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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 rare clinical syndrome characterized by exaggerated startle responses and neonatal hypertonia that can be lethal in neonates. It is caused by loss of function mutations in crucial proteins for glycinergic neurotransmission, such as the neuronal glycine transporter GlyT2 (SLC6A5 gene). This year we have continued with the characterization of the newly identified variant of GlyT2 in a child patient with hyperekplexia in the United Kingdom. We have advanced by demonstrating an increased interaction of the mutant with the chaperone calnexin in the endoplasmic reticulum, from where it is abundantly degraded. Through differential labeling and coexpression of wild type and mutant transporters, we have verified that the wild type traffic is not altered, ruling out a dominant negative action. For the rescue of this and other hyperekplexia mutants we are using the ligands we previously established as chemical chaperones. Another objective led us to recognize that a serine protease (and not calpain) is responsible for the differential proteolysis of another hyperekplexia variant, which generates a N-terminal fragment able to prevent certain GlyT2 interactions. Finally, to study the effect of hyperekplexia mutations on signaling pathways which control the perinatal GlyT2 development, we studied the signaling cascades that affect GlyT2 colocalization with the neuronal differentiation marker protein Gap43 in PC12 cells differentiated using NGF. We also study how these cascades regulate GlyT2 in primary neurons. The regulation of GlyT2 by the hedgehog pathway evidenced by our group has been extended to selected mutants with alterations in ubiquitination in primary neurons to evaluate possible defects in this regulation. This project will lead us to discover the contribution of development to human hyperekplexia phenotypes in several experimental systems that we finally want to evaluate in an in vivo system such as zebrafish.


Scientific Production
Magazine Articles 1
Communications at national conferences 3
Communications at international conferences 2


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