POU1F1/Pou1f1 c.143-83A > G Variant Disrupts the Branch Site in Pre-mRNA and Leads to Dwarfism.

Autor:	Akiba K; Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.; Division of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan., Hasegawa Y; Division of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan., Katoh-Fukui Y; Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan., Terao M; Department of Systems BioMedicine, National Research Institute for Child Health and Development, Tokyo, Japan., Takada S; Department of Systems BioMedicine, National Research Institute for Child Health and Development, Tokyo, Japan., Hasegawa T; Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan., Fukami M; Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan., Narumi S; Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
Jazyk:	angličtina
Zdroj:	Endocrinology [Endocrinology] 2022 Dec 19; Vol. 164 (2).
DOI:	10.1210/endocr/bqac198
Abstrakt:	POU Class 1 Homeobox1 (POU1F1/Pou1f1) is a well-established pituitary-specific transcription factor, and causes, when mutated, combined pituitary hormone deficiency in humans and mice. POU1F1/Pou1f1 has 2 isoforms: the alpha and beta isoforms. Recently, pathogenic variants in the unique coding region of the beta isoform (beta domain) and the intron near the exon-intron boundary for the beta domain were reported, although their functional consequences remain obscure. In this study, we generated mice carrying the Pou1f1 c.143-83A>G substitution that recapitulates the human intronic variant near the exon-intron boundary for the beta domain. Homozygous mice showed postnatal growth failure, with an average body weight that was 35% of wild-type littermates at 12 weeks, which was accompanied by anterior pituitary hypoplasia and deficiency of circulating insulin-like growth factor 1 and thyroxine. The results of RNA-seq analysis of the pituitary gland were consistent with reduction of somatotrophs, and this was confirmed immunohistochemically. Reverse transcription polymerase chain reaction of pituitary Pou1f1 mRNA showed abnormal splicing in homozygous mice, with a decrease in the alpha isoform, an increase in the beta isoform, and the emergence of the exon-skipped transcript. We further characterized artificial variants in or near the beta domain, which were candidate positions of the branch site in pre-mRNA, using cultured cell-basis analysis and found that only c.143-83A>G produced transcripts similar to the mice model. Our report is the first to show that the c.143-83A>G variant leads to splicing disruption and causes morphological and functional abnormalities in the pituitary gland. Furthermore, our mice will contribute understanding the role of POU1F1/Pou1f1 transcripts in pituitary development. (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)
Databáze:	MEDLINE
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