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Cytogenetics and molecular genetics

Breaking the spatial constraint between neighboring zinc fingers: a new germline mutation in GATA2 deficiency syndrome

Leukemia volume 35, pages 264–268 (2021)Cite this article

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GATA2 deficiency syndrome is an autosomal dominant disorder caused by germline mutations in the GATA2 gene, which encodes a transcription factor with two zinc fingers that is essential for hematopoiesis. There are four classes of these GATA2 mutations: truncating mutations proximal to the C-finger, C-finger missense mutations, noncoding mutations within an intron, and mutations resulting in aberrant mRNA splicing. Here, we report a novel GATA2 mutation that defines a new class of germline mutation: an in-frame insertion mutation that increases the separation of the two zinc fingers through the addition of nine amino acids. By several functional tests, this mutation was shown to be defective, establishing it as a pathogenic mutation and a new type of germline GATA2 mutation.

GATA2 deficiency syndrome is a phenotypically heterogeneous autosomal dominant disorder caused by mutations in the GATA2 gene, which encodes a transcription factor essential for hematopoiesis [1]. GATA2 deficiency has a varied clinical presentation that includes congenital lymphedema, immunodeficiency, viral/fungal/bacterial infections, especially of atypical mycobacterial species, and alveolar proteinosis among others [2]. GATA2 deficiency patients, both pediatric and adult, are predisposed to bone marrow failure and have an elevated risk of developing myeloid malignancies [2].

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Fig. 1: Personal and family history of the proband.
Fig. 2: Quantitative comparison of GATA2 and GATA2 mutant activities.

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Acknowledgements

The authors are indebted to the patient and her family for willingness to participate in our research. MCAS was supported by a grant from CAPES/PDSE/8888.1/188484/2018-01. EHB was supported by National Institutes of Health grant DK68634, the Edward Evans Foundation, and the Carbone Cancer Center P30CA014520.

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Author notes

  1. These authors contributed equally: Marcela Cavalcante de Andrade Silva, Koichi R. Katsumura

Authors and Affiliations

  1. Serviço de Hematologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, BR Av. Dr. Eneas de Carvalho 155, Cerqueira César, 01246-000, São Paulo, SP, Brazil

    Marcela Cavalcante de Andrade Silva & Elvira D. R. P. Velloso

  2. Section of Hematology/Oncology and Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA

    Marcela Cavalcante de Andrade Silva & Lucy A. Godley

  3. Department of Cell and Regenerative Biology, UW-Madison Blood Research Program, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Koichi R. Katsumura, Charu Mehta & Emery H. Bresnick

Authors
  1. Marcela Cavalcante de Andrade Silva
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  2. Koichi R. Katsumura
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  3. Charu Mehta
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  4. Elvira D. R. P. Velloso
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  5. Emery H. Bresnick
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  6. Lucy A. Godley
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Contributions

MCAS analyzed clinical and sequencing data and wrote the manuscript; KRK performed genetic rescue analyses, analyzed data, and edited the manuscript; CM modeled zinc finger structure and edited the manuscript; EDRPV, EHB, and LAG reviewed the data and wrote the manuscript.

Corresponding authors

Correspondence to Emery H. Bresnick or Lucy A. Godley.

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Conflict of interest

LAG serves on the Scientific Advisory Board of Invitae, Inc., and receives royalties from UptoDate, Inc. MCAS, KRK, CM, EDRPV, and EHB declare no competing financial interests.

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Cavalcante de Andrade Silva, M., Katsumura, K.R., Mehta, C. et al. Breaking the spatial constraint between neighboring zinc fingers: a new germline mutation in GATA2 deficiency syndrome. Leukemia 35, 264–268 (2021). https://doi.org/10.1038/s41375-020-0820-2

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