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Thyroid receptor alpha1 and alpha2 mutations in nonfunctioning pituitary tumors
C J McCabe1, N J Gittoes, M C Sheppard
1Department of Medicine, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom.
Abstract:
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.
Insights
Nonfunctioning pituitary tumors show altered thyroid receptor (TR) expression. Researchers identified novel mutations in TRalpha, suggesting a role for these receptors in pituitary tumor growth.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Nonfunctioning pituitary tumors often display reduced thyroid receptor (TR) expression, potentially disrupting T3-mediated negative regulation of the glycoprotein hormone alpha-subunit.
- Previous findings indicated reduced TR protein and TRbeta mRNA, but TRalpha mRNA levels were comparable to normal pituitaries, suggesting complex regulatory mechanisms.
Purpose of the Study:
- To investigate potential mutations in thyroid receptor alpha (TRalpha) and thyroid receptor beta (TRbeta) coding and regulatory sequences in nonfunctioning pituitary tumors.
- To explore the role of aberrant TR expression and potential mutations in the pathogenesis of pituitary tumors.
Main Methods:
- Screening of TRalpha mRNA and TRbeta T3 response elements and ligand binding domains for sequence anomalies in pituitary tumor samples.
- Sequencing of identified candidate fragments from TRalpha mRNA.
- Comparison of sequences with published wild-type sequences.
Main Results:
- Three novel missense mutations (ser45ile, lys370asn in TRalpha; ser377leu in TRalpha2) were identified in TRalpha mRNA.
- One silent change in TRalpha mRNA was also noted.
- No significant differences in TRbeta response elements or ligand binding domains were found between tumors and normal tissues.
Conclusions:
- Novel mutations in TRalpha may contribute to altered TR function in nonfunctioning pituitary tumors.
- The functional significance of these TRalpha mutations requires further investigation to understand their role in pituitary cell growth control.