Homozygous GLUL deletion is embryonically viable and leads to glutamine synthetase deficiency.

Autor:	Roifman M; Division of Clinical and Metabolic Genetics, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada.; Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, Canada., Niles KM; Division of Clinical and Metabolic Genetics, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada.; Division of Maternal Fetal Medicine, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, Canada., MacNeil L; Department of Pathology and Laboratory Medicine, Hospital for Sick Children, University of Toronto, Toronto, Canada.; Department of Medical Genetics, Alberta Precision Laboratories, University of Alberta, Edmonton, Alberta, Canada., Blaser S; Division of Neuroradiology, Department of Diagnostic Imaging, Hospital for Sick Children, University of Toronto, Toronto, Canada., Noor A; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Canada., Godoy R; Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, Canada., van Mieghem T; Division of Maternal Fetal Medicine, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, Canada., Ryan G; Division of Maternal Fetal Medicine, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, Canada., Seaward G; Division of Maternal Fetal Medicine, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, Canada., Sondheimer N; Division of Clinical and Metabolic Genetics, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada., Mercimek-Andrews S; Division of Clinical and Metabolic Genetics, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada., Schulze A; Division of Clinical and Metabolic Genetics, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada.; Department of Biochemistry, University of Toronto, Toronto, Canada., Hewson S; Division of Clinical and Metabolic Genetics, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada., Ovadia A; Division of Immunology, Department of Pediatrics, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, Holon, Israel.; Department of Pediatrics, Edith Wolfson Medical Center, Holon, Israel., Chitayat D; Division of Clinical and Metabolic Genetics, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada.; Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, Canada., Morgen EK; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Canada.; BioAge Labs, Richmond, California, USA., Hojilla C; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Canada., Kolomietz E; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Canada., Watkins N; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Canada., Häberle J; Division of Metabolism and Children's Research Center, University Children's Hospital, University of Zurich, Zurich, Switzerland., Shannon P; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Canada.
Jazyk:	angličtina
Zdroj:	Clinical genetics [Clin Genet] 2020 Dec; Vol. 98 (6), pp. 613-619. Date of Electronic Publication: 2020 Oct 01.
DOI:	10.1111/cge.13844
Abstrakt:	Glutamine synthetase (GS) is the enzyme responsible for the biosynthesis of glutamine, providing the only source of endogenous glutamine necessary for several critical metabolic and developmental pathways. GS deficiency, caused by pathogenic variants in the glutamate-ammonia ligase (GLUL) gene, is a rare autosomal recessive inborn error of metabolism characterized by systemic glutamine deficiency, persistent moderate hyperammonemia, and clinically devastating seizures and multi-organ failure shortly after birth. The four cases reported thus far were caused by homozygous GLUL missense variants. We report a case of GS deficiency caused by homozygous GLUL gene deletion, diagnosed prenatally and likely representing the most severe end of the spectrum. We expand the known phenotype of this rare condition with novel dysmorphic, radiographic and neuropathologic features identified on post-mortem examination. The biallelic deletion identified in this case also included the RNASEL gene and was associated with immune dysfunction in the fetus. This case demonstrates that total absence of the GLUL gene in humans is viable beyond the embryonic period, despite the early embryonic lethality found in GLUL animal models. (© 2020 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)
Databáze:	MEDLINE
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