An inherited mutation leading to production of only the short isoform of GATA-1 is associated with impaired erythropoiesis

Author(s)

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. ^[8] ; Costa, Fernando F. ^[9]

• Document type: Journal article
• Source: Nature Genetics; v. 38, n. 7, p. 807-812, July 2006.
• Field of knowledge: Health Sciences - Medicine

Abstract

Acquired somatic mutations1, 2, 3, 4, 5, 6 in exon 2 of the hematopoietic transcription factor GATA-1 have been found in individuals with Down syndrome with both transient myeloproliferative disorder2, 3, 4, 5, 6, 7, 8, 9, 10 and acute megakaryoblastic leukemia1, 2, 3, 4, 6, 8, 9, 10. These mutations prevent the synthesis of the full-length protein but allow the synthesis of its short isoform, GATA-1s. Experiments in mice11 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. (AU)

• FAPESP's process: 02/13801-7 - Hereditary hemoglobin disorders: molecular genetics, clinical features and animal models with the production of transgenic animals
• Grantee: Fernando Ferreira Costa
• Support Opportunities: Research Projects - Thematic Grants