Gpr37l1 Modulates Seizure Susceptibility: Evidence from Mouse Studies and Analyses of a Human Gpr37l1 Variant

Authors

Michelle M. Giddens, Emory University School of Medicine
Jennifer C. Wong, Emory University School of Medicine
Jason P. Schroeder, Emory University School of Medicine
Emily G. Farrow, Children's Mercy Hospitals and Clinics
Brilee M. Smith, Emory University School of Medicine
Sharon Owino, Emory University School of MedicineFollow
Sarah E. Soden, Children's Mercy Hospitals and Clinics
Rebecca C. Meyer, Emory University School of Medicine
Carol Saunders, Children's Mercy Hospitals and Clinics
J. B. LePichon, Children's Mercy Hospitals and Clinics
David Weinshenker, Emory University School of Medicine
Andrew Escayg, Emory University School of Medicine
Randy A. Hall, Emory University School of Medicine

Document Type

Article

Publication Date

10-1-2017

Publication Title

Neurobiology of Disease

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.

Keywords

Brain, Disease, Epilepsy, Mutant, Mutation, Orphan GPCR, Receptors

Volume

106

First Page

181

Last Page

190

DOI

10.1016/j.nbd.2017.07.006

ISSN

09699961

Comments

Peer reviewed accepted manuscript.

Recommended Citation

Giddens, Michelle M.; Wong, Jennifer C.; Schroeder, Jason P.; Farrow, Emily G.; Smith, Brilee M.; Owino, Sharon; Soden, Sarah E.; Meyer, Rebecca C.; Saunders, Carol; LePichon, J. B.; Weinshenker, David; Escayg, Andrew; and Hall, Randy A., "Gpr37l1 Modulates Seizure Susceptibility: Evidence from Mouse Studies and Analyses of a Human Gpr37l1 Variant" (2017). Neuroscience: Faculty Publications, Smith College, Northampton, MA.
https://scholarworks.smith.edu/nsc_facpubs/58