Key result
In vitro characterization of 109 non-synonymous SNPs in the human ADGRD1 gene identified several variants causing loss of receptor function and one variant (F383S) that increased basal activity by 262%.
A broad spectrum of functionally relevant ADGRD1 variants is present in the human population, causing full or partial loss or gain of receptor function in vitro.
ADGRD1 variants may alter receptor function in humans; hypothesis-generating and leaves open clinical relevance pending further study.
BACKGROUND: A large number of human inherited and acquired diseases and phenotypes are caused by mutations in G protein-coupled receptors (GPCR). Genome-wide association studies (GWAS) have shown that variations in the ADGRD1 (GPR133) locus are linked with differences in metabolism, human height and heart frequency. ADGRD1 is a Gs protein-coupled receptor belonging to the class of adhesion GPCRs. RESULTS: Analysis of more than 1000 sequenced human genomes revealed approximately 9000 single nucleotide polymorphisms (SNPs) in the human ADGRD1 as listed in public data bases. Approximately 2.4 % of these SNPs are located in exons resulting in 129 non-synonymous SNPs (nsSNPs) at 119 positions of ADGRD1. However, the functional relevance of those variants is unknown. In-depth characterization of these amino acid changes revealed several nsSNPs (A448D, Q600stop, C632fs [frame shift], A761E, N795K) causing full or partial loss of receptor function, while one nsSNP (F383S) significantly increased basal activity of ADGRD1. CONCLUSION: Our results show that a broad spectrum of functionally relevant ADGRD1 variants is present in the human population which may cause clinically relevant phenotypes, while being compatible with life when heterozygous.
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Fischer et al. (2016) studied ADGRD1 (GPR133) mutations. In vitro functional characterization of ADGRD1 nsSNPs vs. Wild-type ADGRD1 was evaluated on Receptor signaling activity (basal CRE levels) and cell surface expression. In vitro characterization of 109 non-synonymous SNPs in the human ADGRD1 gene identified several variants causing loss of receptor function and one variant (F383S) that increased basal activity by 262%.
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