Dominant negative action of an abnormal secretin receptor arising from mRNA missplicing in a gastrinoma.
OBJECTIVE
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.
Ding
Wei-Qun
WQ
Center for Basic Research in Digestive Diseases, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Kuntz
Susan
S
Böhmig
Michael
M
Wiedenmann
Bertram
B
Miller
Laurence J
LJ
D000328:Adult; D000595:Amino Acid Sequence; D003001:Cloning, Molecular; D017931:DNA Primers; D018076:DNA, Complementary; D005091:Exons; D015408:Gastrinoma / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
D017931:DNA Primers; D018076:DNA, Complementary; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone; C029937:secretin receptor