Increased glycine contributes to synaptic dysfunction and early mortality in Nprl2 seizure model

Dentel, Brianne; Angeles-Perez, Lidiette; Ren, Cheng; Jakkamsetti, Vikram; Holley, Andrew J.; Caballero, Daniel; Oh, Emily; Gibson, Jay R.; Pascual, Juan M.; Huber, Kimberly M.; Tu, Benjamin P.; Tsai, Peter T.

doi:10.1016/j.isci.2022.104334

Cited by 5 publications

(1 citation statement)

References 97 publications

(146 reference statements)

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“…36 Accordingly, altered glycine metabolism is implicated in various neurodevelopmental defects. [37][38][39][40] Furthermore, increased levels of glycine and serine were detected in the plasma samples of individuals with Rett syndrome (RTT; MIM #312750), a condition including epilepsy, microcephaly and DD/ID among cardinal clinical features. 41 GLDC, encoding the glycine decarboxylase, one of the four proteins forming the mitochondrial glycine cleavage system (GCS), and GAMT, encoding the guanidinoacetate Nmethyltransferase, were among the top downregulated genes in the RNA-seq analysis.…”

Section: Discussionmentioning

confidence: 99%

Further evidence supporting the role of GTDC1 in glycine metabolism and neurodevelopmental disorders

Bonaglia,

Errichiello,

Lecca

et al. 2023

Preprint

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Copy number variants (CNVs) represent the genetic cause of about 15–20% of neurodevelopmental disorders (NDDs). We identified a ~ 67 kb de novo intragenic deletion on chromosome 2q22.3 in a female individual showing a developmental encephalopathy characterized by epilepsy, severe intellectual disability, speech delay, microcephaly, and thin corpus callosum with facial dysmorphisms. The microdeletion involved exons 5–6 of GTDC1, encoding a putative glycosyltransferase, whose expression is particularly enriched in the nervous system. In a previous study, a balanced de novo translocation encompassing GTDC1 was reported in a male child with global developmental delay and delayed speech and language development. Based on these premises, we explored the transcriptomic profile of our proband to evaluate the functional consequences of the novel GTDC1 de novo intragenic deletion in relation to the observed neurodevelopmental phenotype. RNA-seq on the proband’s lymphoblastoid cell line (LCL) showed expression changes of glycine/serine and cytokine/chemokine signalling pathways, which are related to neurodevelopment and epileptogenesis. Subsequent analysis by ELISA (enzyme-linked immunosorbent assay) and HPLC (high-performance liquid chromatography) revealed increased levels of glycine in the proband’s LCL and serum compared to matched controls. Given that an increased level of glycine has been observed in the plasma samples of individuals with Rett syndrome, a condition sharing epilepsy, microcephaly, and intellectual disability with our proband, we proposed that the GTDC1 downregulation is implicated in neurodevelopmental impairment by altering glycine metabolism. Furthermore, our findings expanded the phenotypic spectrum of the novel GTDC1-related condition, including microcephaly and epilepsy among relevant clinical features.

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