11/9/2023 0 Comments Gene construction kit error 199We show here that the mutations affected the amount of mutant protein. Based on our estimates of GATA1s protein expression, the mutations were classified into GATA1s high and low groups. Phenotypic analyses of 66 TAM patients with GATA1 mutations revealed that GATA1s low mutations were significantly associated with a risk of progression to ML-DS ( P <. 001) and lower white blood cell counts ( P =. Our study indicates that quantitative differences in mutant protein levels have significant effects on the phenotype of TAM and warrants further investigation in a prospective study.īlast cells in most patients with TAM and ML-DS have mutations in exon 2 of the gene coding the transcription factor GATA1, 8–14 which is essential for normal development of erythroid and megakaryocytic cells. 15–18 The mutations lead to exclusive expression of a truncated GATA1 protein (referred to as GATA1s) translated from the second methionine on exon 3. These findings strongly suggest that the qualitative deficit of GATA1 contributes to the genesis of TAM and ML-DS. The analysis of megakaryocyte-specific knockdown of GATA1 in vivo has revealed a critical role for this factor in megakaryocytic development. Reduced expression (or complete absence) of GATA1 in megakaryocytes leads to increased proliferation and deficient maturation as well as a reduced number of circulating platelets. 19, 20 Mice harboring a heterozygous GATA1 knockdown allele frequently develop erythroblastic leukemia. 21 These observations indicate that the expression levels of GATA1 are crucial for the proper development of erythroid and megakaryocytic cells and compromised GATA1 expression is a causal factor in leukemia. 22 Nevertheless, the impact of a quantitative deficit of the factor on the pathogenesis of TAM and ML-DS has not been examined. This study was approved by the Ethics Committee of Hirosaki University Graduate School of Medicine, and all clinical samples were obtained with informed consent from the parents of all patients with TAM, in accordance with the Declaration of Helsinki. The following clinical data were collected: sex, gestational age, birth weight, time of diagnosis, symptom at diagnosis, and clinical presentation. The following laboratory data were obtained: a complete blood cell count at diagnosis including WBC and the percentage of blasts in the peripheral blood, coagulation parameters, liver enzymes (alanine aminotransferase and aspartate aminotransferase), and total bilirubin. The procedure for the detection of GATA1 mutations was described previously. 13 Genomic DNA was directly extracted from peripheral blood or bone marrow with the QIAamp blood mini kit (QIAGEN). Total RNA was extracted from white blood cells prepared by removal of erythrocytes by hypotonic buffer treatment of peripheral blood.
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