GATA1 – Diamond-Blackfan Anemia

Diamond-Blackfan anemia (DBA) is a congenital erythroid aplasia most often caused by ribosomal protein haploinsufficiency; rare X-linked cases are due to GATA1 defects. In total, 23 unrelated probands with GATA1 variants have been described, including de novo initiation codon, splice, and frameshift mutations in males and females with skewed X inactivation (PMID:36029112; PMID:35328001).

Inheritance is X-linked with disease manifesting in hemizygous males; one pedigree showed cosegregation in two affected male relatives (PMID:35846220). Female patients may present with transient erythroblastopenia due to skewed lyonization of the wild-type allele (PMID:38149846).

The variant spectrum includes loss-of-function mutations: initiation codon (c.3G>A (p.Met1Ile)) leading to exclusive production of the short GATA1s isoform (PMID:36029112), splice site mutations (c.220+1G>A), frameshifts, and deep-intronic changes impairing full-length GATA1 translation (PMID:22706301).

Pathogenic mechanism is haploinsufficiency of full-length GATA1: initiation codon and splice site mutations abolish the N-terminal transactivation domain, producing a truncated isoform that fails to fully support erythroid differentiation. Ex vivo culture of patient CD34+ cells shows reduced proliferation and delayed maturation in GATA1-mediated DBA (PMID:28377399).

Animal and cellular models corroborate human findings: a knockdown in mice with decreased GATA1 levels impairs erythroid maturation in a dose-dependent manner (PMID:9192642), and a zebrafish gata1 nonsense mutant exhibits bloodless phenotypes analogous to DBA (PMID:11960002).

Collectively, these data meet ClinGen criteria for a Strong gene–disease relationship. GATA1 testing is clinically actionable for male patients and select females with unexplained erythroid aplasia.

References

• Clinical genetics • 2022 • Diamond-Blackfan anaemia caused by a de novo initiation codon mutation resulting in a shorter isoform of GATA1. PMID:36029112
• Pediatric blood & cancer • 2024 • Transient erythroblastopenia due to a GATA1 variant in an infant female. PMID:38149846
• The Journal of clinical investigation • 2012 • Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia. PMID:22706301
• Genes • 2022 • GATA-1 Defects in Diamond-Blackfan Anemia: Phenotypic Characterization Points to a Specific Subset of Disease. PMID:35328001
• EJHaem • 2022 • Dyserythropoietic anaemia with an intronic GATA1 splicing mutation in patients suspected to have Diamond-Blackfan anaemia. PMID:35846220
• Proceedings of the National Academy of Sciences of the United States of America • 1997 • A "knockdown" mutation created by cis-element gene targeting reveals the dependence of erythroid cell maturation on the level of transcription factor GATA-1. PMID:9192642
• Proceedings of the National Academy of Sciences of the United States of America • 2002 • A nonsense mutation in zebrafish gata1 causes the bloodless phenotype in vlad tepes. PMID:11960002
• Blood • 2017 • Molecular convergence in ex vivo models of Diamond-Blackfan anemia. PMID:28377399

Evidence Based Scoring (AI generated)