Background & Aims: The provocative secretin-stimulation test has an important role in the diagnosis and management of gastrin-secreting neuroendocrine tumors. The aim of the present study was to explore the molecular basis for positive and false-negative secretinstimulation test results in patients with these tumors. Methods: One of the rare patients with this histologically proven tumor who had a normal serum gastrin level and a negative secretin-stimulation test result, and 2 more typical patients with this syndrome were investigated using immunohistochemistry, reverse-transcription polymerase chain reaction, receptor binding, and signaling assays. Results: We confirmed the molecular nature of the secretin receptor in the gastrinomas with a positive provocative test result and identified a novel mechanism for a false-negative result. Tumor expression of the class B G protein-coupled secretin receptor mediates a positive result. The false-negative result was explained by messenger RNA missplicing, resulting in a receptor variant missing exon 3 that encodes residues 44-79 in the amino-terminal tail of the mature receptor. This variant with an in-frame deletion was shown to be synthesized and to traffic to the cell surface normally, where it could neither bind secretin nor mediate a secretin-stimulated adenosine 3′,5′-cyclic monophosphate response. It was able to act as a dominant negative inhibitor of wild-type secretin receptor function. Conclusions: These data may explain some of the atypical presentations of this syndrome and provide important insights into basic mechanisms of disease.
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