A mutation of the ß-domain in POU1F1 causes pituitary deficiency due to dominant PIT-1ß expression.
Eur J Endocrinol
; 185(1): 1-12, 2021 May 21.
Article
em En
| MEDLINE
| ID: mdl-33886498
ABSTRACT
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-1ß, which contains an insertion of 26-amino acids (ß-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-1ß 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 ß-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-1ß (NM_001122757). Gene splicing experiments showed that this mutation yielded the PIT-1ß transcript without other transcripts. The lymphocyte PIT-1ß mRNA expression was significantly higher in the patients with the heterozygous mutation than a control. A luciferase reporter assay revealed that the PIT-1ß-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-1ß mutation can cause CPHD through a novel genetic mechanism, such as PIT-1ß 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-1ß mutations.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fator de Transcrição Pit-1
/
Hipopituitarismo
/
Hipotireoidismo
Tipo de estudo:
Etiology_studies
Limite:
Adolescent
/
Adult
/
Aged
/
Animals
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
Eur J Endocrinol
Assunto da revista:
ENDOCRINOLOGIA
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Japão