Decreased Activity of the<i>Ghrhr</i>and<i>Gh</i>Promoters Causes Dominantly Inherited GH Deficiency

<jats:title>Abstract</jats:title><jats:p>Isolated growth hormone deficiency type II (IGHD2) is mainly caused by heterozygous splice-site mutations in intron 3 of the<jats:italic>GH1</jats:italic>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<jats:italic>GH1</jats:italic>gene, replacing each of the endogenous mouse<jats:italic>Gh</jats:italic>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 (<jats:italic>Ghrhr</jats:italic>) and<jats:italic>Gh</jats:italic>gene promoter activities. Decreases in<jats:italic>Ghrhr</jats:italic>and<jats:italic>Gh</jats:italic>promoter activities were likely caused by reduced levels of nuclear CREB3L2, which was demonstrated to stimulate the activity of the<jats:italic>Ghrhr</jats:italic>and<jats:italic>Gh</jats:italic>promoters. This is the first<jats:italic>in vivo</jats:italic>study revealing a novel molecular mechanism of GH deficiency in IGHD2, representing a new paradigm, differing from widely accepted models.</jats:p>