A mutation of the β-domain in POU1F1 causes pituitary deficiency due to dominant PIT-1β expression
| العنوان: | A mutation of the β-domain in POU1F1 causes pituitary deficiency due to dominant PIT-1β expression |
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| المؤلفون: | 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 |
| المصدر: | European Journal of Endocrinology. 185:1-12 |
| بيانات النشر: | Oxford University Press (OUP), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| تدمد: | 1479-683X 0804-4643 0011-2275 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6330c08426c2edd0287654e3cabfa263 https://doi.org/10.1530/eje-20-1313 |
| رقم الأكسشن: | edsair.doi.dedup.....6330c08426c2edd0287654e3cabfa263 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1479683X 08044643 00112275 |
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