{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T10:19:46Z","timestamp":1781086786035,"version":"3.54.1"},"reference-count":40,"publisher":"American Society of Hematology","issue":"13","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,7,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>This report identifies a novel variant form of the inherited bleeding disorder Glanzmann thrombasthenia, exhibiting only mild bleeding in a physically active individual. The platelets cannot aggregate ex\u00a0vivo with physiologic agonists of activation, although microfluidic analysis with whole blood displays moderate ex\u00a0vivo platelet adhesion and aggregation consistent with mild bleeding. Immunocytometry shows reduced expression of \u03b1IIb\u03b23 on quiescent platelets that spontaneously bind\/store fibrinogen, and activation-dependent antibodies (ligand-induced binding site\u2013319.4 and PAC-1) report \u03b23 extension suggesting an intrinsic activation phenotype. Genetic analysis reveals a single F153S\u03b23 substitution within the \u03b2I-domain from a heterozygous T556C nucleotide substitution of ITGB3 exon 4 in conjunction with a previously reported IVS5(+1)G&amp;gt;A splice site mutation with undetectable platelet messenger RNA accounting for hemizygous expression of S153\u03b23. F153 is completely conserved among \u03b23 of several species and all human \u03b2-integrin subunits suggesting that it may play a vital role in integrin structure\/function. Mutagenesis of \u03b1IIb-F153S\u03b23 also displays reduced levels of a constitutively activated \u03b1IIb-S153\u03b23 on HEK293T cells. The overall structural analysis suggests that a bulky aromatic, nonpolar amino acid (F,W)153\u03b23 is critical for maintaining the resting conformation of \u03b12- and \u03b11-helices of the \u03b2I-domain because small amino acid substitutions (S,A) facilitate an unhindered inward movement of the \u03b12- and \u03b11-helices of the \u03b2I-domain toward the constitutively active \u03b1IIb\u03b23 conformation, while a bulky aromatic, polar amino acid (Y) hinders such movements and restrains \u03b1IIb\u03b23 activation. The data collectively demonstrate that disruption of F153\u03b23 can significantly alter normal integrin\/platelet function, although reduced expression of \u03b1IIb-S153\u03b23 may be compensated by a hyperactive conformation that promotes viable hemostasis.<\/jats:p>","DOI":"10.1182\/bloodadvances.2022009495","type":"journal-article","created":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T16:54:19Z","timestamp":1678294459000},"page":"3180-3191","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":4,"title":["A single F153S\u03b23 mutation causes constitutive integrin \u03b1IIb\u03b23 activation in a variant form of Glanzmann thrombasthenia"],"prefix":"10.1182","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5931-5491","authenticated-orcid":false,"given":"Sevasti B.","family":"Koukouritaki","sequence":"first","affiliation":[{"name":"1Department of Pediatrics, Medical College of Wisconsin, Milwaukee, 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Children\u2019s Wisconsin, Milwaukee, WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haley S.","family":"Slater","sequence":"additional","affiliation":[{"name":"1Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI"},{"name":"2Children\u2019s Research Institute, Children\u2019s Wisconsin, Milwaukee, WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lily M.","family":"Du","sequence":"additional","affiliation":[{"name":"1Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI"},{"name":"2Children\u2019s Research Institute, Children\u2019s Wisconsin, Milwaukee, WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huong Thi Thu","family":"Nguyen","sequence":"additional","affiliation":[{"name":"3Versiti Blood Research Institute, Milwaukee, WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"Pillois","sequence":"additional","affiliation":[{"name":"6Xavier Arnozan H\u00f4pital, Institut de Rythmologie et de Mod\u00e9lisation Cardiaque, Pessac, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7878-8307","authenticated-orcid":false,"given":"Alan T.","family":"Nurden","sequence":"additional","affiliation":[{"name":"6Xavier Arnozan H\u00f4pital, Institut de Rythmologie et de Mod\u00e9lisation Cardiaque, Pessac, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Ng","sequence":"additional","affiliation":[{"name":"7Department of Pediatrics, Section of Hematology\/Oncology\/Bone Marrow Transplant, University of Colorado Anschutz Medical Campus, Aurora, CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Di Paola","sequence":"additional","affiliation":[{"name":"5Department of Pediatrics, Division of Hematology & Oncology, Washington University School of Medicine, Washington University in St. Louis, St. Louis, 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