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

NEUROBIOLOGY OF DISEASE

卷:106

Article

Giddens, Michelle M.¹  Wong, Jennifer C.²  Schroeder, Jason P.²  Farrow, Emily G.³  Smith, Brilee M.¹  Owino, Sharon¹  Soden, Sarah E.³  Meyer, Rebecca C.^1,4  Saunders, Carol³  LePichon, J. B.³  Weinshenker, David²  Escayg, Andrew²  Hall, Randy A.¹ 

[1] Emory Univ, Sch Med, Dept Pharmacol, Atlanta, GA 30322 USA

[2] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA

[3] Childrens Mercy Hosp, Ctr Pediat Genom Med, Kansas City, MO 64108 USA

[4] Harvard Med Sch, Dept Cell Biol, Boston, MA USA

关键词: Brain;    Epilepsy;    Disease;    Receptors;    Mutation;    Mutant;    Orphan GPCR;   

DOI  :  10.1016/j.nbd.2017.07.006

来源: Elsevier

【 摘 要 】

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. (C) 2017 Elsevier Inc. All rights reserved.

【 授权许可】

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