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GPR37L1 modulates seizure susceptibility: Evidence from mouse studies and analyses of a human GPR37L1 variant.
- Source :
-
Neurobiology of disease [Neurobiol Dis] 2017 Oct; Vol. 106, pp. 181-190. Date of Electronic Publication: 2017 Jul 06. - Publication Year :
- 2017
-
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.<br /> (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Subjects :
- Adolescent
Animals
Brain physiopathology
Child
Female
Genetic Variation
HEK293 Cells
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Myoclonic Epilepsies, Progressive genetics
NIH 3T3 Cells
Receptors, G-Protein-Coupled genetics
Receptors, G-Protein-Coupled metabolism
Seizures genetics
Young Adult
Genetic Predisposition to Disease
Myoclonic Epilepsies, Progressive metabolism
Receptors, G-Protein-Coupled deficiency
Seizures metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1095-953X
- Volume :
- 106
- Database :
- MEDLINE
- Journal :
- Neurobiology of disease
- Publication Type :
- Academic Journal
- Accession number :
- 28688853
- Full Text :
- https://doi.org/10.1016/j.nbd.2017.07.006