GATA2 – Myelodysplastic Syndrome

GATA2 encodes a zinc-finger transcription factor essential for hematopoietic stem and progenitor cell maintenance. Heterozygous germline mutations in GATA2 lead to autosomal dominant haploinsufficiency, manifesting as bone marrow failure and a high risk of progression to myelodysplastic syndrome (MDS) (PMID:21892162). Clinical phenotypes often include monocytopenia, B-cell lymphopenia, and NK-cell deficiency, reflecting disrupted myeloid and lymphoid lineages.

A range of case series and familial studies have identified over 50 unrelated individuals with MDS carrying GATA2 mutations, including missense variants clustered in zinc finger domains and loss-of-function alleles due to frameshifts or noncoding deletions (PMID:22147895; PMID:24345756). The most recurrent variant, c.1061C>T (p.Thr354Met), alters the second zinc finger critical for DNA binding and protein–protein interactions. Functional classification of mutations includes missense in ZF1/ZF2, splice-site and frameshift mutations, as well as intronic enhancer lesions, underscoring a broad variant spectrum.

Segregation analysis across at least four multiplex families demonstrates co-segregation of GATA2 variants with MDS phenotypes, affecting more than 19 first-degree relatives with concordant cytopenias and bone marrow dysplasia (segregation in 4 families) (PMID:21892162). Compound heterozygotes or cis-allelic missense combinations have not been reported, supporting a haploinsufficiency mechanism rather than dominant-negative effects.

Experimental studies confirm that GATA2 mutations impair transcriptional autoregulation and target gene activation. Chromatin immunoprecipitation and luciferase assays show reduced promoter occupancy and self-activation by p.Thr354Met and p.Arg396Gln alleles, leading to ~60% of normal transcript levels in patient cells (PMID:25624456). Mouse models of enhancer and coding mutations recapitulate defective stress hematopoiesis, further validating the requirement of full GATA2 dosage for stem cell regeneration (PMID:30620726).

No substantial conflicting evidence has been reported; all mutation types across zinc fingers or regulatory elements converge on reduced GATA2 function. Somatic second hits (e.g., ASXL1, monosomy 7) frequently accompany GATA2-driven MDS, indicating cooperative leukemogenic events.

Integration of genetic and functional data supports a Strong association: multiple unrelated probands, multigenerational segregation, and robust mechanistic concordance. Additional evidence, including deep sequencing of germline predisposition in young adult MDS cohorts, underscores the significance of GATA2 screening in unexplained cytopenias. Key take-home: Germline GATA2 testing should be integrated into diagnostic workflows for MDS, as early identification guides surveillance and consideration of hematopoietic stem cell transplantation.

References

• Nature Genetics • 2011 • Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia PMID:21892162
• Blood • 2012 • Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature PMID:22147895
• Blood • 2014 • The evolution of cellular deficiency in GATA2 mutation PMID:24345756
• Journal of Immunology • 2015 • GATA2 germline mutations impair GATA2 transcription, causing haploinsufficiency: functional analysis of the p.Arg396Gln mutation PMID:25624456
• The Journal of Clinical Investigation • 2019 • Single-nucleotide human disease mutation inactivates a blood-regenerative GATA2 enhancer PMID:30620726

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