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Background  POU1F1 encodes both PIT-1α, which plays pivotal roles in pituitary development and  GH , PRL and  TSHB  expression, and the alternatively spliced isoform PIT-1β, which contains an insertion of 26-amino acids (β-domain) in the transactivation domain of PIT-1α due to the use of an alternative splice acceptor at the end of the first intron. PIT-1β is expressed at much lower levels than PIT-1α and represses endogenous PIT-1α transcriptional activity. Although  POU1F1  mutations lead to combined pituitary hormone deficiency (CPHD), no patients with β-domain mutations have been reported.    Results  Here, we report that a three-generation family exhibited different degrees of CPHD, including growth hormone deficiency with intrafamilial variability of prolactin/TSH insufficiency and unexpected prolactinoma occurrence. The CPHD was due to a novel  POU1F1  heterozygous variant (c.143-69T&gt;G) in intron 1 of PIT-1α (RefSeq number NM_000306) or as c.152T&gt;G (p.Ile51Ser) in exon 2 of PIT-1β (NM_001122757). Gene splicing experiments showed that this mutation yielded the PIT-1β transcript without other transcripts. The lymphocyte PIT-1β mRNA expression was significantly higher in the patients with the heterozygous mutation than a control. A luciferase reporter assay revealed that the PIT-1β-Ile51Ser mutant repressed PIT-1α and abolished transactivation capacity for the rat prolactin promoter in GH3 pituitary cells.    Conclusions  We describe, for the first time, that the PIT-1β mutation can cause CPHD through a novel genetic mechanism, such as PIT-1β overexpression, and that  POU1F1  mutation might be associated with a prolactinoma. Analysis of new patients and long-term follow-up are needed to clarify the characteristics of PIT-1β mutations.

A mutation of the β-domain in POU1F1 causes pituitary deficiency due to dominant PIT-1β expression