Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase.

Autor:	Jones AG; Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand., Aquilino M; Neuroscience Center, HiLIFE - Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland., Tinker RJ; Vanderbilt University Medical Center, Nashville, TN, USA., Duncan L; Center for Individualized Medicine, Mayo Clinic, Jacksonville, FL, USA., Jenkins Z; Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand., Carvill GL; Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA., DeWard SJ; GeneDx, Gaithersburg, MD, USA., Grange DK; Washington University, St. Louis, Missouri, USA., Hajianpour MJ; Albany Medical College, Albany, NY, USA., Halliday BJ; Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand., Holder-Espinasse M; Department of Clinical Genetics, Guys Hospital, London, UK., Horvath J; Münster University Hospital, Münster, Germany., Maitz S; Medical Genetics Service, Oncology Department of Southern Switzerland, Ente Ospedaliero Cantonale, Lugano, Switzerland., Nigro V; Department of Precision Medicine, University of Campania 'Luigi Vanvitelli,' Naples, Italy., Morleo M; Department of Precision Medicine, University of Campania 'Luigi Vanvitelli,' Naples, Italy., Paul V; Münster University Hospital, Münster, Germany., Spencer C; Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; Department of Medicine, Division of Human Genetics, Groote Schuur Hospital, Cape Town, South Africa., Esterhuizen AI; Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; Neuroscience Institute, University of Cape Town, Cape Town, South Africa; National Health Laboratory Service, Groote Schuur Hospital, Cape Town, South Africa., Polster T; Department of Epileptology (Krankenhaus Mara, Bethel Epilepsy Center) Medical School OWL, Bielefeld University, Bielefeld, Germany., Spano A; Maggiore Della Carità Hospital, Novara, Italy., Gómez-Lozano I; Neuroscience Center, HiLIFE - Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland., Kumar A; Centre for Protein Research, University of Otago, Dunedin, New Zealand., Poke G; Genetics Health Service New Zealand, Wellington Hospital, Wellington, New Zealand., Phillips JA 3rd; Vanderbilt University Medical Center, Nashville, TN, USA., Underhill HR; University of Utah, Salt Lake City, UT, USA., Gimenez G; Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand., Namba T; Neuroscience Center, HiLIFE - Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland., Robertson SP; Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand. Electronic address: stephen.robertson@otago.ac.nz.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2024 Apr 04; Vol. 111 (4), pp. 729-741.
DOI:	10.1016/j.ajhg.2024.03.005
Abstrakt:	Glutamine synthetase (GS), encoded by GLUL, catalyzes the conversion of glutamate to glutamine. GS is pivotal for the generation of the neurotransmitters glutamate and gamma-aminobutyric acid and is the primary mechanism of ammonia detoxification in the brain. GS levels are regulated post-translationally by an N-terminal degron that enables the ubiquitin-mediated degradation of GS in a glutamine-induced manner. GS deficiency in humans is known to lead to neurological defects and death in infancy, yet how dysregulation of the degron-mediated control of GS levels might affect neurodevelopment is unknown. We ascertained nine individuals with severe developmental delay, seizures, and white matter abnormalities but normal plasma and cerebrospinal fluid biochemistry with de novo variants in GLUL. Seven out of nine were start-loss variants and two out of nine disrupted 5' UTR splicing resulting in splice exclusion of the initiation codon. Using transfection-based expression systems and mass spectrometry, these variants were shown to lead to translation initiation of GS from methionine 18, downstream of the N-terminal degron motif, resulting in a protein that is stable and enzymatically competent but insensitive to negative feedback by glutamine. Analysis of human single-cell transcriptomes demonstrated that GLUL is widely expressed in neuro- and glial-progenitor cells and mature astrocytes but not in post-mitotic neurons. One individual with a start-loss GLUL variant demonstrated periventricular nodular heterotopia, a neuronal migration disorder, yet overexpression of stabilized GS in mice using in utero electroporation demonstrated no migratory deficits. These findings underline the importance of tight regulation of glutamine metabolism during neurodevelopment in humans. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 American Society of Human Genetics. All rights reserved.)
Databáze:	MEDLINE
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