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Molecular Regulation and Neuroendocrinology Section (S.A., N.J.S., J.K., X.F., P.M.Y.), Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, and Surgical Neurology Branch (E.H.O.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892; Departments of Pediatrics and Medicine (S.R.), University of Chicago, Chicago, Illinois 60637; and Cold Spring Harbor Laboratory (M.Q.Z.), Cold Spring Harbor, New York 11724
Patients with TSH-secreting pituitary tumors (TSHomas) have high
serum TSH levels despite elevated thyroid hormone levels. The mechanism
for this defect in the negative regulation of TSH secretion is not
known. We performed RT-PCR to detect mutations in TRß from a
surgically resected TSHoma. Analyses of the RT-PCR products revealed a
135-bp deletion within the sixth exon that encodes the ligand-binding
domain of TRß2. This deletion was caused by alternative splicing of
TRß2 mRNA, as near-consensus splice sequences were found at the
junction site and no deletion or mutations were detected in the tumoral
genomic DNA. This TRß variant (TRß2spl) lacked thyroid hormone
binding and had impaired T3-dependent negative regulation
of both TSHß and glycoprotein hormone 
-subunit genes in
cotransfection studies. Furthermore, TRß2spl showed dominant negative
activity against the wild-type TRß2. These findings strongly suggest
that aberrant alternative splicing of TRß2 mRNA generated an abnormal
TR protein that accounted for the defective negative regulation of TSH
in the TSHoma. This is the first example of aberrant alternative
splicing of a nuclear hormone receptor causing hormonal dysregulation.
This novel posttranscriptional mechanism for generating abnormal
receptors may occur in other hormone-resistant states or tumors in
which no receptor mutation is detected in genomic DNA.
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