title: Homozygous P86S mutation of the human glucagon receptor is associated with hyperglucagonemia, alpha cell hyperplasia, and islet cell tumor.
abstract: OBJECTIVE
  The goal of the study was to investigate the genetic and molecular basis of a novel syndrome of marked hyperglucagonemia and pancreatic alpha cell hyperplasia without glucagonoma syndrome.
  
  
  METHODS
  The glucagon receptor (GCGR) gene and the glucagon gene were sequenced in a patient with hyperglucagonemia and pancreatic alpha cell hyperplasia without glucagonoma syndrome. Enhanced green fluorescent protein-conjugated wild type (WT) and mutant GCGR were used to characterize the functions of the mutant GCGR.
  
  
  RESULTS
  The glucagon gene sequence was normal, but the GCGR sequencing uncovered a homozygous missense mutation, c.256C>T, p.P86S in the extracellular domain of GCGR. When expressed in human embryonic kidney 293 cells, GCGR P86S localized to the plasma membrane but bound 96% less radiolabeled glucagon than WT GCGR. The median effective concentration of glucagon-induced cyclic adenosine monophosphate production was 24 nmol/L for GCGR P86S but 2.4 nmol/L for WT GCGR. The patient's alpha cells also express glucagonlike peptide 1 and pancreatic polypeptide.
  
  
  CONCLUSIONS
  We hereby report the first homozygous missense mutation in the human GCGR, which is associated with alpha cell hyperplasia and hyperglucagonemia. This mutation lowers the receptor's affinity to glucagon and decreases cyclic adenosine monophosphate production with physiological concentrations of glucagon. Thus, the P86S mutation in GCGR likely causes alpha cell hyperplasia and hyperglucagonemia.
authors: Division of Endocrinology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors: Cuiqi
authors: C
authors: Zhou
authors: Deepti
authors: D
authors: Dhall
authors: Nicholas N
authors: NN
authors: Nissen
authors: Chun-Rong
authors: CR
authors: Chen
authors: Run
authors: R
authors: Yu
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D018273:Carcinoma, Islet Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D005455:Fluorescent Antibody Technique; D005934:Glucagon / Q000097:blood*; D050416:Glucagon-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D006965:Hyperplasia; D015151:Immunoblotting; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010375:Pedigree; D018027:Receptors, Glucagon / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D018027:Receptors, Glucagon; D049452:Green Fluorescent Proteins; D005934:Glucagon