Hollanda Luciana M, Lima Carmen S P, Cunha Anderson F, Albuquerque Dulcinéia M, Vassallo José, Ozelo Margareth C, Joazeiro Paulo P, Saad Sara T O, Costa Fernando F
Department of Internal Medicine, Hemocentro, School of Medical Science, Universidade Estadual de Campinas, Campinas, São Paulo 13083-970, Brazil.
Nat Genet. 2006 Jul;38(7):807-12. doi: 10.1038/ng1825. Epub 2006 Jun 18.
Acquired somatic mutations in exon 2 of the hematopoietic transcription factor GATA-1 have been found in individuals with Down syndrome with both transient myeloproliferative disorder and acute megakaryoblastic leukemia. These mutations prevent the synthesis of the full-length protein but allow the synthesis of its short isoform, GATA-1s. Experiments in mice suggest that GATA-1s supports normal adult megakaryopoiesis, platelet formation and erythropoiesis. Here we report a mutation, 332G --> C, in exon 2 of GATA1, leading to the synthesis of only the short isoform in seven affected males from two generations of a family. Hematological profiles of affected males demonstrate macrocytic anemia, normal platelet counts and neutropenia in most cases. Altogether, data suggest that GATA-1s alone, produced in low or normal levels, is not sufficient to support normal erythropoiesis. Moreover, this is the first study to indicate that a germline splicing mutation does not lead to leukemia in the absence of other cooperating events, such as Down syndrome.
在患有唐氏综合征且伴有短暂性骨髓增殖性疾病和急性巨核细胞白血病的个体中，发现造血转录因子GATA-1外显子2存在获得性体细胞突变。这些突变阻止了全长蛋白的合成，但允许其短异构体GATA-1s的合成。小鼠实验表明，GATA-1s支持正常的成年巨核细胞生成、血小板形成和红细胞生成。在此，我们报告了GATA1外显子2中的一个突变332G→C，该突变导致来自一个家族两代的七名受影响男性仅合成短异构体。受影响男性的血液学特征在大多数情况下表现为大细胞性贫血、血小板计数正常和中性粒细胞减少。总体而言，数据表明，低水平或正常水平产生的单独的GATA-1s不足以支持正常的红细胞生成。此外，这是第一项表明在没有其他协同事件（如唐氏综合征）的情况下，种系剪接突变不会导致白血病的研究。
