Very Large G Protein-coupled Receptor-1, the Largest Known Cell Surface Protein, Is Highly Expressed in the Developing Central Nervous System

Abstract

We previously identified a member of the G proteincoupled receptor family, very large G protein-coupled receptor-1 (VLGR1). VLGR1 has a large ectodomain containing multiple calcium exchanger ␤ repeats that resemble regulatory domains of sodium-calcium exchanger proteins. Similar repeats are found in the extracellular aggregation factor of marine sponges, which mediates species-specific cell aggregation. We now report that the protein encoded by the originally described human cDNA (now termed VLGR1a) is, in fact, at 1967 amino acids, the smallest of three expressed human isoforms. It is encoded by an alternative transcript that begins within intron 64 of the VLGR1 gene. The longest gene product, VLGR1b, is 6307 amino acids (6298 amino acids in mice) due to a much larger ectodomain containing 35 calcium exchanger ␤ repeats and a pentraxin homology domain. VLGR1b is apparently the largest known cell surface protein. The VLGR1 gene comprises 90 exons and is >600 kb long. In situ hybridization studies with mouse embryo sections show that high level expression of VLGR1 is restricted to the developing central nervous system and eye. Strong expression in the ventricular zone, home of neural progenitor cells during embryonal neurogenesis, suggests a fundamental role for VLGR1 in the development of the central nervous system.

A novel microdeletion syndrome involving 5q14.3-q15: clinical and molecular cytogenetic characterization of three patients

“…20 Mouse embryos show a high level of expression restricted to the eyes and the developing CNS, particularly in the ventricular zone, home of neural progenitor cells during embryonal neurogenesis. 21 GPR98/MASS1, a known epilepsy gene, contains both the epilepsy-associated repeat (EAR) and the epitempin (EPTP) repeat. 22 GPR98/MASS1 knockout mice show audiogenic seizure susceptibility.…”

The Very Large G-Protein-Coupled Receptor VLGR1: A Component of the Ankle Link Complex Required for the Normal Development of Auditory Hair Bundles

“…The threedimensional structure of a Calx-␤ repeat has yet to be solved, but each contains ϳ120 amino acids and would have a diameter of ϳ4 nm if assumed to be approximately globular. The Vlgr1 ectodomain has 35 Calx-␤ repeats and an estimated length of ϳ180 nm (McMillan et al, 2002) so it could readily span the gap of ϳ150 nm present between adjacent stereocilia in the ankle link region.…”

“…It was identified as a large, Concanavalin A (ConA) reactive glycoprotein using a monoclonal antibody (mAb) generated from a mouse immunized with a crude membrane fraction derived from the sensory organs of the chick inner ear . In this study, we identify the ALA as the avian ortholog of the very large G-protein-coupled receptor VLGR1, the largest known cell-surface protein (McMillan et al, 2002) and a product of the Usher syndrome 2C locus (Weston et al, 2004). Usher syndrome consists of sensorineural deafness, retinitis pigmentosa, and, in some forms, vestibular dysfunction.…”

Vlgr1 is required for proper stereocilia maturation of cochlear hair cells

“…Vlgr1b, whose mRNA is approximately 19 kb in size, is one of the G-protein coupled receptors with a huge extracellular domain in which there are many Calx-β domains, potential calcium binding domains, as inferred from the deduced amino acid sequence. We identified two alternative splicing variants, Vlgr1d and Vlgr1e, and made Vlgr1 knockout mice that lost the functional products of Vlgr1b, Vlgr1d, Vlgr1e and Vlgr1c, which is another alternative splicing variant of Vlgr1 (McMillan et al 2002;Yagi et al 2005). Mass1, which is one of the Vlgr1 alternative splicing variants, was reported to be the gene responsible for the susceptibility to audiogenic seizure of Frings mice (Skradski et al 2001).…”

“…Among them, Usher type 2C patients have been shown to have atrophic changes in the organ of Corti, and mutations in the very large G-protein coupled receptor 1 (( VLGR1 ), also named MGR1) locus (also called the mass1 locus) are highly likely to be involved in the pathogenesis of Usher type 2C syndrome (Weston et al 2004). Several splicing variants are transcribed from the Vlgr1 locus, the longest of which is Vlgr1b (McMillan et al 2002;Yagi et al 2005). Vlgr1b, whose mRNA is approximately 19 kb in size, is one of the G-protein coupled receptors with a huge extracellular domain in which there are many Calx-β domains, potential calcium binding domains, as inferred from the deduced amino acid sequence.…”