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

LM Hollanda, CSP Lima, AF Cunha, DM Albuquerque… - Nature …, 2006 - nature.com
Nature genetics, 2006nature.com
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→ …
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.
nature.com