Takumi Yonemori

Isolated Growth Hormone Deficiency Type 2 (IGHD2) is caused by a heterozygous splice site variant in intron 3 of the GH1 gene. The resulting exon 3-skipped growth hormone (Δ3 GH), produced from the mutated allele, exerts a dominant-negative effect, leading to growth hormone (GH) deficiency. However, the precise molecular mechanisms underlying this effect remain poorly understood. While several model murine models expressing human Δ3 GH have been developed, no IGHD2 mouse models featuring variants in the endogenous Gh gene currently exist. We generated a mouse model (Gh^+/Δ3) with a heterozygous deletion of exon 3 in the Gh gene using CRISPR/Cas9 system. The Gh^+/Δ3 model exhibited GH deficiency caused by a dominant-negative effect at the mRNA level, characterized by reduced Gh mRNA expression. This mechanism parallels findings in our previous humanized IGHD2 mouse model, where the deficiency was driven by decreased Ghrhr mRNA expression. Transcriptome analysis of the pituitary revealed widespread downregulation of mRNAs encoding membrane and secretory proteins. The dominant-negative effect of Δ3 GH in IGHD2 is mediated by properties of Δ3 GH that are conserved across both humans and mice. This mechanism involves the downregulation of mRNAs, including those encoding membrane and secretory proteins, such as Ghrhr mRNA.