title: An inherited mutation leading to production of only the short isoform of GATA-1 is associated with impaired erythropoiesis.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Hemocentro, School of Medical Science, Universidade Estadual de Campinas, Campinas, São Paulo 13083-970, Brazil.
authors.forename: Luciana M
authors.initials: LM
authors.lastname: Hollanda
authors.forename: Carmen S P
authors.initials: CS
authors.lastname: Lima
authors.forename: Anderson F
authors.initials: AF
authors.lastname: Cunha
authors.forename: Dulcinéia M
authors.initials: DM
authors.lastname: Albuquerque
authors.forename: José
authors.initials: J
authors.lastname: Vassallo
authors.forename: Margareth C
authors.initials: MC
authors.lastname: Ozelo
authors.forename: Paulo P
authors.initials: PP
authors.lastname: Joazeiro
authors.forename: Sara T O
authors.initials: ST
authors.lastname: Saad
authors.forename: Fernando F
authors.initials: FF
authors.lastname: Costa
mesh_terms: D000293:Adolescent; D000328:Adult; D000748:Anemia, Macrocytic / Q000097:blood / Q000235:genetics / Q000473:pathology; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism / Q000648:ultrastructure; D001853:Bone Marrow / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004920:Erythropoiesis / Q000235:genetics*; D005260:Female; D050982:GATA1 Transcription Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D010375:Pedigree; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D020033:Protein Isoforms