Glycine decarboxylase deficiency-induced motor dysfunction in zebrafish is rescued by counterbalancing glycine synaptic level

• Published in: JCI insight 2018-11, Vol.3 (21)
• Main Authors: Riché, Raphaëlle, Liao, Meijiang, Pena, Izabella A, Leung, Kit-Yi, Lepage, Nathalie, Greene, Nicolas DE, Sarafoglou, Kyriakie, Schimmenti, Lisa A, Drapeau, Pierre, Samarut, Éric
• Format: Article
• Language: English
• Subjects: Animals; Brain - diagnostic imaging; Brain - metabolism; Brain - physiopathology; CRISPR-Associated Protein 9 - metabolism; Dextromethorphan - administration & dosage; Dextromethorphan - therapeutic use; Excitatory Amino Acid Antagonists - therapeutic use; Fatal Outcome; Female; Food Preservatives - therapeutic use; Glycine - blood; Glycine - cerebrospinal fluid; Glycine Dehydrogenase (Decarboxylating) - deficiency; Glycine Dehydrogenase (Decarboxylating) - metabolism; Humans; Hyperglycinemia, Nonketotic - diagnosis; Hyperglycinemia, Nonketotic - enzymology; Hyperglycinemia, Nonketotic - genetics; Infant, Newborn; Male; Middle Aged; Motor Disorders - enzymology; Motor Disorders - physiopathology; Mutation; Phenotype; Sodium Benzoate - administration & dosage; Sodium Benzoate - therapeutic use; Synaptic Transmission - drug effects; Treatment Outcome; Zebrafish
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.124642

Glycine encephalopathy (GE), or nonketotic hyperglycinemia (NKH), is a rare recessive genetic disease caused by defective glycine cleavage and characterized by increased accumulation of glycine in all tissues. Here, based on new case reports of GLDC loss-of-function mutations in GE patients, we aimed to generate a zebrafish model of severe GE in order to unravel the molecular mechanism of the disease. Using CRISPR/Cas9, we knocked out the gldc gene and showed that gldc-/- fish recapitulate GE on a molecular level and present a motor phenotype reminiscent of severe GE symptoms. The molecular characterization of gldc-/- mutants showed a broad metabolic disturbance affecting amino acids and neurotransmitters other than glycine, with lactic acidosis at stages preceding death. Although a transient imbalance was found in cell proliferation in the brain of gldc-/- zebrafish, the main brain networks were not affected, thus suggesting that GE pathogenicity is mainly due to metabolic defects. We confirmed that the gldc-/- hypotonic phenotype is due to NMDA and glycine receptor overactivation, and demonstrated that gldc-/- larvae depict exacerbated hyperglycinemia at these synapses. Remarkably, we were able to rescue the motor dysfunction of gldc-/- larvae by counterbalancing pharmacologically or genetically the level of glycine at the synapse.