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

in European Journal of Endocrinology
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  • 1 Department of Pediatrics, Asahikawa Medical University, Asahikawa, Japan
  • | 2 Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
  • | 3 Department of Pediatrics, Asahikawa Medial University, Asahikawa, Japan
  • | 4 Asahikawa Medical University, Asahikawa, Japan

Correspondence should be addressed to S Suzuki; Email: shige5p@asahikawa-med.ac.jp

(K Matsuo is now at Department of Pediatrics, Mombetsu General Hospital, Mombetsu, Japan)

(Y Ito is now at Faculty of Nursing, Japanese Red Cross Hokkaido College of Nursing, Kitami, Japan)

§(O Ueda is now at Department of Internal Medicine, Toya Onsen Hospital, Toyako, Japan)

(T Mukai is now at Department of Pediatrics, Japanese Red Cross Asahikawa Hospital, Asahikawa, Japan)

(K Yano is now at Health & Welfare Bureau, Sapporo City Government, Sapporo, Japan)

*(Deceased)

(Y Tanahashi and H Azuma contributed equally as senior authors)

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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>G) in intron 1 of PIT-1α (RefSeq number NM_000306) or as c.152T>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.

 

     European Society of Endocrinology

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