Thyroid receptor alpha1 and alpha2 mutations in nonfunctioning pituitary tumors.

We previously reported that nonfunctioning tumors of the anterior pituitary exhibit reduced expression of thyroid receptor (TR) alpha and beta isoforms, an observation that may account for abnormalities of T3-mediated negative regulation of the glycoprotein hormone common alpha-subunit. Reduced TR protein was associated with a parallel reduction in TRbeta messenger RNA (mRNA), although TRalpha1 and alpha2 mRNA levels were similar in nonfunctioning tumors and normal pituitaries. Because TRalpha shows aberrant posttranscriptional processing, and TRbeta 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 TRalpha mRNA and TRbeta T3 response elements and ligand binding domains for sequence anomalies. Screening TRalpha mRNA in 23 tumors and subsequently sequencing candidate fragments identified one silent change from published sequences and three novel missense mutations, two in the common TRalpha region (ser45ile and lys370asn) and one that was alpha2 specific (ser377leu). TRbeta response elements failed to show any differences from published sequences in 14 nonfunctioning tumors. Sequencing of TRbeta ligand binding domains were also identical to wild type in 23 nonfunctioning tumors. The functional significance of the novel TRalpha mutations is unknown; definition of mutant TR action may provide insight into the role of TRs in the growth control of pituitary cells.