{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T09:53:43Z","timestamp":1762509223488,"version":"build-2065373602"},"reference-count":81,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T00:00:00Z","timestamp":1732579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008982","name":"Qatar National Research Fund","doi-asserted-by":"publisher","award":["ECRA02\u2013008-3-007","QUST-2-CHS-2022-675","QUCG-CHS-23\/24-201"],"award-info":[{"award-number":["ECRA02\u2013008-3-007","QUST-2-CHS-2022-675","QUCG-CHS-23\/24-201"]}],"id":[{"id":"10.13039\/100008982","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004252","name":"Qatar University","doi-asserted-by":"publisher","award":["ECRA02\u2013008-3-007","QUST-2-CHS-2022-675","QUCG-CHS-23\/24-201"],"award-info":[{"award-number":["ECRA02\u2013008-3-007","QUST-2-CHS-2022-675","QUCG-CHS-23\/24-201"]}],"id":[{"id":"10.13039\/501100004252","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>GNAS (Guanine Nucleotide-Binding Protein, Alpha Stimulating) is a complex gene that encodes the alpha subunit of the stimulatory G protein (Gs\u03b1), critical for signaling through various G protein-coupled receptors. Inactivating genetic and epigenetic changes in GNAS, resulting in Gs\u03b1 deficiency, cause different variants of pseudohypoparathyroidism, which may manifest features of Albright hereditary osteodystrophy (AHO, a syndrome characterized by early-onset obesity and other developmental defects). Recent findings have linked Gs\u03b1 deficiency with isolated, severe, early-onset obesity, suggesting it as a potential, underrecognized cause of monogenic, non-syndromic obesity. This study was prompted by identifying several GNAS variants of uncertain significance (VUSs) in pediatric patients presenting with unexplained, severe, early-onset obesity at Sidra Medicine in Qatar. To functionally characterize these variants, we developed the first zebrafish model of Gs\u03b1 deficiency, offering numerous advantages over other model systems. This was achieved by knockdown of the ortholog through microinjection of translation-blocking Morpholino antisense oligonucleotides into the yolks of 1-8-cell-stage zebrafish embryos. The morphant larvae displayed an obese phenotype, marked by significantly enlarged yolk sacs, increased neutral lipid accumulation, and reduced metabolic rates, among other developmental abnormalities resembling those in AHO. This zebrafish model lays the foundation for efficient functional characterization of GNAS VUSs and paves the way for enhancing our understanding of Gs\u03b1 deficiency-associated early-onset obesity.<\/jats:p>","DOI":"10.3390\/ijms252312674","type":"journal-article","created":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T04:02:18Z","timestamp":1732593738000},"page":"12674","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["gnas Knockdown Induces Obesity and AHO Features in Early Zebrafish Larvae"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4383-5596","authenticated-orcid":false,"given":"Alaa","family":"Abbas","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha P.O. Box 2713, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayat S","family":"Hammad","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha P.O. Box 2713, Qatar"},{"name":"Biomedical Research Center, Qatar University, Doha P.O. Box 2713, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zain Z.","family":"Zakaria","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha P.O. Box 2713, Qatar"},{"name":"Biomedical Research Center, Qatar University, Doha P.O. Box 2713, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maha","family":"Al-Asmakh","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha P.O. Box 2713, Qatar"},{"name":"Biomedical Research Center, Qatar University, Doha P.O. Box 2713, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5480-7112","authenticated-orcid":false,"given":"Khalid","family":"Hussain","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Department of Pediatric Medicine, Sidra Medicine, Doha P.O. Box 26999, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mashael","family":"Al-Shafai","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha P.O. Box 2713, Qatar"},{"name":"Biomedical Research Center, Qatar University, Doha P.O. Box 2713, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/s13679-020-00418-6","article-title":"Clinical Assessment and Treatment of Early-Onset Severe Obesity","volume":"10","author":"Raatz","year":"2021","journal-title":"Curr. Obes. Rep."},{"key":"ref_2","unstructured":"WHO (2023, January 05). Obesity and Overweight. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/obesity-and-overweight."},{"key":"ref_3","first-page":"8","article-title":"A systematic review of childhood obesity in the Middle East and North Africa (MENA) region: Prevalence and risk factors meta-analysis","volume":"4","author":"Farrag","year":"2017","journal-title":"Adv. Pediatr. 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