Homozygous P86S mutation of the human glucagon receptor is associated with hyperglucagonemia, alpha cell hyperplasia, and islet cell tumor.
Homozygous P86S mutation of the human glucagon receptor is associated with hyperglucagonemia, alpha cell hyperplasia, and islet cell tumor.
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DOI：
10.1097/mpa.0b013e3181b2bb03
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发表时间：
2009-11
期刊：
影响因子：
2.9
通讯作者：
Yu R
中科院分区：
文献类型：
--
作者：
Zhou C;Dhall D;Nissen NN;Chen CR;Yu R
该研究的目的是研究一种新的综合征，即明显的高胰高血糖素血症和无胰高血糖素综合征的胰腺α细胞增生的遗传和分子基础。对1例无胰高血糖素综合征的高胰高血糖素血症合并胰α细胞增生患者的胰高血糖素受体基因（GCGR）和胰高血糖素基因进行了测序。使用增强绿色荧光蛋白（EGFP）共轭WT和突变体GCGR来表征突变体GCGR的功能。胰高血糖素基因序列正常，但GCGR测序发现在GCGR胞外结构域出现c.256C>T, p.P86S纯合错义突变。当在HEK293细胞中表达时，GCGR P86S定位于质膜，但与WT GCGR相比，其结合的放射性标记胰高血糖素少96%。GCGR P86S组胰高血糖素诱导cAMP产生的EC50为24 nM， WT组为2.4 nM。患者的α细胞也表达胰高血糖素样肽1和胰多肽。我们在此报告了人类GCGR中第一个与α细胞增生和高胰高血糖素血症相关的纯合错义突变。这种突变降低了受体对胰高血糖素的亲和力，并随着胰高血糖素的生理浓度降低了cAMP的产生。因此，GCGR中的P86S突变可能导致α细胞增生和高胰高血糖素血症。
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 gene (GCGR) and glucagon gene were sequenced in a patient with hyperglucagonemia and pancreatic α cell hyperplasia without glucagonoma syndrome. Enhanced green fluorescent protein (EGFP)-conjugated WT and mutant GCGR were used to characterize the functions of the mutant GCGR. The glucagon gene sequence was normal but GCGR sequencing uncovered a homozygous missense mutation, c.256C>T, p.P86S in the extracellular domain of GCGR. When expressed in HEK293 cells, GCGR P86S localized to the plasma membrane but bound 96% less radiolabeled glucagon than WT GCGR. The EC50 of glucagon-induced cAMP production was 24 nM for GCGR P86S but 2.4 nM for WT GCGR. The patient's α cells also express glucagon-like 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 cAMP production with physiological concentrations of glucagon. Thus, the P86S mutation in GCGR likely causes α cells hyperplasia and hyperglucagonemia.