Loss of Glycine Transporter 1 Causes a Subtype of Glycine Encephalopathy with Arthrogryposis and Mildly Elevated Cerebrospinal Fluid Glycine

Alina Kurolap, Anja Armbruster, Tova Hershkovitz, Katharina Hauf, Adi Mory, Tamar Paperna, Ewald Hannappel, Galit Tal, Yusif Nijem, Ella Sella, Muhammad Mahajnah, Anat Ilivitzki, Dov Hershkovitz, Nina Ekhilevitch, Hanna Mandel, Volker Eulenburg*, Hagit N. Baris

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1172-1180
Number of pages9
JournalAmerican Journal of Human Genetics
Volume99
Issue number5
DOIs
StatePublished - 3 Nov 2016
Externally publishedYes

Keywords

  • GLYT1
  • Glycine transporter
  • SLC6A9
  • arthrogryposis
  • encephalopathy
  • hypertonicity
  • hypotonia
  • respiratory failure

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