Dominant negative action of an abnormal secretin receptor arising from mRNA missplicing in a gastrinoma.

Abstract

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 secretin-stimulation 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.

• Authors: Wei-Qun Ding, Susan Kuntz, Michael Böhmig, Bertram Wiedenmann, Laurence J Miller
• Journal: Gastroenterology (Gastroenterology) Vol. 122 Issue 2 Pg. 500-11 (Feb 2002) ISSN: 0016-5085 [Print] United States
• PMID: 11832464 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA Primers
• DNA, Complementary
• RNA, Messenger
• Receptors, G-Protein-Coupled
• Receptors, Gastrointestinal Hormone
• secretin receptor

Topics

• Adult
• Amino Acid Sequence
• Cloning, Molecular
• DNA Primers
• DNA, Complementary
• Exons
• Gastrinoma (genetics, metabolism)
• Gene Expression (physiology)
• Humans
• Molecular Sequence Data
• Pancreatic Neoplasms (genetics, metabolism)
• Protein Structure, Tertiary
• Protein Transport (physiology)
• RNA Splicing (genetics)
• RNA, Messenger (genetics)
• Receptors, G-Protein-Coupled
• Receptors, Gastrointestinal Hormone (chemistry, genetics, metabolism)
• Transfection