GLS hyperactivity causes glutamate excess, infantile cataract and profound developmental delay
| العنوان: | GLS hyperactivity causes glutamate excess, infantile cataract and profound developmental delay |
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| المؤلفون: | Gijs van Haaften, Nanda M. Verhoeven-Duif, Marjo S. van der Knaap, Holger Rehmann, Graeme C.M. Black, Jeroen Bakkers, Lynne Rumping, Peter M. van Hasselt, Hester Y. Kroes, Ruben Ramos, Tobias B. Dansen, Hubertus C.M.T. Prinsen, Sanne M C Savelberg, Judith J.M. Jans, Dennis W. J. Klomp, Rachel L. Taylor, Alex A. Bhogal, Esmee Vringer, Federico Tessadori, Jannie P. Wijnen, Peter A W J F Schellekens, Mark J.G. Bakkers, Fried J. T. Zwartkruis, Petra J. W. Pouwels, Roderick H. J. Houwen, Karen Duran |
| المساهمون: | ARD - Amsterdam Reproduction and Development, Hubrecht Institute for Developmental Biology and Stem Cell Research, Radiology and nuclear medicine, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam Reproduction & Development (AR&D), Pediatric surgery |
| المصدر: | Taylor, R L & Black, G 2019, ' GLS hyperactivity causes glutamate excess, infantile cataract and profound developmental delay ', Human Molecular Genetics, vol. 28, no. 1, pp. 96-104 . https://doi.org/10.1093/hmg/ddy330 Rumping, L, Tessadori, F, Pouwels, P J W, Vringer, E, Wijnen, J P, Bhogal, A A, Savelberg, S M C, Duran, K J, Bakkers, M J G, Ramos, R B J J, Schellekens, P A W, Kroes, H Y, Klomp, D W J, Black, G C M, Taylor, R L, Bakkers, J P W, Prinsen, H C M T, van der Knaap, M S, Dansen, T B, Rehmann, H, Zwartkruis, F J T, Houwen, R H J, van Haaften, G, Verhoeven-Duif, N M, Jans, J J M & van Hasselt, P M 2019, ' GLS hyperactivity causes glutamate excess, infantile cataract and profound developmental delay ', Human Molecular Genetics, vol. 28, no. 1, pp. 96-104 . https://doi.org/10.1093/hmg/ddy330 Human molecular genetics, 28(1), 96-104. Oxford University Press Human Molecular Genetics. Oxford University Press Human Molecular Genetics, 28(1), 96-104. Oxford University Press Human Molecular Genetics, 28(1), 96. Oxford University Press |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Male, GLS, Developmental Disabilities, Glutamine, medicine.disease_cause, loss-of-function, Glutamate homeostasis, Genetics(clinical), Child, Genetics (clinical), Zebrafish, 0303 health sciences, Glutaminase, 030305 genetics & heredity, Glutamate receptor, Brain, General Medicine, Cataract/genetics, Glutaminase/genetics, Glutamic Acid/genetics, Glutamine/metabolism, cataract, Gain of Function Mutation, Child, Preschool, Female, medicine.medical_specialty, Gain of Function Mutation/genetics, Adolescent, Glutamic Acid, Biology, Cataract, Glutamine synthetase, 03 medical and health sciences, Downregulation and upregulation, Glutamate-Ammonia Ligase, Reactive Oxygen Species/metabolism, Internal medicine, medicine, Glutamate-Ammonia Ligase/genetics, Genetics, Animals, Brain/metabolism, Humans, Gain-of-function, Preschool, Molecular Biology, Animal, Neurotoxicity, Fibroblasts, medicine.disease, Disease Models, Animal, Oxidative Stress, Endocrinology, HEK293 Cells, Disease Models, Reactive Oxygen Species, Oxidative stress, Developmental Disabilities/genetics |
| الوصف: | Loss-of-function mutations in glutaminase (GLS), the enzyme converting glutamine into glutamate, and the counteracting enzyme glutamine synthetase (GS) cause disturbed glutamate homeostasis and severe neonatal encephalopathy. We report a de novo Ser482Cys gain-of-function variant in GLS encoding GLS associated with profound developmental delay and infantile cataract. Functional analysis demonstrated that this variant causes hyperactivity and compensatory downregulation of GLS expression combined with upregulation of the counteracting enzyme GS, supporting pathogenicity. Ser482Cys-GLS likely improves the electrostatic environment of the GLS catalytic site, thereby intrinsically inducing hyperactivity. Alignment of +/−12.000 GLS protein sequences from >1000 genera revealed extreme conservation of Ser482 to the same degree as catalytic residues. Together with the hyperactivity, this indicates that Ser482 is evolutionarily preserved to achieve optimal—but submaximal—GLS activity. In line with GLS hyperactivity, increased glutamate and decreased glutamine concentrations were measured in urine and fibroblasts. In the brain (both grey and white matter), glutamate was also extremely high and glutamine was almost undetectable, demonstrated with magnetic resonance spectroscopic imaging at clinical field strength and subsequently supported at ultra-high field strength. Considering the neurotoxicity of glutamate when present in excess, the strikingly high glutamate concentrations measured in the brain provide an explanation for the developmental delay. Cataract, a known consequence of oxidative stress, was evoked in zebrafish expressing the hypermorphic Ser482Cys-GLS and could be alleviated by inhibition of GLS. The capacity to detoxify reactive oxygen species was reduced upon Ser482Cys-GLS expression, providing an explanation for cataract formation. In conclusion, we describe an inborn error of glutamate metabolism caused by a GLS hyperactivity variant, illustrating the importance of balanced GLS activity. |
| وصف الملف: | application/pdf; image/pdf |
| اللغة: | English |
| تدمد: | 0964-6906 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::efa4edf932c3eefca85db219883f75f1 https://doi.org/10.1093/hmg/ddy330 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....efa4edf932c3eefca85db219883f75f1 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 09646906 |
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