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 growth hormone (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 associated with intact cellular architecture and mildly activated ER stress in the pituitary gland, caused by decreases in the growth hormone releasing hormone receptor (Ghrhr) and Gh gene promoter activities. Decreases in Ghrhr and Gh promoter activities were likely caused by reduced levels of nuclear CREB3L2, which was demonstrated to stimulate the activity of the Ghrhr and Gh promoters. This is the first in vivo study revealing a novel molecular mechanism of GH deficiency in IGHD2, representing a new paradigm, differing from widely accepted models.