Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia

Abstract

Diamond-Blackfan anemia (DBA) is a hypoplastic anemia characterized by impaired production of red blood cells, with approximately half of all cases attributed to ribosomal protein gene mutations. We performed exome sequencing on two siblings who had no known pathogenic mutations for DBA and identified a mutation in the gene encoding the hematopoietic transcription factor GATA1. This mutation, which occurred at a splice site of the GATA1 gene, impaired production of the full-length form of the protein. We further identified an additional patient carrying a distinct mutation at the same splice site of the GATA1 gene. These findings provide insight into the pathogenesis of DBA, showing that the reduction in erythropoiesis associated with the disease can arise from causes other than defects in ribosomal protein genes. These results also illustrate the multifactorial role of GATA1 in human hematopoiesis.

Pluripotent stem cells reveal erythroid-specific activities of the GATA1 N-terminus

“…In contrast, mice with germline Gata1s mutations exhibit moderate-to-severe anemia and enhanced megakaryopoiesis between E9.5 and E14.5, but some survive to birth, after which hematopoiesis normalizes postnatally (12,13). Overall, studies of human patients and genetically manipulated mice demonstrate that the functions of the GATA1 N-terminus and the consequences of its loss depend on gene dosage, cell context, developmental stage, and species (2,3,9,(12)(13)(14).…”

“…In normal humans, alternative splicing or translation initiation site usage produces 2 forms of GATA1 protein: full-length (GATA1fl) and a truncated isoform lacking the first 83 amino acids (GATA1s) (1,2). Germline GATA1 mutations that favor GATA1s expression over fulllength GATA1 (hereafter referred to as "GATA1s mutations") were identified in a pedigree with congenital hypoplastic anemia and neutropenia (2) and in patients with Diamond Blackfan anemia (DBA), a rare congenital anemia with erythroid hypoplasia (3,4). In individuals with germline trisomy 21 (T21, Down syndrome [DS]), somatic GATA1s mutations in fetal hematopoietic progenitors promote 2 clonal disorders, transient myeloproliferative disease (TMD) and acute megakaryoblastic leukemia (AMKL) (5,6).…”

Clinical aspects and pathogenesis of congenital dyserythropoietic anemias: from morphology to molecular approach

“…81 Although the bone marrow examination from these patients confirmed the clinical diagnosis of DBA, the absence of a dominant inheritance, as well as the mildly low platelet count in one of 2 patients, make it more appropriate to consider these cases as DBA-like conditions. This further underlined the variability of the GATA-1-related phenotypes.…”

“…80 Very recently, this mutation has been found in 2 siblings affected by Diamond-Blackfan anemia (DBA), a Clinical aspects and pathogenesis of CDAs haematologica | 2012; 97 (12) 1791 © F e r r a t a S t o r t i F o u n d a t i o n dominant disorder characterized by reduced proliferation and survival of erythroid progenitors leading to hypoproliferative anemia. 81 Although the bone marrow examination from these patients confirmed the clinical diagnosis of DBA, the absence of a dominant inheritance, as well as the mildly low platelet count in one of 2 patients, make it more appropriate to consider these cases as DBA-like conditions. This further underlined the variability of the GATA-1-related phenotypes.…”

Society for Pediatric Research 2015 Young Investigator Award: genetics of human hematopoiesis—what patients can teach us about blood cell production

“…How mutations in ubiquitous ribosomal proteins can lead to such a cell-type-specific defect remained a major mystery. By utilizing whole-exome sequencing, we were able to show that rare cases of DBA can be caused in males by mutations that reduce the production of the key hematopoietic transcription factor GATA1 (20). However, whether such rare mutations related to the much more commonly observed ribosomal protein mutations remained a mystery.…”