Homozygous P86S Mutation of the Human Glucagon Receptor Is Associated With Hyperglucagonemia, α Cell Hyperplasia, and Islet Cell Tumor
- 1 November 2009
- journal article
- case report
- Published by Ovid Technologies (Wolters Kluwer Health) in Pancreas
- Vol. 38 (8), 941-946
- https://doi.org/10.1097/mpa.0b013e3181b2bb03
Abstract
The goal of the study was to investigate the genetic and molecular basis of a novel syndrome of marked hyperglucagonemia and pancreatic α cell hyperplasia without glucagonoma syndrome. The glucagon receptor (GCGR) gene and the glucagon gene were sequenced in a patient with hyperglucagonemia and pancreatic α 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. 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 α cells also express glucagonlike peptide 1 and pancreatic polypeptide. We hereby report the first homozygous missense mutation in the human GCGR, which is associated with α 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 α cell hyperplasia and hyperglucagonemia.Keywords
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