{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T10:57:00Z","timestamp":1773053820938,"version":"3.50.1"},"reference-count":33,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Craniosynostosis is characterized by premature fusion of cranial sutures, often with a complex genetic basis. While multiple genes have been implicated, the role of\n                    <jats:italic>TGFBR3<\/jats:italic>\n                    mutations remains largely uncharacterized in human craniosynostosis. We report two Kuwaiti male siblings, born to consanguineous parents, who presented with syndromic features including craniosynostosis involving the lambdoid and posterior sagittal sutures, hypertelorism, midface hypoplasia, bilateral low\u2010set ears, undescended testes, and developmental hip dysplasia. Duo whole exome sequencing research re\u2010analysis identified a novel homozygous nonsense variant segregating with the phenotype in\n                    <jats:italic>TGFBR3<\/jats:italic>\n                    (NM_003243.4: c.2418G&gt;A, p.Trp806Ter), which encodes the betaglycan protein. Functional studies were performed to assess the pathogenicity of the variant. Expression of the mutant TGFBR3 in HEK293T cells demonstrated correct plasma membrane localization but revealed a truncated protein lacking its intracellular C\u2010terminus. The mutant receptor retained canonical co\u2010receptor function. In luciferase reporter assays, both wild\u2010type and mutant TGFBR3 enhanced TGF\u2010\u03b21, TGF\u2010\u03b22, and TGF\u2010\u03b23 signaling. Mutant TGFBR3 produced an increase in luciferase activity relative to wild type only at the highest TGF\u03b21 concentration tested (10 pM). At lower TGF\u03b21 concentrations (0.1 and 1 pM) and across all concentrations of TGF\u03b22 and TGF\u03b23, mutant and wild\u2010type receptors behaved similarly. This is the first report implicating a biallelic\n                    <jats:italic>TGFBR3<\/jats:italic>\n                    nonsense variant in a syndromic, autosomal recessive form of craniosynostosis in a Middle Eastern population. The premature stop codon truncates the C\u2010terminal region of the protein, perhaps disrupting critical regulatory or interaction domains. Our results suggest that dysregulated TGF\u03b2 signaling via the intracellular C\u2010terminus of the protein may represent a novel pathogenic mechanism in cranial suture biology.\n                  <\/jats:p>","DOI":"10.1002\/ajmga.70009","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T11:20:34Z","timestamp":1764328834000},"page":"846-853","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel Biallelic\n                    <i>TGFBR3<\/i>\n                    Mutation in Brothers Presenting With Craniosynostosis"],"prefix":"10.1002","volume":"200","author":[{"given":"Reem M.","family":"Elshafie","sequence":"first","affiliation":[{"name":"Kuwait Medical Genetics Centre Ministry of Health  Sulaibikhat Kuwait"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yeu\u2010Farn","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics McGill University  Montreal Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7566-3224","authenticated-orcid":false,"given":"Isabella","family":"Pecora","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics McGill University  Montreal Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evan R. S.","family":"Buddle","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics McGill University  Montreal Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nawal Y.","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Radiology, Ibn Sina Hospital Ministry of Health  Sulaibikhat Kuwait"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dana","family":"Marafi","sequence":"additional","affiliation":[{"name":"Kuwait Medical Genetics Centre Ministry of Health  Sulaibikhat Kuwait"},{"name":"Department of Pediatrics, College of Medicine Kuwait University  Safat Kuwait"},{"name":"Department of Pediatrics, Adan Hospital Ministry of Health  Hadiya Kuwait"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asmaa M.","family":"Alshammari","sequence":"additional","affiliation":[{"name":"Kuwait Medical Genetics Centre Ministry of Health  Sulaibikhat Kuwait"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Doaa I.","family":"Sadik","sequence":"additional","affiliation":[{"name":"Kuwait Medical Genetics Centre Ministry of Health  Sulaibikhat Kuwait"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alaa Eldin","family":"Elshafey","sequence":"additional","affiliation":[{"name":"Kuwait Medical Genetics Centre Ministry of Health  Sulaibikhat Kuwait"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laila","family":"Bastaki","sequence":"additional","affiliation":[{"name":"Kuwait Medical Genetics Centre Ministry of Health  Sulaibikhat Kuwait"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel J.","family":"Bernard","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics McGill University  Montreal Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hind","family":"Alsharhan","sequence":"additional","affiliation":[{"name":"Kuwait Medical Genetics Centre Ministry of Health  Sulaibikhat Kuwait"},{"name":"Department of Pediatrics, College of Medicine Kuwait University  Safat Kuwait"},{"name":"Department of Pediatrics, Farwaniya Hospital, Ministry of Health  Sabah Al\u2010Nasser Kuwait"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.201017"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M106831200"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2023.1113061"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1083195"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.2478\/bjmg\u20102022\u20100004"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.2478\/bjmg\u20102022\u20100004"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/17.11.3091"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a022053"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.32782"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.50448"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38159"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgp271"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2014.03.011"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092\u20108674(91)90073\u20108"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.124.4.557"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092\u20108674(93)90368\u2010z"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a022269"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2014.12.004"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a021873"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0812879106"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600\u20100544.2002.01179.x"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.1997.12.3.311"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.4103\/jpn.JPN_25_22"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpha.2025.101372"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.049390"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.4c00066"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2011.09.006"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2015.07.006"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2018.09.002"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010025\u201056796\u20109"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.29183"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.21873\/invivo.13052"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmga.70009","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ajmga.70009","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmga.70009","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T09:00:05Z","timestamp":1773046805000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmga.70009"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,28]]},"references-count":33,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1002\/ajmga.70009"],"URL":"https:\/\/doi.org\/10.1002\/ajmga.70009","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"value":"1552-4825","type":"print"},{"value":"1552-4833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,28]]},"assertion":[{"value":"2025-08-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-19","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}