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The neuronal glycine transporter GlyT2 in herplexia: a glycinergic pathology of development

20th national competition for scientific and technical research

Rare diseases

Senior Researcher : Beatriz López Corcuera

Research Centre or Institution : Centro de Biología Molecular Severo Ochoa. CSIC - UAM


Hyperekplexia (OMIM 149400) is a syndrome of great perinatal clinical relevance. Neonates suffer energic and sustained startle in response to trivial stimuli, generally tactile or acoustic, which can cause sudden death due to apnea. The disease is caused by total or partial blockade of inhibitory glycinergic neurotransmission. Some mutations in the neuronal glycine transporter GlyT2 gene (SLC6A5) are the second most common cause of human hyperekplexia. In this project, we analyze the repercussions of mutations in GlyT2 found in hyperekplexia patients on the three-dimensional structure of the transporter protein, its intracellular traffic and its possible role in the development of glycinergic neurotransmission. The first objective of the project is the identification and characterization of new mutations in GlyT2 in patients with diagnosed hyperekplexia. 

We have identified a new variant of GlyT2 in a child patient with hyperekplexia that we are characterizing. It is an inactive transporter blocked in its cell processing and whose intracellular traffic is defective. To undertake the second objective, the study of the effects of mutations on the structure of the transporter, we use our new model of the three-dimensional structure of GlyT2 in which we have located some regions in the protein that are susceptible to pharmacological intervention on its folding. We have also found some small ligands able to rescue the phenotype of some mutants with trafficking defects expressed in primary neurons. As the third objective, we have initiated the study of the effect of hyperekplexia mutations on signaling pathways controling the perinatal development of GlyT2 both in differentiated PC12 cells and in primary neurons. To understand the contribution of development, where symptoms are most evident, to human hyperekplexia phenotypes, we will use the zebrafish system.  The knowledge of the causes of inactivity of GlyT2 mutants or its developmental consequences will guide future therapeutic approaches.


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