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Thyroid Receptor 1 and 2 Mutations in Nonfunctioning Pituitary Tumors¹

Department of Medicine, Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2TH, United Kingdom

Address all correspondence and requests for reprints to: J.A. Franklyn, Department of Medicine, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2TH, United Kingdom. E-mail: franklja{at}bham.ac.uk

We previously reported that nonfunctioning tumors of the anterior pituitary exhibit reduced expression of thyroid receptor (TR) and ß isoforms, an observation that may account for abnormalities of T₃-mediated negative regulation of the glycoprotein hormone common -subunit. Reduced TR protein was associated with a parallel reduction in TRß messenger RNA (mRNA), although TR1 and 2 mRNA levels were similar in nonfunctioning tumors and normal pituitaries. Because TR shows aberrant posttranscriptional processing, and TRß 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 mRNA and TRß T₃ response elements and ligand binding domains for sequence anomalies. Screening TR 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 TR region (ser45ile and lys370asn) and one that was 2 specific (ser377leu). TRß response elements failed to show any differences from published sequences in 14 nonfunctioning tumors. Sequencing of TRß ligand binding domains were also identical to wild type in 23 nonfunctioning tumors. The functional significance of the novel TR mutations is unknown; definition of mutant TR action may provide insight into the role of TRs in the growth control of pituitary cells.

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