRIN2A in Malignant Melanoma Results in Loss of Tumor Suppressor Activity via Aberrant NMDAR Complex Formation
The Journal of investigative dermatology, 2014Co-Authors: Todd D. Prickett, Brad Zerlanko, Victoria Hill, Jared J. Gartner, Nouar Qutob, Jiji Jiang, May Simaan, John R. Wunderlich, J. Silvio Gutkind, Steven A. RosenbergAbstract:The ionotropic glutamate receptors (N-methyl-D-aspartate receptors (NMDARs)) are composed of large complexes of multi-protein subunits creating ion channels in the cell plasma membranes that allow for influx or efflux of mono- or divalent cations (e.g., Ca2+) important for synaptic transmissions, cellular migration, and survival. Recently, we discovered the high prevalence of somatic mutations within one of the ionotropic glutamate receptors, GRIN2A, in malignant melanoma. Functional characterization of a subset of GRIN2A mutants demonstrated a loss of NMDAR complex formation between GRIN1 and GRIN2A, increased anchorage-independent growth in soft agar, and increased migration. Somatic mutation of GRIN2A results in a dominant negative effect inhibiting the tumor-suppressive phenotype of wild-type (WT) GRIN2A in melanoma. Depletion of endogenous GRIN2A in melanoma cells expressing WT GRIN2A resulted in increased proliferation compared with control. In contrast, short-hairpin RNA depletion of GRIN2A in mutant cell lines slightly reduced proliferation. Our data show that somatic mutation of GRIN2A results in increased survival, and we demonstrate the functional importance of GRIN2A mutations in melanoma and the significance that ionotropic glutamate receptor signaling has in malignant melanoma.
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Abstract LB-48: Somatic mutation of the NMDAR subunit GRIN2A in malignant melanoma results in loss of tumor suppressor activity.
Molecular and Cellular Biology, 2013Co-Authors: Todd D. Prickett, Brad Zerlanko, Victoria Hill, Jared J. Gartner, Jiji Jiang, John R. Wunderlich, J. Silvio Gutkind, Steven A. Rosenberg, May Samaan, Yardena SamuelsAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Glutamate receptors regulate many different cellular processes such as; homeostasis, growth, neurotransmission, proliferation, survival and cell death. These receptors are composed of two different major types; the ionotropic and the metabotropic family. The ionotropic glutamate receptors are composed of large complexes of multi-protein subunits creating ion channels in the cell plasma membranes that allow for influx or efflux of mono- or divalent cations (e.g., Ca2+)1. Upon binding of glutamate, these ligand gated-ion channels change their conformation giving rise to ion permeability and oscillations that in many neuronal cells (cerebellar granule cells, neurons, astrocytes, and glial cells) are important for synaptic transmissions, cellular migration and survival. We recently discovered the high prevalence of somatic mutations within one of the ionotropic glutamate receptors, GRIN2A, in malignant melanoma (1). Whole-exome sequencing of 14 tumor and matched normal samples from treatment naive melanoma patients revealed that GRIN2A harbored 34 somatic mutations across 125 melanoma samples (25.2%). The mutations were distributed throughout the gene, with clustering of mutations within important functional domains. We also observed three recurrent alterations (S278F, E371K, and E1175K) as well as 5 nonsense mutations. Recently, additional groups have since observed high mutation frequencies of GRIN2A within separate melanoma cohorts, suggesting that genetic alteration of this gene is important (2-3). Functional characterization of a subset of GRIN2A mutants demonstrated loss of complex formation between GRIN1 and GRIN2A, decreased cell death, increased anchorage-independent growth in soft agar, increased migration and decreased Ca2+-channel influx promoting cell survival whilst expression of GRIN1:GRIN2A wild-type complexes resulted in decreased cell proliferation via Ca2+ -mediated programmed cell death. Depletion of endogenous GRIN2A in melanoma cells expressing wild-type GRIN2A resulted in increased proliferation compared to control. In contrast, shRNA depletion of GRIN2A in mutant cell lines had little to no effect. Our data shows that somatic mutation of GRIN2A results in decreased Ca2+-mediated apoptosis in melanoma cells causing increased survival and is the first to demonstrate the functional implications of GRIN2A mutations in melanoma. Importantly, our whole-exome study was the first to demonstrate that the glutamate signaling pathway is significantly altered in melanoma. Citation Format: Todd D. Prickett, Victoria Hill, Jared Gartner, Brad Zerlanko, Jiji Jiang, May Samaan, John Wunderlich, Silvio Gutkind, Steven A. Rosenberg, Yardena Samuels. Somatic mutation of the NMDAR subunit GRIN2A in malignant melanoma results in loss of tumor suppressor activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-48. doi:10.1158/1538-7445.AM2013-LB-48
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Towards Deciphering the Genetic Landscape in Melanoma
Annals of Oncology, 2012Co-Authors: Yardena Samuels, Todd D. Prickett, Xiaomu Wei, Jimmy C. Lin, Jamie K. Teer, Steven A. RosenbergAbstract:ABSTRACT Melanoma is the deadliest form of human skin cancer, accounting for 70% of skin-cancer related deaths although it comprises only 4% of skin cancer cases. As opposed to the steady decrease in overall rate of other cancers, the incidence of melanoma continues to rise worldwide. The median patient survival is six months following diagnosis. There is a clear need to develop improved therapy for this disease. Melanoma develops through acquired mutations in cancer genes. Cancer genome sequencing can identify recurring genetic alterations that will generate new approaches to the treatment of melanoma, enabling a more personalized approach, based on gene mutation profiles of each patient's tumor. To systematically survey mutations in melanoma, we performed whole-exome sequencing of 14 matched normal and metastatic tumor DNAs. This allowed us to discover GRIN2A, a member of the ionotropic glutamate receptor family (iGluR), to be a significantly mutated gene that had not previously been identified as playing a role in melanoma. The comprehensive nature of the acquired data in this study allowed the identification of the glutamate signaling pathway to be significantly mutated, which includes GRIN2A, GRM3 and ERBB4, found to be mutated at 25, 16 and 19 percent of melanomas, respectively GRIN2A and GRM3, a metabotropic glutamate receptor (mGluR) are regulated by glutamate. GRIN2A, which is a ligand-gated ion channel, allows cations such as calcium to pass through the plasma membrane of the cell after the binding of glutamate to the receptor. GRM3 activates pathways such as the MEK pathway upon glutamate binding. The functional interplay between GRIN2A, GRM3 and ERBB4 in melanoma will be discussed and preliminary data presented. Our findings have potential therapeutic implications, as glutamate pathway modification has previously been shown to limit tumor growth. Further investigation of the glutamate pathway in melanoma a development of glutamate pathway inhibitors is therefore warranted. Disclosure All authors have declared no conflicts of interest.
Angela Vincent - One of the best experts on this subject based on the ideXlab platform.
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op13 2799 landau kleffner syndrome lks continuous spike and waves during slow wave sleep syndrome cswss and rolandic epilepsy re a genetic and immunological study
European Journal of Paediatric Neurology, 2015Co-Authors: Sukhvir Wright, Patrick Waters, G Lesca, G Rudolf, D Sanlaville, Leslie Jacobson, E Hirsch, A Labalme, P Szepetowski, Angela VincentAbstract:Objective LKS and CSWSS present with seizures, language and cognitive regression. Genetic studies have identified mutations in the GRIN2A gene, and copy-number-variants in genes encoding cell adhesion proteins (including CASPR2, contactin-2). Given that some affected patients respond to steroids we looked for autoantibodies to similar neuronal targets. Methods A previously genetically characterised cohort of patients with LKS (4 patients), CSWSS (23), RE (14), epilepsy with autism or neurodevelopmental disorder (2) and unaffected controls (10) was tested for neuronal surface antibodies (Abs) to GRIN1, GRIN2A and 2B, CASPR2 and contactin-2 proteins using cell-based-assays, and VGKC-complex-Abs by radioimmunoprecipitation. Results 8 samples were positive (8/53; 15%), 4 for CASPR2-Abs (low positive) and 4 for VGKC-complex-Abs (113–1102 pM). All samples were negative for contactin-2, GRIN1, 2A and 2B-Abs. Positive results were found in CSWSS patients (n=3; 2 VGKC-complex, 1 CASPR2), Rolandic epilepsy (n=3; 1 VGKC-complex, 2 CASPR2-Ab positive), and a neurodevelopmental disorder (dyspraxia, CASPR2-Ab); one control was VGKC-complex-Ab positive (unaffected father of an antibody positive patient). 3 positives were found in a single three-generation French family affected by LKS, CSWSS and RE, 2 also had GRIN2A mutations. Conclusion Overall, none of the 4 LKS patients in the cohort were antibody positive, 13% CSWSS (3/23) and 21% Rolandic epilepsies (3/14) had low positive CASPR2 or VGKC-complex-Abs. The three positive results in 3 different generations of the same GRIN2A family, which included an unaffected sibling with the disease associated GRIN2A mutation and an unaffected father with a positive antibody, suggests a possible dual aetiology in a small subset of epilepsy patients where autoantibodies might influence the presentation and severity of genetic cases. However, low level neuronal antibodies, and even genetic mutations, may not always be causal, but their coexistence in some patients suggests that these complex genetic diseases may also have a neuroinflammatory component.
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OP13 – 2799: Landau-Kleffner syndrome (LKS), continuous spike and waves during slow-wave sleep syndrome (CSWSS), and Rolandic epilepsy (RE) – A genetic and immunological study
European Journal of Paediatric Neurology, 2015Co-Authors: Sukhvir Wright, Patrick Waters, G Lesca, G Rudolf, D Sanlaville, Leslie Jacobson, E Hirsch, A Labalme, P Szepetowski, Angela VincentAbstract:Objective LKS and CSWSS present with seizures, language and cognitive regression. Genetic studies have identified mutations in the GRIN2A gene, and copy-number-variants in genes encoding cell adhesion proteins (including CASPR2, contactin-2). Given that some affected patients respond to steroids we looked for autoantibodies to similar neuronal targets. Methods A previously genetically characterised cohort of patients with LKS (4 patients), CSWSS (23), RE (14), epilepsy with autism or neurodevelopmental disorder (2) and unaffected controls (10) was tested for neuronal surface antibodies (Abs) to GRIN1, GRIN2A and 2B, CASPR2 and contactin-2 proteins using cell-based-assays, and VGKC-complex-Abs by radioimmunoprecipitation. Results 8 samples were positive (8/53; 15%), 4 for CASPR2-Abs (low positive) and 4 for VGKC-complex-Abs (113–1102 pM). All samples were negative for contactin-2, GRIN1, 2A and 2B-Abs. Positive results were found in CSWSS patients (n=3; 2 VGKC-complex, 1 CASPR2), Rolandic epilepsy (n=3; 1 VGKC-complex, 2 CASPR2-Ab positive), and a neurodevelopmental disorder (dyspraxia, CASPR2-Ab); one control was VGKC-complex-Ab positive (unaffected father of an antibody positive patient). 3 positives were found in a single three-generation French family affected by LKS, CSWSS and RE, 2 also had GRIN2A mutations. Conclusion Overall, none of the 4 LKS patients in the cohort were antibody positive, 13% CSWSS (3/23) and 21% Rolandic epilepsies (3/14) had low positive CASPR2 or VGKC-complex-Abs. The three positive results in 3 different generations of the same GRIN2A family, which included an unaffected sibling with the disease associated GRIN2A mutation and an unaffected father with a positive antibody, suggests a possible dual aetiology in a small subset of epilepsy patients where autoantibodies might influence the presentation and severity of genetic cases. However, low level neuronal antibodies, and even genetic mutations, may not always be causal, but their coexistence in some patients suggests that these complex genetic diseases may also have a neuroinflammatory component.
Sukhvir Wright - One of the best experts on this subject based on the ideXlab platform.
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op13 2799 landau kleffner syndrome lks continuous spike and waves during slow wave sleep syndrome cswss and rolandic epilepsy re a genetic and immunological study
European Journal of Paediatric Neurology, 2015Co-Authors: Sukhvir Wright, Patrick Waters, G Lesca, G Rudolf, D Sanlaville, Leslie Jacobson, E Hirsch, A Labalme, P Szepetowski, Angela VincentAbstract:Objective LKS and CSWSS present with seizures, language and cognitive regression. Genetic studies have identified mutations in the GRIN2A gene, and copy-number-variants in genes encoding cell adhesion proteins (including CASPR2, contactin-2). Given that some affected patients respond to steroids we looked for autoantibodies to similar neuronal targets. Methods A previously genetically characterised cohort of patients with LKS (4 patients), CSWSS (23), RE (14), epilepsy with autism or neurodevelopmental disorder (2) and unaffected controls (10) was tested for neuronal surface antibodies (Abs) to GRIN1, GRIN2A and 2B, CASPR2 and contactin-2 proteins using cell-based-assays, and VGKC-complex-Abs by radioimmunoprecipitation. Results 8 samples were positive (8/53; 15%), 4 for CASPR2-Abs (low positive) and 4 for VGKC-complex-Abs (113–1102 pM). All samples were negative for contactin-2, GRIN1, 2A and 2B-Abs. Positive results were found in CSWSS patients (n=3; 2 VGKC-complex, 1 CASPR2), Rolandic epilepsy (n=3; 1 VGKC-complex, 2 CASPR2-Ab positive), and a neurodevelopmental disorder (dyspraxia, CASPR2-Ab); one control was VGKC-complex-Ab positive (unaffected father of an antibody positive patient). 3 positives were found in a single three-generation French family affected by LKS, CSWSS and RE, 2 also had GRIN2A mutations. Conclusion Overall, none of the 4 LKS patients in the cohort were antibody positive, 13% CSWSS (3/23) and 21% Rolandic epilepsies (3/14) had low positive CASPR2 or VGKC-complex-Abs. The three positive results in 3 different generations of the same GRIN2A family, which included an unaffected sibling with the disease associated GRIN2A mutation and an unaffected father with a positive antibody, suggests a possible dual aetiology in a small subset of epilepsy patients where autoantibodies might influence the presentation and severity of genetic cases. However, low level neuronal antibodies, and even genetic mutations, may not always be causal, but their coexistence in some patients suggests that these complex genetic diseases may also have a neuroinflammatory component.
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OP13 – 2799: Landau-Kleffner syndrome (LKS), continuous spike and waves during slow-wave sleep syndrome (CSWSS), and Rolandic epilepsy (RE) – A genetic and immunological study
European Journal of Paediatric Neurology, 2015Co-Authors: Sukhvir Wright, Patrick Waters, G Lesca, G Rudolf, D Sanlaville, Leslie Jacobson, E Hirsch, A Labalme, P Szepetowski, Angela VincentAbstract:Objective LKS and CSWSS present with seizures, language and cognitive regression. Genetic studies have identified mutations in the GRIN2A gene, and copy-number-variants in genes encoding cell adhesion proteins (including CASPR2, contactin-2). Given that some affected patients respond to steroids we looked for autoantibodies to similar neuronal targets. Methods A previously genetically characterised cohort of patients with LKS (4 patients), CSWSS (23), RE (14), epilepsy with autism or neurodevelopmental disorder (2) and unaffected controls (10) was tested for neuronal surface antibodies (Abs) to GRIN1, GRIN2A and 2B, CASPR2 and contactin-2 proteins using cell-based-assays, and VGKC-complex-Abs by radioimmunoprecipitation. Results 8 samples were positive (8/53; 15%), 4 for CASPR2-Abs (low positive) and 4 for VGKC-complex-Abs (113–1102 pM). All samples were negative for contactin-2, GRIN1, 2A and 2B-Abs. Positive results were found in CSWSS patients (n=3; 2 VGKC-complex, 1 CASPR2), Rolandic epilepsy (n=3; 1 VGKC-complex, 2 CASPR2-Ab positive), and a neurodevelopmental disorder (dyspraxia, CASPR2-Ab); one control was VGKC-complex-Ab positive (unaffected father of an antibody positive patient). 3 positives were found in a single three-generation French family affected by LKS, CSWSS and RE, 2 also had GRIN2A mutations. Conclusion Overall, none of the 4 LKS patients in the cohort were antibody positive, 13% CSWSS (3/23) and 21% Rolandic epilepsies (3/14) had low positive CASPR2 or VGKC-complex-Abs. The three positive results in 3 different generations of the same GRIN2A family, which included an unaffected sibling with the disease associated GRIN2A mutation and an unaffected father with a positive antibody, suggests a possible dual aetiology in a small subset of epilepsy patients where autoantibodies might influence the presentation and severity of genetic cases. However, low level neuronal antibodies, and even genetic mutations, may not always be causal, but their coexistence in some patients suggests that these complex genetic diseases may also have a neuroinflammatory component.
