Skip to main content

Advertisement

SpringerLink
Log in

Cytopenia: a report of haplo-cord transplantation in twin brothers caused by a novel germline GATA1 mutation and family survey

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

Cytopenia due to the abnormal regulation of GATA1 could manifest as varying degrees of thrombocytopenia and/or anemia and more severely in male children than in female children. Here, we describe the case of pancytopenic and transfusion-dependent twin brothers at our center whose bone marrow puncture revealed low bone marrow hyperplasia. Whole-exome sequencing revealed that the twins had a new germline GATA1 mutation (nm_002049: exon 3:c.515 T >C:p.F172S), which confirmed the diagnosis of GATA1 mutation–related pancytopenia. The mutation was inherited from their mother, who was heterozygous for the mutation. Sanger sequencing verified the pathogenicity of the mutation. Further family morbidity survey confirmed that GATA1 mutation–related pancytopenia is an X-linked recessive genetic disorder. We developed haploid hematopoietic stem cell transplantation programs for twins, with the father as the only donor, and finally, the hematopoietic reconstruction was successful. Although they experienced acute graft-versus-host disease, hemorrhagic cystitis, and a viral infection in the early stage, no abnormal manifestations or transplant-related complications were observed 3 months after transplantation. Through hematopoietic stem cell transplantation technology for one donor and two receptors, we eventually cured the twins. The p.F172S variant in the new germline GATA1 mutation may play an essential role in the pathogenesis of GATA1 mutation–related cytopenia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Takasaki K, Kacena MA, Raskind WH, Weiss MJ, Chou ST (2006) GATA1-Related Cytopenia. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A (eds) GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2023 Nov 22 updated 2023 Feb 16

  2. Freson K, Wijgaerts A, Van Geet C (2017) GATA1 gene variants associated with thrombocytopenia and anemia. Platelets 28:731–734. https://doi.org/10.1080/09537104.2017.1361525

    Article  CAS  PubMed  Google Scholar 

  3. Ling T, Crispino JD (2020) GATA1 mutations in red cell disorders. IUBMB Life 72:106–118. https://doi.org/10.1002/iub.2177

    Article  CAS  PubMed  Google Scholar 

  4. Crispino JD, Horwitz MS (2017) GATA factor mutations in hematologic disease. Blood 129:2103–2110. https://doi.org/10.1182/blood-2016-09-687889

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Varadi M, Anyango S, Deshpande M, Nair S, Natassia C, Yordanova G, Yuan D, Stroe O, Wood G, Laydon A, Žídek A, Green T, Tunyasuvunakool K, Petersen S, Jumper J, Clancy E, Green R, Vora A, Lutfi M, Figurnov M, Cowie A, Hobbs N, Kohli P, Kleywegt G, Birney E, Hassabis D, Velankar S (2022) AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models. Nucleic Acids Res 50:D439-d444. https://doi.org/10.1093/nar/gkab1061

    Article  CAS  PubMed  Google Scholar 

  6. Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, Tunyasuvunakool K, Bates R, Žídek A, Potapenko A, Bridgland A, Meyer C, Kohl SAA, Ballard AJ, Cowie A, Romera-Paredes B, Nikolov S, Jain R, Adler J, Back T, Petersen S, Reiman D, Clancy E, Zielinski M, Steinegger M, Pacholska M, Berghammer T, Silver D, Vinyals O, Senior AW, Kavukcuoglu K, Kohli P, Hassabis D (2021) Applying and improving AlphaFold at CASP14. Proteins 89:1711–1721. https://doi.org/10.1002/prot.26257

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, Tunyasuvunakool K, Bates R, Žídek A, Potapenko A, Bridgland A, Meyer C, Kohl SAA, Ballard AJ, Cowie A, Romera-Paredes B, Nikolov S, Jain R, Adler J, Back T, Petersen S, Reiman D, Clancy E, Zielinski M, Steinegger M, Pacholska M, Berghammer T, Bodenstein S, Silver D, Vinyals O, Senior AW, Kavukcuoglu K, Kohli P, Hassabis D (2021) Highly accurate protein structure prediction with AlphaFold. Nature 596:583–589. https://doi.org/10.1038/s41586-021-03819-2

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Ferreira R, Ohneda K, Yamamoto M, Philipsen S (2005) GATA1 function, a paradigm for transcription factors in hematopoiesis. Mol Cell Biol 25:1215–1227. https://doi.org/10.1128/mcb.25.4.1215-1227.2005

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Crispino JD, Weiss MJ (2014) Erythro-megakaryocytic transcription factors associated with hereditary anemia. Blood 123:3080–3088. https://doi.org/10.1182/blood-2014-01-453167

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Wechsler J, Greene M, McDevitt MA, Anastasi J, Karp JE, Le Beau MM, Crispino JD (2002) Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet 32:148–152. https://doi.org/10.1038/ng955

    Article  CAS  PubMed  Google Scholar 

  11. Mundschau G, Gurbuxani S, Gamis AS, Greene ME, Arceci RJ, Crispino JD (2003) Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis. Blood 101:4298–4300. https://doi.org/10.1182/blood-2002-12-3904

    Article  CAS  PubMed  Google Scholar 

  12. Nichols KE, Crispino JD, Poncz M, White JG, Orkin SH, Maris JM, Weiss MJ (2000) Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1. Nat Genet 24:266–270. https://doi.org/10.1038/73480

    Article  CAS  PubMed  Google Scholar 

  13. Raskind WH, Niakan KK, Wolff J, Matsushita M, Vaughan T, Stamatoyannopoulos G, Watanabe C, Rios J, Ochs HD (2000) Mapping of a syndrome of X-linked thrombocytopenia with Thalassemia to band Xp11-12: further evidence of genetic heterogeneity of X-linked thrombocytopenia. Blood 95:2262–2268

    Article  CAS  PubMed  Google Scholar 

  14. Mehaffey MG, Newton AL, Gandhi MJ, Crossley M, Drachman JG (2001) X-linked thrombocytopenia caused by a novel mutation of GATA-1. Blood 98:2681–2688. https://doi.org/10.1182/blood.v98.9.2681

    Article  CAS  PubMed  Google Scholar 

  15. Del Vecchio GC, Giordani L, De Santis A, De Mattia D (2005) Dyserythropoietic anemia and thrombocytopenia due to a novel mutation in GATA-1. Acta Haematol 114:113–116. https://doi.org/10.1159/000086586

    Article  PubMed  Google Scholar 

  16. Kratz CP, Niemeyer CM, Karow A, Volz-Fleckenstein M, Schmitt-Gräff A, Strahm B (2008) Congenital transfusion-dependent anemia and thrombocytopenia with myelodysplasia due to a recurrent GATA1(G208R) germline mutation. Leukemia 22:432–434. https://doi.org/10.1038/sj.leu.2404904

    Article  CAS  PubMed  Google Scholar 

  17. Yu C, Niakan KK, Matsushita M, Stamatoyannopoulos G, Orkin SH, Raskind WH (2002) X-linked thrombocytopenia with thalassemia from a mutation in the amino finger of GATA-1 affecting DNA binding rather than FOG-1 interaction. Blood 100:2040–2045. https://doi.org/10.1182/blood-2002-02-0387

    Article  CAS  PubMed  Google Scholar 

  18. Balduini CL, Pecci A, Loffredo G, Izzo P, Noris P, Grosso M, Bergamaschi G, Rosti V, Magrini U, Ceresa IF, Conti V, Poggi V, Savoia A (2004) Effects of the R216Q mutation of GATA-1 on erythropoiesis and megakaryocytopoiesis. Thromb Haemost 91:129–140. https://doi.org/10.1160/th03-05-0290

    Article  CAS  PubMed  Google Scholar 

  19. Hughan SC, Senis Y, Best D, Thomas A, Frampton J, Vyas P, Watson SP (2005) Selective impairment of platelet activation to collagen in the absence of GATA1. Blood 105:4369–4376. https://doi.org/10.1182/blood-2004-10-4098

    Article  CAS  PubMed  Google Scholar 

  20. Åström M, Hahn-Strömberg V, Zetterberg E, Vedin I, Merup M, Palmblad J (2015) X-linked thrombocytopenia with thalassemia displays bone marrow reticulin fibrosis and enhanced angiogenesis: comparisons with primary myelofibrosis. Am J Hematol 90:E44-48. https://doi.org/10.1002/ajh.23907

    Article  CAS  PubMed  Google Scholar 

  21. Phillips JD, Steensma DP, Pulsipher MA, Spangrude GJ, Kushner JP (2007) Congenital erythropoietic porphyria due to a mutation in GATA1: the first trans-acting mutation causative for a human porphyria. Blood 109:2618–2621. https://doi.org/10.1182/blood-2006-06-022848

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Freson K, Devriendt K, Matthijs G, Van Hoof A, De Vos R, Thys C, Minner K, Hoylaerts MF, Vermylen J, Van Geet C (2001) Platelet characteristics in patients with X-linked macrothrombocytopenia because of a novel GATA1 mutation. Blood 98:85–92. https://doi.org/10.1182/blood.v98.1.85

    Article  CAS  PubMed  Google Scholar 

  23. Freson K, Matthijs G, Thys C, Mariën P, Hoylaerts MF, Vermylen J, Van Geet C (2002) Different substitutions at residue D218 of the X-linked transcription factor GATA1 lead to altered clinical severity of macrothrombocytopenia and anemia and are associated with variable skewed X inactivation. Hum Mol Genet 11:147–152. https://doi.org/10.1093/hmg/11.2.147

    Article  CAS  PubMed  Google Scholar 

  24. Hermans C, De Waele L, Van Geet C, Freson K (2014) Novel GATA1 mutation in residue D218 leads to macrothrombocytopenia and clinical bleeding problems. Platelets 25:305–307. https://doi.org/10.3109/09537104.2013.815339

    Article  CAS  PubMed  Google Scholar 

  25. Svidnicki M, Filho MAF, Brandão MM, Dos Santos M, de Oliveira Dias R, Tavares RS, Assis-Mendonça GR, Traina F, Saad STO (2021) New germline GATA1 variant in females with anemia and thrombocytopenia. Blood Cells Mol Dis 88:102545. https://doi.org/10.1016/j.bcmd.2021.102545

    Article  CAS  PubMed  Google Scholar 

  26. Hollanda LM, Lima CS, Cunha AF, Albuquerque DM, Vassallo J, Ozelo MC, Joazeiro PP, Saad ST, Costa FF (2006) An inherited mutation leading to production of only the short isoform of GATA-1 is associated with impaired erythropoiesis. Nat Genet 38:807–812. https://doi.org/10.1038/ng1825

    Article  CAS  PubMed  Google Scholar 

  27. Sankaran VG, Ghazvinian R, Do R, Thiru P, Vergilio JA, Beggs AH, Sieff CA, Orkin SH, Nathan DG, Lander ES, Gazda HT (2012) Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia. J Clin Invest 122:2439–2443. https://doi.org/10.1172/jci63597

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Parrella S, Aspesi A, Quarello P, Garelli E, Pavesi E, Carando A, Nardi M, Ellis SR, Ramenghi U, Dianzani I (2014) Loss of GATA-1 full length as a cause of Diamond-Blackfan anemia phenotype. Pediatr Blood Cancer 61:1319–1321. https://doi.org/10.1002/pbc.24944

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Zucker J, Temm C, Czader M, Nalepa G (2016) A child with dyserythropoietic anemia and megakaryocyte dysplasia due to a novel 5’UTR GATA1s splice mutation. Pediatr Blood Cancer 63:917–921. https://doi.org/10.1002/pbc.25871

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the Clinical Research Plan of SHDC (grant number SHDC2020CR4089), the Research Foundation of Shanghai Municipal Health Commission (grant number 20194Y0112), and the Excellent Youth Talent Training Plan of Shanghai Children’s Hospital (grant number 2021YQ01).

Author information

Author notes

  1. Xing-Hua Sun and Qin Liu are co-first authors and contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology and Oncology, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, No. 24, Lane 1400, Beijing West Road, Jing’an District, Shanghai, 200040, China

    Xing-Hua Sun, Qin Liu, Kai Chen, Jing-Bo Shao & Hui Jiang

  2. Central Laboratory, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Sheng-Nan Wu & Wu-Hen Xu

Authors
  1. Xing-Hua Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sheng-Nan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wu-Hen Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kai Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jing-Bo Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hui Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Xing-Hua Sun and Qin Liu contributed to the operation and follow-up of the study. Sheng-Nan Wu and Wu-Hen Xu contributed to the supervision and visualization of the study. Kai Chen contributed to the operation of the study, literature research, and drafting and editing of the manuscript. Jing-Bo Shao and Hui Jiang contributed to the supervision of the study and reviewing and editing of the manuscript. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Kai Chen.

Ethics declarations

Ethics approval

The study was approved by the Ethics Committee of Shanghai Children’s Hospital (Approval number: 2019R035-F01).

Consent

Informed consent was obtained from the parents of the participants.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sun, XH., Liu, Q., Wu, SN. et al. Cytopenia: a report of haplo-cord transplantation in twin brothers caused by a novel germline GATA1 mutation and family survey. Ann Hematol 102, 3177–3184 (2023). https://doi.org/10.1007/s00277-023-05363-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-023-05363-7

Keywords

Search

Navigation