A mutation of the β-domain in POU1F1 causes pituitary deficiency due to dominant PIT-1β expression
| Autor: | Takahide Kokumai, Koichi Yano, Yoshiya Ito, Kumihiro Matsuo, Shigeru Suzuki, Atsushi Kobayashi, Akimasa Okuno, Kenji Fujieda, Hiroshi Azuma, Akiko Furuya, Yusuke Tanahashi, Tokuo Mukai, Osamu Ueda |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Endocrinology Diabetes and Metabolism Mutant medicine.disease_cause Transactivation Exon 0302 clinical medicine Endocrinology Protein Isoforms Lymphocytes Promoter Regions Genetic Mutation General Medicine Middle Aged Pedigree 030220 oncology & carcinogenesis Female Transcription Factor Pit-1 Adult Heterozygote medicine.medical_specialty Adolescent 030209 endocrinology & metabolism In Vitro Techniques Biology Hypopituitarism 03 medical and health sciences Hypothyroidism Cell Line Tumor Internal medicine medicine Animals Humans Pituitary Neoplasms Prolactinoma RNA Messenger Aged Alternative splicing Intron medicine.disease Prolactin Rats Alternative Splicing Growth Hormone ras Proteins HeLa Cells |
| Zdroj: | European Journal of Endocrinology. 185:1-12 |
| ISSN: | 1479-683X 0804-4643 0011-2275 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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