Glanzmann's thrombasthenia (GT) is an inherited disorder of platelet aggregation, characterized by qualitative and quantitative defect on platelet αIIbβ3 integrin (GpIIb/IIIa), resulting in lifelong bleeding tendency due to defective platelet plug formation. The αIIb gene (ITGA2B) and β3 gene (ITGB3) are closely located at chromosome 17q21.31-32. ITGA2B consist of 30 exons and encoding α chain, whereas ITGB3 has 15 exons and encoding β chain. Until now, according to the Human Gene Mutation Database (HGMD), 138 mutations at ITGA2B gene and 101 mutations at ITGB3 gene have been identified. We aimed to determine whether there was any mutation in the ITGA2B and ITGB3 genes, and a correlation between clinical phenotype and genotype in Turkish GT patients. We examined 20 patients with GT followed at the Department of Pediatric Hematology, Meram Faculty of Medicine, for Clinical and Laboratory Findings and Molecular Genetic Analysis. Peripheral blood was collected from patients, and a written informed consent for genetic analysis was obtained from parents. DNA was isolated from by proteinase K and phenol/chloroform extraction. ITGA2B and ITGB3 genes were screened by polymerase chain reaction. There were 12 females and 8 males with a median age of 15.25 years. Major clinical presentations of these patients were mucocutaneous bleedings. The most common bleeding type was epistaxis (85%). Life-threatening bleedings were seen in five patients. Seven (35%) patients showed various mutations in the ITGA2B or ITGB3 genes. We detected four novel mutations in three different regions and two mutations defined previously within the ITGA2B gene. These changes are at exon 4; c.570 T > G alteration, at exon 13 c.1277 T > A, c.1291 T > G alterations, at exon 19 c.1921A > G alterations. And from the start point of exon 14, behind 107 bases, we detected a heterozygous alteration at Thymine to Guanine. According to PolyPhen Database Program and NCBI Multiple Alignment Tool Database, four transitions are conserved at evolutionary process, so we can say that these transitions are novel mutations. c. 468T > G alteration at exon 4 and c. 1378 T > A alteration at exon 13 were reported to HGMD previously. Screening the exons of the ITGB3 gene from the same patient groups, we reported a novel missense mutation at exon 5, at nucleotide 680. No correlation was found between clinical phenotype and genotype. These mutations were described for the first time in Turkish population, and all novel mutations are not defined previously. Furthermore, collaborative studies are needed for the population point of view.
The advanced age, low serum albumin levels, and high serum total bilirubin levels are independent risk factors for colistin-induced nephrotoxicity.
Background/aim: Macrothrombocytopenia is an autosomal dominant disorder characterized by increased platelet size and decreased number of circulating platelets. Membrane skeleton and the link between actin filaments of the skeleton and microtubules, which consist of alpha and beta tubulin (including the tubulin beta-1 chain (TUBB1)) heterodimers, are important for the normal platelet morphology and the defects on these systems are also associated with macrothrombocytopenia. Materials and methods: In this study, we have sequenced the exons of the TUBB1 gene using the DNA isolated from peripheral blood samples of the healthy controls (n = 47) and the patients with macrothrombocytopenia (n = 37) from Turkey. TUBB1 expression levels in fractioned blood samples from the patient and healthy controls were analyzed by RT-qPCR and Western Blot. Microtubule organization of the platelets in the patient's peripheral blood smears and in the mutant TUBB1-transfected HeLa cells was analyzed by using immunofluorescence staining. Results: A new TUBB1 c.803G>T (p.T178T) variant was detected in all of the controls and patient samples. Importantly, we found 3 new heterozygous TUBB1 variants predicting amino acid substitutions, G146R (in 1 patient), E123Q (in 1 patient) and T274M (in 4 patients), the latter variant being associated with milder thrombocytopenia in cancer patients treated with paclitaxel. Ectopic expression of TUBB1 T274M/R307H variant in HeLa cells resulted in irregular microtubule organization. Conclusion: Further clinical and functional studies of the newly identified TUBB1 variants might give important insights about their pathogenicity in macrothrombocytopenia.
FDG PET-CT may be useful for determining activity and the efficacy of treatments. Methylprednisolone is effective in reducing metabolic activity but does not lead to improvement in functional parameters.
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