title: Functional relevance of naturally occurring mutations in adhesion G protein-coupled receptor ADGRD1 (GPR133).
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors: From the Section of Molecular Biochemistry, Institute of Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, 04103, Leipzig, Germany.
authors: Liane
authors: L
authors: Fischer
authors: From the Section of Molecular Biochemistry, Institute of Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, 04103, Leipzig, Germany.
authors: Caroline
authors: C
authors: Wilde
authors: From the Section of Molecular Biochemistry, Institute of Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, 04103, Leipzig, Germany. schoberg@medizin.uni-leipzig.de.
authors: Torsten
authors: T
authors: Schöneberg
authors: From the Section of Molecular Biochemistry, Institute of Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, 04103, Leipzig, Germany. liebscher@medizin.uni-leipzig.de.
authors: Ines
authors: 0000-0003-4480-8987
authors: I
authors: Liebscher
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D058070:Asymptomatic Diseases; D001827:Body Height / Q000235:genetics; D019556:COS Cells; D002522:Chlorocebus aethiops; D030541:Databases, Genetic; D005091:Exons; D015870:Gene Expression; D015894:Genome, Human; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006339:Heart Rate / Q000235:genetics; D006801:Humans; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*
chemical_list: C547021:ADGRD1 protein, human; D043562:Receptors, G-Protein-Coupled
keywords: ADGRD1; Adhesion GPCR; Database; GPR133; Mutations; SNP