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Author Notes:

Correspondence: rhall3@emory.edu

We would like to acknowledge the family for their participation in this study.

Subject:

Research Funding:

This work was supported by grants R01-NS088413 and R21-NS091986 (RAH), R01-NS090319 (AE), and T32-NS00748016 (JCW) from the National Institutes of Health.

This study was also supported in part by the Emory University Integrated Cellular Imaging Microscopy Core and the Emory Rodent Behavioral Core, which are subsidized by the Emory University School of Medicine and are part of the Emory Integrated Core Facilities.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • Brain
  • Epilepsy
  • Disease
  • Receptors
  • Mutation
  • Mutant
  • Orphan GPCR
  • PROGRESSIVE MYOCLONUS EPILEPSY
  • PROTEIN-COUPLED RECEPTORS
  • PARKINSONS-DISEASE
  • MICE LACKING
  • PAEL RECEPTOR
  • MUTATIONS
  • NEURONS
  • BRAIN
  • TRANSCRIPTOME
  • TRAFFICKING

GPR37L1 modulates seizure susceptibility: Evidence from mouse studies and analyses of a human GPR37L1 variant

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Journal Title:

Neurobiology of Disease

Volume:

Volume 106

Publisher:

, Pages 181-190

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Progressive myoclonus epilepsies (PMEs) are disorders characterized by myoclonic and generalized seizures with progressive neurological deterioration. While several genetic causes for PMEs have been identified, the underlying causes remain unknown for a substantial portion of cases. Here we describe several affected individuals from a large, consanguineous family presenting with a novel PME in which symptoms begin in adolescence and result in death by early adulthood. Whole exome analyses revealed that affected individuals have a homozygous variant in GPR37L1 (c.1047G > T [Lys349Asn]), an orphan G protein-coupled receptor (GPCR) expressed predominantly in the brain. In vitro studies demonstrated that the K349N substitution in Gpr37L1 did not grossly alter receptor expression, surface trafficking or constitutive signaling in transfected cells. However, in vivo studies revealed that a complete loss of Gpr37L1 function in mice results in increased seizure susceptibility. Mice lacking the related receptor Gpr37 also exhibited an increase in seizure susceptibility, while genetic deletion of both receptors resulted in an even more dramatic increase in vulnerability to seizures. These findings provide evidence linking GPR37L1 and GPR37 to seizure etiology and demonstrate an association between a GPR37L1 variant and a novel progressive myoclonus epilepsy.

Copyright information:

© 2017 Elsevier Inc.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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