title: Loss of Glycine Transporter 1 Causes a Subtype of Glycine Encephalopathy with Arthrogryposis and Mildly Elevated Cerebrospinal Fluid Glycine.
abstract: Glycine is a major neurotransmitter that activates inhibitory glycine receptors and is a co-agonist for excitatory glutamatergic N-methyl-D-aspartate (NMDA) receptors. Two transporters, GLYT1 and GLYT2, regulate extracellular glycine concentrations within the CNS. Dysregulation of the extracellular glycine has been associated with hyperekplexia and nonketotic hyperglycinemia. Here, we report four individuals from two families who presented at birth with facial dysmorphism, encephalopathy, arthrogryposis, hypotonia progressing to hypertonicity with startle-like clonus, and respiratory failure. Only one individual survived the respiratory failure and was weaned off ventilation but has significant global developmental delay. Mildly elevated cerebrospinal fluid (CSF) glycine and normal serum glycine were observed in two individuals. In both families, we identified truncating mutations in SLC6A9, encoding GLYT1. We demonstrate that pharmacologic or genetic abolishment of GlyT1 activity in mice leads to mildly elevated glycine in the CSF but not in blood. Additionally, previously reported slc6a9-null mice and zebrafish mutants also display phenotypes consistent with the affected individuals we examined. Our data suggest that truncating SLC6A9 mutations lead to a distinct human neurological syndrome hallmarked by mildly elevated CSF glycine and normal serum glycine.
authors: The Genetics Institute, Rambam Health Care Campus, Haifa 3109601, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 3525433, Israel.
authors: Alina
authors: A
authors: Kurolap
authors: Institute of Biochemistry, University of Erlangen-Nuremberg, Erlangen 91054, Germany.
authors: Anja
authors: A
authors: Armbruster
authors: The Genetics Institute, Rambam Health Care Campus, Haifa 3109601, Israel.
authors: Tova
authors: T
authors: Hershkovitz
authors: Institute of Biochemistry, University of Erlangen-Nuremberg, Erlangen 91054, Germany.
authors: Katharina
authors: K
authors: Hauf
authors: The Genetics Institute, Rambam Health Care Campus, Haifa 3109601, Israel.
authors: Adi
authors: A
authors: Mory
authors: The Genetics Institute, Rambam Health Care Campus, Haifa 3109601, Israel.
authors: Tamar
authors: T
authors: Paperna
authors: Institute of Biochemistry, University of Erlangen-Nuremberg, Erlangen 91054, Germany.
authors: Ewald
authors: E
authors: Hannappel
authors: Metabolic Unit, Rambam Health Care Campus, Haifa 3109601, Israel.
authors: Galit
authors: G
authors: Tal
authors: Pediatric and Neonatal Unit, EMMS Nazareth Hospital, Nazareth 1607907, Israel.
authors: Yusif
authors: Y
authors: Nijem
authors: Pediatric and Neonatal Unit, EMMS Nazareth Hospital, Nazareth 1607907, Israel.
authors: Ella
authors: E
authors: Sella
authors: The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 3525433, Israel; Child Neurology and Development Center, Hillel Yaffe Medical Center, Hadera 3810101, Israel.
authors: Muhammad
authors: M
authors: Mahajnah
authors: The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 3525433, Israel; Pediatric Radiology Unit, Radiology Department, Rambam Health Care Campus, Haifa 3109601, Israel.
authors: Anat
authors: A
authors: Ilivitzki
authors: The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 3525433, Israel; Department of Pathology, Rambam Health Care Campus, Haifa 3109601, Israel.
authors: Dov
authors: D
authors: Hershkovitz
authors: The Genetics Institute, Rambam Health Care Campus, Haifa 3109601, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 3525433, Israel.
authors: Nina
authors: N
authors: Ekhilevitch
authors: The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 3525433, Israel; Metabolic Unit, Rambam Health Care Campus, Haifa 3109601, Israel.
authors: Hanna
authors: H
authors: Mandel
authors: Institute of Biochemistry, University of Erlangen-Nuremberg, Erlangen 91054, Germany. Electronic address: volker.eulenburg@fau.de.
authors: Volker
authors: V
authors: Eulenburg
authors: The Genetics Institute, Rambam Health Care Campus, Haifa 3109601, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 3525433, Israel. Electronic address: hb_feldman@rambam.health.gov.il.
authors: Hagit N
authors: HN
authors: Baris
mesh_terms: D000818:Animals; D001176:Arthrogryposis / Q000175:diagnosis / Q000235:genetics*; D002675:Child, Preschool; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005998:Glycine / Q000097:blood / Q000134:cerebrospinal fluid*; D050487:Glycine Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020158:Hyperglycinemia, Nonketotic / Q000175:diagnosis / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010375:Pedigree
chemical_list: D050487:Glycine Plasma Membrane Transport Proteins; C493271:SLC6A5 protein, human; C493268:SLC6A9 protein, human; D005998:Glycine
keywords: GLYT1; Glycine transporter; SLC6A9; arthrogryposis; encephalopathy; hypertonicity; hypotonia; respiratory failure