Aberrant alternative splicing of thyroid hormone receptor in a TSH-secreting pituitary tumor is a mechanism for hormone resistance

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 TR beta from a surgically resected TSHoma. Analyses of the RT-PGR products revealed a 135-bp deletion within the sixth exon that encodes the ligand-binding domain of TR beta2. This deletion was caused by alternative splicing of TR beta2 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 TR beta variant (TR beta 2spl) lacked thyroid hormone binding and had impaired T-3-dependent negative regulation of both TSH beta and glycoprotein hormone alpha -subunit genes in cotransfection studies. Furthermore, TR beta 2spl showed dominant negative activity against the wild-type TR beta2. These findings strongly suggest that aberrant alternative splicing of TR beta2 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.