The endoplasmic reticulum (ER) is the organelle where secretory and membrane proteins are synthesized and folded. Unfolded proteins that are retained within the ER can cause ER stress. Eukaryotic cells have a defense system called the “unfolded protein response” (UPR), which protects cells from ER stress. Cells undergo apoptosis when ER stress exceeds the capacity of the UPR, which has been revealed to cause human diseases. Although neurodegenerative diseases are well-known ER stress-related diseases, it has been discovered that endocrine diseases are also related to ER stress. In this review, we focus on ER stress-related human endocrine disorders. In addition to diabetes mellitus, which is well characterized, several relatively rare genetic disorders such as familial neurohypophyseal diabetes insipidus (FNDI), Wolfram syndrome, and isolated growth hormone deficiency type II (IGHD2) are discussed in this article.

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.

5α-reductase type 2 (5αRD2) deficiency is a 46,XY disorder of sex development caused by impaired conversion of testosterone (T) to dihydrotestosterone (DHT). Penile enlargement therapy is important for male patients with 46,XY 5αRD2 deficiency who have undermasculinized external genitalia, such as severe micropenis. High-dose T and percutaneous DHT replacement are reportedly efficacious for penile enlargement in patients with this disorder. We presented herein the longitudinal course of four patients with 46,XY 5αRD2 deficiency who received T and DHT. T replacement therapy during infancy increased the stretched penile length (SPL) in three of the patients but was ineffective in one patient. DHT was administered to the three patients after T replacement therapy and further increased the SPL. During and after puberty, two patients asked for and received T replacement therapy, which contributed to increasing their SPL. A semen test in one patient with T replacement therapy at age 27 years revealed cryptozoospermia despite normal testicular volume. The clinical course of our patients during infancy indicated that DHT therapy may be preferrable to T replacement therapy for penile enlargement in patients with 5αRD2 deficiency. During and after puberty, T replacement therapy promoted penile enlargement possibly because of increased conversion of T to DHT via increased 5α-reductase type 1 activity even in patients in whom it was ineffective during infancy. In conclusion, DHT is effective for penile enlargement during infancy in patients with 5αRD2 deficiency while T replacement therapy is a viable option during puberty.

Isolated growth hormone deficiency type II (IGHD2) is mainly caused by heterozygous splice-site mutations in intron 3 of theGH1gene. 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 humanGH1gene, replacing each of the endogenous mouseGhloci. 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) andGhgene promoter activities. Decreases inGhrhrandGhpromoter activities were likely caused by reduced levels of nuclear CREB3L2, which was demonstrated to stimulate the activity of theGhrhrandGhpromoters. This is the firstin vivostudy revealing a novel molecular mechanism of GH deficiency in IGHD2, representing a new paradigm, differing from widely accepted models.