IMPORTANCE The identification and understanding of the monogenic causes of neurodevelopmental disorders are of high importance for personalized treatment and genetic counseling. OBJECTIVE To identify and characterize novel genes for a specific neurodevelopmental disorder characterized by refractory seizures, respiratory failure, brain abnormalities, and death in the neonatal period; describe the outcome of glutaminase deficiency in humans; and understand the underlying pathological mechanisms. DESIGN, SETTING, AND PARTICIPANTS We performed exome sequencing of cases of neurodevelopmental disorders without a clear genetic diagnosis, followed by genetic and bioinformatic evaluation of candidate variants and genes. Establishing pathogenicity of the variants was achieved by measuring metabolites in dried blood spots by a hydrophilic interaction liquid chromatography method coupled with tandem mass spectrometry. The participants are 2 families with a total of 4 children who each had lethal, therapy-refractory early neonatal seizures with status epilepticus and suppression bursts, respiratory insufficiency, simplified gyral structures, diffuse volume loss of the brain, and cerebral edema. Data analysis occurred from October 2017 to June 2018. MAIN OUTCOMES AND MEASURES Early neonatal epileptic encephalopathy with glutaminase deficiency and lethal outcome. RESULTS A total of 4 infants from 2 unrelated families, each of whom died less than 40 days after birth, were included. We identified a homozygous frameshift variant p.(Asp232Glufs*2) in GLS in the first family, as well as compound heterozygous variants p.(Gln81*) and p.(Arg272Lys) in GLS in the second family. The GLS gene encodes glutaminase (Enzyme Commission 3.5.1.2), which plays a major role in the conversion of glutamine into glutamate, the main excitatory neurotransmitter of the central nervous system. All 3 variants probably lead to a loss of function and thus glutaminase deficiency. Indeed, glutamine was increased in affected children (available z scores, 3.2 and 11.7). We theorize that the potential reduction of glutamate and the excess of glutamine were a probable cause of the described physiological and structural abnormalities of the central nervous system. CONCLUSIONS AND RELEVANCE We identified a novel autosomal recessive neurometabolic disorder of loss of function of glutaminase that leads to lethal early neonatal encephalopathy. This inborn error of metabolism underlines the importance of GLS for appropriate glutamine homeostasis and respiratory regulation, signal transduction, and survival.
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 glutaminase 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 almost undetectable, using ultra-high field magnetic resonance spectroscopic imaging. 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.
HCoV-NL63 is a recently identified respiratory virus. Its pathogenesis has not been fully unraveled because an animal model is currently lacking. Here we examined whether rhesus macaques encounter HCoV-NL63 infections during life, by examining the levels of antibodies to HCoV-NL63 in time. The animals were followed for 7 up till 19 years, and in three animals we observed a steep rise in antibodies during follow up, indicative of a natural infection with HCoV-NL63.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.