Alternative titles; symbolsENDOTHELIN TYPE B RECEPTOR-LIKE PROTEIN 2; ETBRLP2HGNC Approved Gene Symbol: GPR37L1Cytogenetic location: 1q32.1 Genomic coordinat...
Alternative titles; symbols
HGNC Approved Gene Symbol: GPR37L1
Cytogenetic location: 1q32.1 Genomic coordinates (GRCh38): 1:202,118,668-202,133,591 (from NCBI)
GPR37L1 is a G protein-coupled receptor expressed predominantly in the brain, with highest expression in astrocytes and Bergmann glia. GPR37L1 is predicted to influence neuronal development and function (Marazziti et al., 2013).
▼ Cloning and Expression
By searching an EST database for sequences similar to endothelin receptor B (EDNRB 131244), followed by PCR of a human brain cDNA library and screening a caudate nucleus cDNA library, Valdenaire et al. (1998) cloned GPR37 (602583) and GPR37L1, which they called ETBRLP and ETBRLP2, respectively. The deduced 481-amino acid ETBRLP2 protein has characteristics of a G protein-coupled receptor, including an N-terminal signal sequence, 7 putative transmembrane domains, 2 cysteines in the first 2 extracellular loops, an aspartic acid in transmembrane domain 2, and a D/ERY/F motif in cytoplasmic loop 2. It also has an N-glycosylation site, a potential phosphorylation site, and a C-terminal cluster of cysteines that may be palmitoylated. ETBRLP2 shares 48% identity with ETBRLP. Northern blot analysis detected high expression of a 2.8-kb ETBRLP2 transcript in brain only. Transcripts of 4.5 and 7.5 kb were also detected in brain only. Similar ETBRLP2 transcripts was detected in cerebellum, cortex, medulla, spinal cord, and putamen, and in occipital, frontal, and temporal lobes. In situ hybridization detected ETBRLP2 in cerebellar Bergmann glia of the Purkinje cell layer, in internal capsule fibers of caudate putamen, and in temporal cortex.
Using immunohistochemical analysis, Marazziti et al. (2013) found that Gpr37l1 localized to basal membrane of primary cilia in Bergmann glia cells in newborn and adult mouse cerebellum.
Using confocal microscopy, Giddens et al. (2017) detected fluorescence-tagged human GPR37L1 expressed on the cell surface of mouse NIH-3T3 fibroblasts.
▼ Gene Function
Using mouse cerebellar lysates, Marazziti et al. (2013) found that Gpr37l1 coimmunoprecipitated with the Shh (600725) signaling component Ptch1 (601309).
By screening orphan neuropeptides for ligands that bound epitope-tagged GPR37 and GPR37L1, Meyer et al. (2013) identified prosaptide, a synthetic peptide designed to functionally mimic the neuroprotective region of prosaposin (PSAP; 176801) (Meyer et al., 2014). Full-length prosaposin also bound both receptors, and both receptors were internalized following ligand binding. Both prosaposin and prosaptide induced Erk (see 601795) phosphorylation and protected primary mouse cortical astrocytes against oxidative stress. Knockdown of Gpr37 or Gpr37l1 via short interfering RNA attenuated the protective effect.
Coleman et al. (2016) stated that human cerebrospinal fluid contains N-terminal fragments of GPR37L1. Using transfected HEK293 cells, they found that fluorescence-tagged GPR37L1 was N-terminally processed by an enzyme sensitive to a nonspecific ADAM-type (see 601533) metalloprotease inhibitor. The remainder of the protein was expressed on the cell surface. Full-length GPR37L1 stimulated cAMP production via Gs-alpha (GNAS; 139320) in a constitutive manner, and N-terminal processing, or deletion of 122 N-terminal residues, inactivated the receptor. Gpr37l1 was also rapidly processed and inactivated in mouse and rat cerebellum and cerebellar organotypic cultures, and Gpr37l1 inactivation was attenuated by a metalloprotease inhibitor.
Hartz (2017) mapped the GPR37L1 gene to chromosome 1q32.1 based on an alignment of the GPR37L1 sequence (GenBank Y16280) with the genomic sequence (GRCh38).
▼ Molecular Genetics
Associations Pending Confirmation
For discussion of a possible association between progressive myoclonic epilepsy (see, e.g., EPM1A, 254800) and variation in the GPR37L1 gene, see 617630.0001.
▼ Animal Model
Marazziti et al. (2013) found that adult Gpr37l1 -/- mice appeared normal, were fertile, and showed no abnormality in cerebellar cytoanatomy and organization. However, ablation of Gpr37l1 prematurely inhibited proliferation in granule neuron precursors and caused precocious maturation of Bergmann glia and Purkinje neurons, with enhanced elaboration of Purkinje dendritic trees and greater alignment of Purkinje cell bodies. Gpr37l1 -/- cerebella exhibited early activation of the Shh-mediated mitogenic pathway. Gpr37l1 -/- mice showed early eye opening, and Gpr37l1 -/- males showed improved motor coordination and learning compared with wildtype.
Giddens et al. (2017) found that knockout of Gpr37l1 or Gpr37 in mice variably increased their sensitivity to seizure-inducing stimuli. Knockout of both genes had an additive effect.
▼ ALLELIC VARIANTS ( 1 Selected Example):
.0001 VARIANT OF UNKNOWN SIGNIFICANCE
This variant is classified as a variant of unknown significance because its contribution to progressive myoclonic epilepsy (see, e.g., EPM1A, 254800) has not been confirmed.
In a girl, born of consanguineous Iraqi parents, with progressive myoclonic epilepsy, Giddens et al. (2017) identified a heterozygous c.1047G-T transversion (c.1047G-T, NM_004767.3) in the GPR37L1 gene, resulting in a lys349-to-asn (K349N) substitution in the third intracellular loop. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was heterozygous in the unaffected parents. The variant was not found in 3,970 in-house control exomes, but was found in heterozygous state at a low frequency (0.002%) in the ExAC database. There were 5 additional deceased family members with a similar disorder, although DNA was not available. These affected individuals presented around the age of puberty with recurrent headaches, visual hallucinations, seizures, and EEG abnormalities, followed by progressive myoclonic epilepsy and cognitive decline, resulting in death in young adulthood. Two younger brothers of the proband were also homozygous for the variant: both had recurrent headaches and 1 also had visual hallucinations, suggesting that they were similarly affected. In vitro functional expression studies in HEK293 cells showed that the variant receptor had normal expression, surface trafficking, and localization, and did not alter signaling when compared to wildtype.