Mutations in the large GPR98 gene underlie Usher syndrome type 2C (USH2C), and all patients described to date have been female. It was speculated that GPR98 mutations cause a more severe, and eventually lethal, phenotype in males. We describe for the first time two male patients with USH2 with novel GPR98 mutations. Clinical characterization of a male patient and his affected sister revealed a typical USH2 phenotype in both. GPR98 may have been excluded from systematic investigation in previous studies, and the proportion of patients with USH2C probably underestimated. GPR98 should be considered in patients with USH2 of both sexes.
"Vlgr1 (USH2C) mutations account for 6.4 % in all USH2 mutations (Besnard et al. 2012). Several mutations of Vlgr1 gene have been shown to associate with USH2C, including F112fsX29, P522fsX8, Q753fsX8, K1786fsX8, Q2301X, I2906fsX6, M2931fsX11, V3363fsX11, E4186fsX17, E4321X, M5890fsX10, Y6044C, A6216fsX13, and Y6244fsX1 (Figs. 1b and 2a; Bonnet et al. 2011; Ebermann et al. 2009; Hmani-Aifa et al. 2009; Weston et al. 2004). A large deletion of 136 kb spanning exons 84 and 85 was also shown to associate with USH2C (Hilgert et al. 2009). "
[Show abstract][Hide abstract] ABSTRACT: The very large G protein coupled receptor (Vlgr1) is a member of adhesion receptors or large N-terminal family B-7 transmembrane helixes (LNB7TM) receptors within the seven trans-membrane receptor superfamily. Vlgr1 is the largest GPCR identified to date; its mRNA spans 19 kb and encodes 6,300 amino acids. Vlgr1 is a core component of ankle-link complex in inner ear hair cells. Knock-out and mutation mouse models show that loss of Vlgr1 function leads to abnormal stereociliary development and hearing loss, indicating crucial roles of Vlgr1 in hearing transduction or auditory system development. Over the past 10 or so years, human genetics data suggested that Vlgr1 mutations cause Usher syndromes and seizures. Although significant progresses have been made, the details of Vlgr1's function in hair cells, its signaling cascade, and the mechanisms underlying causative effects of Vlgr1 mutations in human diseases remain elusive and ask for further investigation.
"GPR126 has been reported to play an essential role for peripheral nerve development and myelination in mammals ; its limited expression in the ileum and colon could suggest an involvement in myelination of neurons of the myenteric plexuses crucial for GI motility, or submucosal plexuses, which regulate luminal and epithelial cell function. Mutations on VLGR1 are known to underlie human Usher syndrome type II . The complex extracellular domain of the VLGR1 receptor, with a Calx-β cation binding motif, has led to a suggested role in the sensing of Ca2+. "
[Show abstract][Hide abstract] ABSTRACT: Background
G protein-coupled receptors (GPCRs) represent one of the largest families of transmembrane receptors and the most common drug target. The Adhesion subfamily is the second largest one of GPCRs and its several members are known to mediate neural development and immune system functioning through cell-cell and cell-matrix interactions. The distribution of these receptors has not been characterized in detail in the gastrointestinal (GI) tract. Here we present the first comprehensive anatomical profiling of mRNA expression of all 30 Adhesion GPCRs in the rat GI tract divided into twelve subsegments.
Using RT-qPCR, we studied the expression of Adhesion GPCRs in the esophagus, the corpus and antrum of the stomach, the proximal and distal parts of the duodenum, ileum, jejunum and colon, and the cecum.
We found that twenty-one Adhesion GPCRs (70%) had a widespread (expressed in five or more segments) or ubiquitous (expressed in eleven or more segments) distribution, seven (23%) were restricted to a few segments of the GI tract and two were not expressed in any segment. Most notably, almost all Group III members were ubiquitously expressed, while the restricted expression was characteristic for the majority of group VII members, hinting at more specific/localized roles for some of these receptors.
Overall, the distribution of Adhesion GPCRs points to their important role in GI tract functioning and defines them as a potentially crucial target for pharmacological interventions.
"Recent studies indicate emerging physiological and pathological roles for these GPS-containing membrane proteins in cancer (Kan et al, 2010), PKD (Qian et al, 2002), brain development (Piao et al, 2004), myelination of neurons (Monk et al, 2009), central nervous system angiogenesis (Kuhnert et al, 2010), attention-deficit/hyperactivity disorder (Arcos-Burgos et al, 2010), cell polarity in neural development (Chae et al, 1999; Usui et al, 1999; Shima et al, 2004; Langenhan et al, 2009), Usher syndrome 2 (Ebermann et al, 2009), mouse male infertility (Davies et al, 2004), and immunity (see Yona et al, 2008 for a review), but the mechanism of GPS-mediated autoproteolysis remains unclear. Cell-adhesion GPCRs are characterized by long N-terminal extracellular sequences comprising multiple domains, and constitute a poorly studied class of GPCRs that is the second largest family of GPCRs in humans (Fredriksson et al, 2003). "
[Show abstract][Hide abstract] ABSTRACT: The G protein-coupled receptor (GPCR) Proteolysis Site (GPS) of cell-adhesion GPCRs and polycystic kidney disease (PKD) proteins constitutes a highly conserved autoproteolysis sequence, but its catalytic mechanism remains unknown. Here, we show that unexpectedly the ∼40-residue GPS motif represents an integral part of a much larger ∼320-residue domain that we termed GPCR-Autoproteolysis INducing (GAIN) domain. Crystal structures of GAIN domains from two distantly related cell-adhesion GPCRs revealed a conserved novel fold in which the GPS motif forms five β-strands that are tightly integrated into the overall GAIN domain. The GAIN domain is evolutionarily conserved from tetrahymena to mammals, is the only extracellular domain shared by all human cell-adhesion GPCRs and PKD proteins, and is the locus of multiple human disease mutations. Functionally, the GAIN domain is both necessary and sufficient for autoproteolysis, suggesting an autoproteolytic mechanism whereby the overall GAIN domain fine-tunes the chemical environment in the GPS to catalyse peptide bond hydrolysis. Thus, the GAIN domain embodies a unique, evolutionarily ancient and widespread autoproteolytic fold whose function is likely relevant for GPCR signalling and for multiple human diseases.
The EMBO Journal 02/2012; 31(6):1364-78. DOI:10.1038/emboj.2012.26 · 10.43 Impact Factor
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