Thyroid receptor alpha 1 and alpha 2 mutations in nonfunctioning pituitarytumors

We previously reported that nonfunctioning tumors of the anterior pituitary exhibit reduced expression of thyroid receptor (TR) alpha and beta isoform s, an observation that may account for abnormalities of T-3-mediated negati ve regulation of the glycoprotein hormone common alpha-subunit. Reduced TR protein was associated with a parallel reduction in TR beta messenger RNA ( mRNA), although TR alpha 1 and alpha 2 mRNA levels were similar in nonfunct ioning tumors and normal pituitaries. Because TR alpha shows aberrant postt ranscriptional processing, and TRP is under ligand-dependent autoregulation , we hypothesized that aberrant TR expression in nonfunctioning tumors may reflect mutation in receptor coding and regulatory sequences, and therefore screened TR alpha mRNA and TR beta T-3 response elements and ligand bindin g domains for sequence anomalies. Screening TR alpha mRNA in 23 tumors and subsequently sequencing candidate fragments identified one silent change fr om published sequences and three novel missense mutations, two in the commo n TR alpha region (ser45ile and lys370asn) and one that was alpha 2 specifi c (ser377leu). TR beta response elements failed to show any differences fro m published sequences in 14 nonfunctioning tumors. Sequencing of TR beta li gand binding domains were also identical to wild type in 23 nonfunctioning tumors. The functional significance of the novel TR alpha mutations is unkn own; definition of mutant TR action may provide insight into the role of TR s in the growth control of pituitary cells.