Novel variants in GALE cause syndromic macrothrombocytopenia by disrupting glycosylation and thrombopoiesis

• DOI: 10.1182/blood.2022016995
• Publication Date: 2022-11-17T19:15:54Z
• Authors: Ana Marín-Quílez; Christian Andrea ...; Lorena Díaz-Ajenjo; Vittorio Abbonante; Elena Vuelta; Paolo Maria Soprano; Cristina Miguel-G...; Sandra Santos-Mín...; Inmaculada Serram...; Pedro Ruiz-Sala; María Jesús Peñar...; Emilia Pardal; Jesús María Herná...; José Ramón Gonzál...; Ignacio García-Tuñón; Rocío Benito; José Rivera; Alessandra Balduini; José María Bastida
• Keywords: Thrombopoiesis; Bleeding diathesis

Abstract Glycosylation is recognized as a key process for proper megakaryopoiesis and platelet formation. The enzyme uridine diphosphate (UDP)-galactose-4-epimerase, encoded by GALE, involved in galactose metabolism protein glycosylation. Here, we studied 3 patients from 2 unrelated families who showed lifelong severe thrombocytopenia, bleeding diathesis, mental retardation, mitral valve prolapse, jaundice. Whole-exome sequencing revealed 4 variants that affect of those previously unreported (Pedigree A, p.Lys78ValfsX32 p.Thr150Met; Pedigree B, p.Val128Met; p.Leu223Pro). Platelet phenotype analysis giant and/or grey platelets, impaired aggregation, severely reduced alpha dense granule secretion. Enzymatic activity the UDP-galactose-4-epimerase was decreased all patients. Immunoblotting lysates GALE levels, significant decrease N-acetyl-lactosamine (LacNAc), showing hypoglycosylation pattern, surface expression gylcoprotein Ibα-IX-V (GPIbα-IX-V) complex mature β1 integrin, increased apoptosis. In vitro studies performed with patients-derived megakaryocytes normal ploidy maturation but proplatelet formation because glycosylation GPIbα externalization to megakaryocyte membranes. Altered distribution filamin A actin delocalization von Willebrand factor were also shown. Overall, this study expands our knowledge GALE-related thrombocytopenia emphasizes critical role physiological proteins production function.