{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T05:55:27Z","timestamp":1791093327295,"version":"4.1.0"},"reference-count":77,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>\n                    Growth hormone (GH) receptor (GHR) mutations give rise to GH-resistance (Laron syndrome). We previously treated GH-resistant Ghr-\/- mice (Laron mice) with adeno-associated virus (AAV) delivering mouse (m)Ghr controlled by a constitutively active liver-specific promoter (HLP). A single injection of AAV-HLP-mGHR resulted in a significant but limited increase in body length and weight, consistent with studies of IGF-1 treatment in humans and mice. Here, we performed RNA-seq on male and female mouse livers comprising the following groups: GHR+\/+ (wild-type), GHR-\/- (Laron), AAV-HLP-mGHR-treated GHR-\/- (treatment group), and AAV-HLP-Luc (Luciferase)-treated GHR-\/- (control group). Only four genes showed significant differential expression in GHR -\/- mouse liver following Luciferase vector treatment, indicating minimal effect of the AAV-HLP vector. AAV-HLP-mGHR stimulated significant expression changes in 448 genes compared to AAV-HLP-Luc control, substantially fewer than the 2781 genes whose expression was altered in GHR-\/- compared to GHR+\/+. AAV-HLP-mGHR treatment induced the GH-responsive IGF signaling genes\n                    <jats:italic>Igf1<\/jats:italic>\n                    and\n                    <jats:italic>Igfals<\/jats:italic>\n                    ~16-fold compared to AAV-HLP-Luc control, but only to 40\u201345% of GHR+\/+ liver levels. The treatment also upregulated a small subset of genes beyond GHR+\/+ expression levels (p-adj &amp;lt; 0.05), including the proto-oncogenes\n                    <jats:italic>Ascl1<\/jats:italic>\n                    ,\n                    <jats:italic>Tmprss4<\/jats:italic>\n                    , and others. Finally, genes dysregulated upon GHR loss and upregulated in livers of AAV-HLP-mGHR-treated mice were significantly enriched for sex-biased genes, consistent with the major role of GH and GHR in regulating liver sex differences. While gene replacement therapy is a potential therapy for Laron syndrome, an unregulated constitutively active promoter may drive unexpected and unbalanced changes in liver gene expression that will require monitoring.\n                  <\/jats:p>","DOI":"10.3389\/fendo.2026.1808977","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T04:49:47Z","timestamp":1779943787000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["GH-resistant (Laron) mice: gene therapy with a liver-specific GH receptor causes unbalanced upregulation of female-biased and growth-related genes"],"prefix":"10.3389","volume":"17","author":[{"given":"Joshua K.","family":"Tay","sequence":"first","affiliation":[{"name":"Department of Otolaryngology-Head & Neck Surgery, National University of Singapore","place":["Singapore, Singapore"]},{"name":"Synthetic Biology Translational Research Programme, National University of Singapore","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kian Chuan","family":"Sia","sequence":"additional","affiliation":[{"name":"Department of Surgery, National University of Singapore","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siti Humairah","family":"Mohd Rodhi","sequence":"additional","affiliation":[{"name":"Department of Surgery, National University of Singapore","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu Uin","family":"Gan","sequence":"additional","affiliation":[{"name":"Department of Surgery, National University of Singapore","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen Ying","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Surgery, National University of Singapore","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxim","family":"Pyatkov","sequence":"additional","affiliation":[{"name":"Department of Biology and Bioinformatics Program, Boston University","place":["Boston, MA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.","family":"Kopchick","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine and Aging, Ohio University","place":["Athens, OH, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Waters","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience, The University of Queensland","place":["Brisbane, QLD, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Waxman","sequence":"additional","affiliation":[{"name":"Department of Biology and Bioinformatics Program, Boston University","place":["Boston, MA, United 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