Identification of a novel mutation in the exon 2 splice donor site of the POU1F1/PIT‐1 gene in Japanese identical twins with mild combined pituitary hormone deficiency

Abstract

This is the first report of a mutation at the exon 2 donor splice site of POU1F1, affecting TAD-R2. The addition of this mutation to the growing list of pathological POU1F1 mutations may provide deeper insights into clinical heterogeneity in the expressions of individual mutations and a better understanding of the structure-function relationships of POU1F1.

A novel heterozygous intronic mutation in <i>POU1F1</i> is associated with combined pituitary hormone deficiency

“…Therefore, mutations in exons 1 and 3-6 in POU1F1 affect both the short and long isoforms of POU1F1 protein. Only one mutation that affects exon 2 of POU1F1, namely c.214+1G>T, has been reported [7]. However, this splice donor site mutation has been shown to affect both the short and long isoforms; therefore, it is unclear whether a decrease in the function of only one of these two isoforms is sufficient for disease onset in humans.…”

“…Sequencing revealed that this product corresponded to a POU1F1 transcript skipping exon 2 (Fig. 3a), which would generate Δ48-72-POU1F1, a previously reported pathogenic protein [7]. The product corresponding to the long isoform was not amplified both in controls and patients.…”

“…It is unclear why RT-PCR of lymphocytes failed to amplify the long isoform of POU1F1, which could not be expressed in lymphocytes. Previously, a heterozygous splice site mutation in POU1F1, namely c.214+1G>T, which results in exon 2 skipping, was described by Inoue et al [7]. Mutant POU1F1 (Δ48-72 POU1F1) has been shown to result in reduced transcriptional activity, having a dominant-negative effect.…”

“…Mutant POU1F1 (Δ48-72 POU1F1) has been shown to result in reduced transcriptional activity, having a dominant-negative effect. As opposed to short isoform, long isoform POU1F1 has been reported to suppress GH, PRL and TSHb promoters in a pituitary-specific manner, blocking Ras-induced PRL promoter activity [7]. Hence, we believe that the heterozygous intronic variant of POU1F1 (c.143-83A>G in the short isoform or c.143-5A>G in the long isoform) is pathogenic and could be responsible for the specific combination of GH, PRL, and TSH deficiencies in our cases.…”

Determination of the novel genetic variants of goat STAT5A gene and their effects on body measurement traits in two Chinese native breeds

“…POU class 1 homeobox 1 (POU1F1) is a positive pituitary specific transcription regulator for GH, PRL, and thyroid-stimulating hormone ␤ (TSH ␤), and thus it plays a key role in milk yield, growth, and fertility of livestock animals (Inoue et al, 2012). Recently, several polymorphisms of the POU1F1 pathway genes such as POU1F1, PROP1, and PITX2 genes that affect production traits have been reported both in the goat and bovine species (Daga et al, 2013;Pan et al, 2013a,b;Zhao et al, 2013).…”