Pediatric Encephalopathy: Clinical, Biochemical and Cellular Insights into the Role of Gln52 of <i>GNAO1</i> and <i>GNAI1</i> for the Dominant Disease
Heterotrimeric G proteins are immediate transducers of G protein-coupled receptors—the biggest receptor family in metazoans—and play innumerate functions in health and disease. A set of de novo point mutations in <i>GNAO1</i> and <i>GNAI1</i>, the genes encoding the α-subunit...
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2021-10-01
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| author | Gonzalo P. Solis Tatyana V. Kozhanova Alexey Koval Svetlana S. Zhilina Tatyana I. Mescheryakova Aleksandr A. Abramov Evgeny V. Ishmuratov Ekaterina S. Bolshakova Karina V. Osipova Sergey O. Ayvazyan Sébastien Lebon Ilya V. Kanivets Denis V. Pyankov Sabina Troccaz Denis N. Silachev Nikolay N. Zavadenko Andrey G. Prityko Vladimir L. Katanaev |
| author_facet | Gonzalo P. Solis Tatyana V. Kozhanova Alexey Koval Svetlana S. Zhilina Tatyana I. Mescheryakova Aleksandr A. Abramov Evgeny V. Ishmuratov Ekaterina S. Bolshakova Karina V. Osipova Sergey O. Ayvazyan Sébastien Lebon Ilya V. Kanivets Denis V. Pyankov Sabina Troccaz Denis N. Silachev Nikolay N. Zavadenko Andrey G. Prityko Vladimir L. Katanaev |
| author_sort | Gonzalo P. Solis |
| collection | DOAJ |
| description | Heterotrimeric G proteins are immediate transducers of G protein-coupled receptors—the biggest receptor family in metazoans—and play innumerate functions in health and disease. A set of de novo point mutations in <i>GNAO1</i> and <i>GNAI1</i>, the genes encoding the α-subunits (Gαo and Gαi1, respectively) of the heterotrimeric G proteins, have been described to cause pediatric encephalopathies represented by epileptic seizures, movement disorders, developmental delay, intellectual disability, and signs of neurodegeneration. Among such mutations, the Gln52Pro substitutions have been previously identified in <i>GNAO1</i> and <i>GNAI1</i>. Here, we describe the case of an infant with another mutation in the same site, Gln52Arg. The patient manifested epileptic and movement disorders and a developmental delay, at the onset of 1.5 weeks after birth. We have analyzed biochemical and cellular properties of the three types of dominant pathogenic mutants in the Gln52 position described so far: Gαo[Gln52Pro], Gαi1[Gln52Pro], and the novel Gαo[Gln52Arg]. At the biochemical level, the three mutant proteins are deficient in binding and hydrolyzing GTP, which is the fundamental function of the healthy G proteins. At the cellular level, the mutants are defective in the interaction with partner proteins recognizing either the GDP-loaded or the GTP-loaded forms of Gαo. Further, of the two intracellular sites of Gαo localization, plasma membrane and Golgi, the former is strongly reduced for the mutant proteins. We conclude that the point mutations at Gln52 inactivate the Gαo and Gαi1 proteins leading to aberrant intracellular localization and partner protein interactions. These features likely lie at the core of the molecular etiology of pediatric encephalopathies associated with the codon 52 mutations in <i>GNAO1</i>/<i>GNAI1</i>. |
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| publishDate | 2021-10-01 |
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| spelling | doaj.art-faa5a15480214143bcdf5ef74f36c1dd2023-11-22T17:48:33ZengMDPI AGCells2073-44092021-10-011010274910.3390/cells10102749Pediatric Encephalopathy: Clinical, Biochemical and Cellular Insights into the Role of Gln52 of <i>GNAO1</i> and <i>GNAI1</i> for the Dominant DiseaseGonzalo P. Solis0Tatyana V. Kozhanova1Alexey Koval2Svetlana S. Zhilina3Tatyana I. Mescheryakova4Aleksandr A. Abramov5Evgeny V. Ishmuratov6Ekaterina S. Bolshakova7Karina V. Osipova8Sergey O. Ayvazyan9Sébastien Lebon10Ilya V. Kanivets11Denis V. Pyankov12Sabina Troccaz13Denis N. Silachev14Nikolay N. Zavadenko15Andrey G. Prityko16Vladimir L. Katanaev17Translational Research Center in Oncohaematology, Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, CH-1211 Geneva, SwitzerlandSt. Luka’s Clinical Research Center for Children, 119620 Moscow, RussiaTranslational Research Center in Oncohaematology, Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, CH-1211 Geneva, SwitzerlandSt. Luka’s Clinical Research Center for Children, 119620 Moscow, RussiaSt. Luka’s Clinical Research Center for Children, 119620 Moscow, RussiaSt. Luka’s Clinical Research Center for Children, 119620 Moscow, RussiaSt. Luka’s Clinical Research Center for Children, 119620 Moscow, RussiaSt. Luka’s Clinical Research Center for Children, 119620 Moscow, RussiaSt. Luka’s Clinical Research Center for Children, 119620 Moscow, RussiaSt. Luka’s Clinical Research Center for Children, 119620 Moscow, RussiaUnit of Pediatric Neurology and Neurorehabilitation, Division of Pediatrics, Woman-Mother-Child Department, Lausanne University Hospital (CHUV), 1011 Lausanne, SwitzerlandCenter of Medical Genetics, Genomed Ltd., 115093 Moscow, RussiaCenter of Medical Genetics, Genomed Ltd., 115093 Moscow, RussiaTranslational Research Center in Oncohaematology, Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, CH-1211 Geneva, SwitzerlandTranslational Research Center in Oncohaematology, Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, CH-1211 Geneva, SwitzerlandDepartment of Neurology, Neurosurgery and Medical Genetics, Faculty of Pediatrics, Pirogov Russian National Research Medical University, 117997 Moscow, RussiaSt. Luka’s Clinical Research Center for Children, 119620 Moscow, RussiaTranslational Research Center in Oncohaematology, Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, CH-1211 Geneva, SwitzerlandHeterotrimeric G proteins are immediate transducers of G protein-coupled receptors—the biggest receptor family in metazoans—and play innumerate functions in health and disease. A set of de novo point mutations in <i>GNAO1</i> and <i>GNAI1</i>, the genes encoding the α-subunits (Gαo and Gαi1, respectively) of the heterotrimeric G proteins, have been described to cause pediatric encephalopathies represented by epileptic seizures, movement disorders, developmental delay, intellectual disability, and signs of neurodegeneration. Among such mutations, the Gln52Pro substitutions have been previously identified in <i>GNAO1</i> and <i>GNAI1</i>. Here, we describe the case of an infant with another mutation in the same site, Gln52Arg. The patient manifested epileptic and movement disorders and a developmental delay, at the onset of 1.5 weeks after birth. We have analyzed biochemical and cellular properties of the three types of dominant pathogenic mutants in the Gln52 position described so far: Gαo[Gln52Pro], Gαi1[Gln52Pro], and the novel Gαo[Gln52Arg]. At the biochemical level, the three mutant proteins are deficient in binding and hydrolyzing GTP, which is the fundamental function of the healthy G proteins. At the cellular level, the mutants are defective in the interaction with partner proteins recognizing either the GDP-loaded or the GTP-loaded forms of Gαo. Further, of the two intracellular sites of Gαo localization, plasma membrane and Golgi, the former is strongly reduced for the mutant proteins. We conclude that the point mutations at Gln52 inactivate the Gαo and Gαi1 proteins leading to aberrant intracellular localization and partner protein interactions. These features likely lie at the core of the molecular etiology of pediatric encephalopathies associated with the codon 52 mutations in <i>GNAO1</i>/<i>GNAI1</i>.https://www.mdpi.com/2073-4409/10/10/2749pediatric encephalopathy<i>GNAO1</i><i>GNAI1</i>G proteinsdominant mutationcase report |
| spellingShingle | Gonzalo P. Solis Tatyana V. Kozhanova Alexey Koval Svetlana S. Zhilina Tatyana I. Mescheryakova Aleksandr A. Abramov Evgeny V. Ishmuratov Ekaterina S. Bolshakova Karina V. Osipova Sergey O. Ayvazyan Sébastien Lebon Ilya V. Kanivets Denis V. Pyankov Sabina Troccaz Denis N. Silachev Nikolay N. Zavadenko Andrey G. Prityko Vladimir L. Katanaev Pediatric Encephalopathy: Clinical, Biochemical and Cellular Insights into the Role of Gln52 of <i>GNAO1</i> and <i>GNAI1</i> for the Dominant Disease Cells pediatric encephalopathy <i>GNAO1</i> <i>GNAI1</i> G proteins dominant mutation case report |
| title | Pediatric Encephalopathy: Clinical, Biochemical and Cellular Insights into the Role of Gln52 of <i>GNAO1</i> and <i>GNAI1</i> for the Dominant Disease |
| title_full | Pediatric Encephalopathy: Clinical, Biochemical and Cellular Insights into the Role of Gln52 of <i>GNAO1</i> and <i>GNAI1</i> for the Dominant Disease |
| title_fullStr | Pediatric Encephalopathy: Clinical, Biochemical and Cellular Insights into the Role of Gln52 of <i>GNAO1</i> and <i>GNAI1</i> for the Dominant Disease |
| title_full_unstemmed | Pediatric Encephalopathy: Clinical, Biochemical and Cellular Insights into the Role of Gln52 of <i>GNAO1</i> and <i>GNAI1</i> for the Dominant Disease |
| title_short | Pediatric Encephalopathy: Clinical, Biochemical and Cellular Insights into the Role of Gln52 of <i>GNAO1</i> and <i>GNAI1</i> for the Dominant Disease |
| title_sort | pediatric encephalopathy clinical biochemical and cellular insights into the role of gln52 of i gnao1 i and i gnai1 i for the dominant disease |
| topic | pediatric encephalopathy <i>GNAO1</i> <i>GNAI1</i> G proteins dominant mutation case report |
| url | https://www.mdpi.com/2073-4409/10/10/2749 |
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