{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T08:29:35Z","timestamp":1771057775923,"version":"3.50.1"},"reference-count":21,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,1,26]],"date-time":"2025-01-26T00:00:00Z","timestamp":1737849600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science KAKENHI","doi-asserted-by":"publisher","award":["JP22H04922"],"award-info":[{"award-number":["JP22H04922"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science KAKENHI","doi-asserted-by":"publisher","award":["JP21K07849"],"award-info":[{"award-number":["JP21K07849"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 (\u03943 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 \u03943 GH have been developed, no IGHD2 mouse models featuring variants in the endogenous Gh gene currently exist. We generated a mouse model (Gh+\/\u03943) with a heterozygous deletion of exon 3 in the Gh gene using CRISPR\/Cas9 system. The Gh+\/\u03943 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 \u03943 GH in IGHD2 is mediated by properties of \u03943 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.<\/jats:p>","DOI":"10.3390\/ijms26031061","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T03:54:27Z","timestamp":1737950067000},"page":"1061","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Mice with Heterozygous Deletion of Exon 3 in the Gh Gene Demonstrate Growth Retardation Caused by Reduced Ghrhr mRNA"],"prefix":"10.3390","volume":"26","author":[{"given":"Daisuke","family":"Ariyasu","sequence":"first","affiliation":[{"name":"Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Honjo 860-0811, Kumamoto, Japan"},{"name":"Department of Pediatrics, Kawasaki Municipal Hospital, Kawasaki 210-0013, Kanagawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daisuke","family":"Higa","sequence":"additional","affiliation":[{"name":"Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Honjo 860-0811, Kumamoto, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryo","family":"Tokudome","sequence":"additional","affiliation":[{"name":"Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Honjo 860-0811, Kumamoto, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takumi","family":"Yonemori","sequence":"additional","affiliation":[{"name":"Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Honjo 860-0811, Kumamoto, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hayate","family":"Shimada","sequence":"additional","affiliation":[{"name":"Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Honjo 860-0811, Kumamoto, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1185-9043","authenticated-orcid":false,"given":"Shinsuke","family":"Shibata","sequence":"additional","affiliation":[{"name":"Division of Microscopic Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-Dori, Chuo-Ku, Niigata 951-8510, Niigata, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1396-1527","authenticated-orcid":false,"given":"Kimi","family":"Araki","sequence":"additional","affiliation":[{"name":"Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Honjo 860-0811, Kumamoto, Japan"},{"name":"Center for Metabolic Regulation of Healthy Aging, Kumamoto University, 1-1-1, Honjo 860-8556, Kumamoto, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,26]]},"reference":[{"key":"ref_1","first-page":"1261","article-title":"Familial growth hormone deficiency: A model of dominant and recessive mutations affecting a monomeric protein","volume":"79","author":"Cogan","year":"1994","journal-title":"J. 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