Decreased Activity of the Ghrhr and Gh Promoters Causes Dominantly Inherited GH Deficiency in Humanized GH1 Mouse Models

Daisuke Ariyasu, Emika Kubo, Daisuke Higa, Shinsuke Shibata, Yutaka Takaoka, Michihiko Sugimoto, Kazunori Imaizumi, Tomonobu Hasegawa, Kimi Araki

Research output: Contribution to journalArticle

Abstract

Isolated growth hormone deficiency type II (IGHD2) is mainly caused by heterozygous splice-site mutations in intron 3 of the GH1 gene. A dominant-negative effect of the mutant GH lacking exon 3 on wild-type GH secretion has been proposed; however, the molecular mechanisms involved are elusive. To uncover the molecular systems underlying GH deficiency in IGHD2, we established IGHD2 model mice, which carry both wild-type and mutant copies of the human GH1 gene, replacing each of the endogenous mouse Gh loci. Our IGHD2 model mice exhibited growth retardation along with intact cellular architecture and mildly activated endoplasmic reticulum stress in the pituitary gland, caused by decreased GH-releasing hormone receptor (Ghrhr) and Gh gene promoter activities. Decreased Ghrhr and Gh promoter activities were likely caused by reduced levels of nuclear CREB3L2, which was demonstrated to stimulate Ghrhr and Gh promoter activity. To our knowledge, this is the first in vivo study to reveal a novel molecular mechanism of GH deficiency in IGHD2, representing a new paradigm that differs from widely accepted models.

Original languageEnglish
Pages (from-to)2673-2691
Number of pages19
JournalEndocrinology
Volume160
Issue number11
DOIs
Publication statusPublished - 2019 Nov 1

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ASJC Scopus subject areas

  • Endocrinology

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