Functional relevance of naturally occurring mutations in adhesion G protein-coupled receptor ADGRD1 (GPR133)

BMC Genomics. 2016 Aug 11;17(1):609. doi: 10.1186/s12864-016-2937-2.


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.

Keywords: ADGRD1; Adhesion GPCR; Database; GPR133; Mutations; SNP.

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Asymptomatic Diseases
  • Body Height / genetics
  • COS Cells
  • Chlorocebus aethiops
  • Databases, Genetic
  • Exons
  • Gene Expression
  • Genome, Human*
  • Genome-Wide Association Study
  • HEK293 Cells
  • Heart Rate / genetics
  • Humans
  • Mutation*
  • Polymorphism, Single Nucleotide*
  • Receptors, G-Protein-Coupled / genetics*


  • ADGRD1 protein, human
  • Receptors, G-Protein-Coupled