# Functional Properties of POU1F1 Mutants in the Transcriptional Regulation of the Thyrotropin β Gene Compared with the Prolactin Gene

## TL;DR

This study examines how mutations in the POU1F1 gene affect the regulation of the TSHβ and PRL genes, revealing differences in their functional impact and implications for TSH deficiency.

## Contribution

The study identifies distinct functional classes of POU1F1 mutants and highlights the role of the suppressor region in TSH deficiency pathogenesis.

## Key findings

- Certain POU1F1 mutants show reduced protein stability and transactivation activity in both TSHβ and PRL promoters.
- Mutants were classified into three groups based on their transcriptional activity, with group II mutations linked to TSH deficiency after GH therapy.
- The suppressor region is critical for TSH deficiency, and some mutants suggest GATA2 interaction may not always be necessary for TSHβ activation.

## Abstract

Mutations in the POU1F1 gene cause defects in the expression of the genes encoding thyroid-stimulating hormone (TSH)-β subunit, growth hormone (GH), and prolactin (PRL). Here, we characterized 15 missense and nonsense mutations. Protein stability was reduced in the P14L, P24L, F135C, K145X, F233S and E250X mutants. Transactivation by 15 mutants in the TSHβ promoter was moderately correlated with that of the PRL promoter. Based on their transcriptional activity, we classified them into three groups: group I, equivalent to the wild type; group II, partial; and group III, substantially lost. A review of case reports on four patients with group II mutations revealed that TSH deficiency manifested after recombinant GH therapy. A transcription factor, GATA2, is the main activator in the TSHβ gene, while POU1F1 protects its function from inhibition by the suppressor region (SR). We found that the SR is critical for the pathogenesis of TSH deficiency. The transactivation of the TSHβ promoter by the K216E mutant was equivalent to that of wild-type POU1F1; however, that of the PRL promoter was low, while the opposite was found in the R271W mutant. The functional property of K216E suggests that the interaction of POU1F1 with GATA2 may not always be necessary for the activation of the TSHβ promoter.