GLS hyperactivity causes glutamate excess, infantile cataract and profound developmental delay

Lynne Rumping, Federico Tessadori, Petra J. W. Pouwels, Esmee Vringer, Jannie P. Wijnen, Alex A. Bhogal, Sanne M. C. Savelberg, Karen J. Duran, Mark J. G. Bakkers, R. ben J. J. Ramos, Peter A. W. Schellekens, Hester Y. Kroes, Dennis W. J. Klomp, Graeme C. M. Black, Rachel L. Taylor, Jeroen P. W. Bakkers, Hubertus C. M. T. Prinsen, Marjo S. van der Knaap, Tobias B. Dansen, Holger Rehmann & 6 others Fried J. T. Zwartkruis, Roderick H. J. Houwen, Gijs van Haaften, Nanda M. Verhoeven-Duif, Judith J. M. Jans, Peter M. van Hasselt

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)96-104
JournalHuman Molecular Genetics
Volume28
Issue number1
DOIs
Publication statusPublished - 2019

Cite this

Rumping, L., Tessadori, F., Pouwels, P. J. W., Vringer, E., Wijnen, J. P., Bhogal, A. A., ... van Hasselt, P. M. (2019). GLS hyperactivity causes glutamate excess, infantile cataract and profound developmental delay. Human Molecular Genetics, 28(1), 96-104. https://doi.org/10.1093/hmg/ddy330
Rumping, Lynne ; Tessadori, Federico ; Pouwels, Petra J. W. ; Vringer, Esmee ; Wijnen, Jannie P. ; Bhogal, Alex A. ; Savelberg, Sanne M. C. ; Duran, Karen J. ; Bakkers, Mark J. G. ; Ramos, R. ben J. J. ; Schellekens, Peter A. W. ; Kroes, Hester Y. ; Klomp, Dennis W. J. ; Black, Graeme C. M. ; Taylor, Rachel L. ; Bakkers, Jeroen P. W. ; Prinsen, Hubertus C. M. T. ; van der Knaap, Marjo S. ; Dansen, Tobias B. ; Rehmann, Holger ; Zwartkruis, Fried J. T. ; Houwen, Roderick H. J. ; van Haaften, Gijs ; Verhoeven-Duif, Nanda M. ; Jans, Judith J. M. ; van Hasselt, Peter M. / GLS hyperactivity causes glutamate excess, infantile cataract and profound developmental delay. In: Human Molecular Genetics. 2019 ; Vol. 28, No. 1. pp. 96-104.
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abstract = "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.",
author = "Lynne Rumping and Federico Tessadori and Pouwels, {Petra J. W.} and Esmee Vringer and Wijnen, {Jannie P.} and Bhogal, {Alex A.} and Savelberg, {Sanne M. C.} and Duran, {Karen J.} and Bakkers, {Mark J. G.} and Ramos, {R. ben J. J.} and Schellekens, {Peter A. W.} and Kroes, {Hester Y.} and Klomp, {Dennis W. J.} and Black, {Graeme C. M.} and Taylor, {Rachel L.} and Bakkers, {Jeroen P. W.} and Prinsen, {Hubertus C. M. T.} and {van der Knaap}, {Marjo S.} and Dansen, {Tobias B.} and Holger Rehmann and Zwartkruis, {Fried J. T.} and Houwen, {Roderick H. J.} and {van Haaften}, Gijs and Verhoeven-Duif, {Nanda M.} and Jans, {Judith J. M.} and {van Hasselt}, {Peter M.}",
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journal = "Human Molecular Genetics",
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Rumping, L, Tessadori, F, Pouwels, PJW, Vringer, E, Wijnen, JP, Bhogal, AA, Savelberg, SMC, Duran, KJ, Bakkers, MJG, Ramos, RBJJ, Schellekens, PAW, Kroes, HY, Klomp, DWJ, Black, GCM, Taylor, RL, Bakkers, JPW, Prinsen, HCMT, van der Knaap, MS, Dansen, TB, Rehmann, H, Zwartkruis, FJT, Houwen, RHJ, van Haaften, G, Verhoeven-Duif, NM, Jans, JJM & van Hasselt, PM 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

GLS hyperactivity causes glutamate excess, infantile cataract and profound developmental delay. / Rumping, Lynne; Tessadori, Federico; Pouwels, Petra J. W.; Vringer, Esmee; Wijnen, Jannie P.; Bhogal, Alex A.; Savelberg, Sanne M. C.; Duran, Karen J.; Bakkers, Mark J. G.; Ramos, R. ben J. J.; Schellekens, Peter A. W.; Kroes, Hester Y.; Klomp, Dennis W. J.; Black, Graeme C. M.; Taylor, Rachel L.; Bakkers, Jeroen P. W.; Prinsen, Hubertus C. M. T.; van der Knaap, Marjo S.; Dansen, Tobias B.; Rehmann, Holger; Zwartkruis, Fried J. T.; Houwen, Roderick H. J.; van Haaften, Gijs; Verhoeven-Duif, Nanda M.; Jans, Judith J. M.; van Hasselt, Peter M.

In: Human Molecular Genetics, Vol. 28, No. 1, 2019, p. 96-104.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - GLS hyperactivity causes glutamate excess, infantile cataract and profound developmental delay

AU - Rumping, Lynne

AU - Tessadori, Federico

AU - Pouwels, Petra J. W.

AU - Vringer, Esmee

AU - Wijnen, Jannie P.

AU - Bhogal, Alex A.

AU - Savelberg, Sanne M. C.

AU - Duran, Karen J.

AU - Bakkers, Mark J. G.

AU - Ramos, R. ben J. J.

AU - Schellekens, Peter A. W.

AU - Kroes, Hester Y.

AU - Klomp, Dennis W. J.

AU - Black, Graeme C. M.

AU - Taylor, Rachel L.

AU - Bakkers, Jeroen P. W.

AU - Prinsen, Hubertus C. M. T.

AU - van der Knaap, Marjo S.

AU - Dansen, Tobias B.

AU - Rehmann, Holger

AU - Zwartkruis, Fried J. T.

AU - Houwen, Roderick H. J.

AU - van Haaften, Gijs

AU - Verhoeven-Duif, Nanda M.

AU - Jans, Judith J. M.

AU - van Hasselt, Peter M.

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/30239721

U2 - 10.1093/hmg/ddy330

DO - 10.1093/hmg/ddy330

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JO - Human Molecular Genetics

JF - Human Molecular Genetics

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