Exome Sequencing Identifies GATA1 Mutations Resulting in Diamond-Blackfan Anemia

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2012 Jun 19

PMID 22706301

Citations 194

Authors

Vijay G Sankaran

Roxanne Ghazvinian

Ron Do

Prathapan Thiru

Jo-Anne Vergilio

Alan H Beggs

Colin A Sieff

Stuart H Orkin

David G Nathan

Eric S Lander

Hanna T Gazda

Affiliations

Soon will be listed here.

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.

Citing Articles

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References

Alford K, Reinhardt K, Garnett C, Norton A, Bohmer K, von Neuhoff C . Analysis of GATA1 mutations in Down syndrome transient myeloproliferative disorder and myeloid leukemia. Blood. 2011; 118(8):2222-38. DOI: 10.1182/blood-2011-03-342774. View

Nichols K, Crispino J, Poncz M, White J, Orkin S, Maris J . Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1. Nat Genet. 2000; 24(3):266-70. PMC: 10576470. DOI: 10.1038/73480. View

Draptchinskaia N, Gustavsson P, Andersson B, Pettersson M, Willig T, Dianzani I . The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia. Nat Genet. 1999; 21(2):169-75. DOI: 10.1038/5951. View

Farrar J, Vlachos A, Atsidaftos E, Carlson-Donohoe H, Markello T, Arceci R . Ribosomal protein gene deletions in Diamond-Blackfan anemia. Blood. 2011; 118(26):6943-51. PMC: 3245214. DOI: 10.1182/blood-2011-08-375170. View

DePristo M, Banks E, Poplin R, Garimella K, Maguire J, Hartl C . A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011; 43(5):491-8. PMC: 3083463. DOI: 10.1038/ng.806. View

Gnirke A, Melnikov A, Maguire J, Rogov P, LeProust E, Brockman W . Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nat Biotechnol. 2009; 27(2):182-9. PMC: 2663421. DOI: 10.1038/nbt.1523. View

Pan X, Ohneda O, Ohneda K, Lindeboom F, Iwata F, Shimizu R . Graded levels of GATA-1 expression modulate survival, proliferation, and differentiation of erythroid progenitors. J Biol Chem. 2005; 280(23):22385-94. DOI: 10.1074/jbc.M500081200. View

Musunuru K, Pirruccello J, Do R, Peloso G, Guiducci C, Sougnez C . Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med. 2010; 363(23):2220-7. PMC: 3008575. DOI: 10.1056/NEJMoa1002926. View

Vlachos A, Ball S, Dahl N, Alter B, Sheth S, Ramenghi U . Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference. Br J Haematol. 2008; 142(6):859-76. PMC: 2654478. DOI: 10.1111/j.1365-2141.2008.07269.x. View

10.

Wechsler J, Greene M, McDevitt M, Anastasi J, Karp J, Le Beau M . Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet. 2002; 32(1):148-52. DOI: 10.1038/ng955. View

11.

Abecasis G, Altshuler D, Auton A, Brooks L, Durbin R, Gibbs R . A map of human genome variation from population-scale sequencing. Nature. 2010; 467(7319):1061-73. PMC: 3042601. DOI: 10.1038/nature09534. View

12.

Li Z, Godinho F, Klusmann J, Garriga-Canut M, Yu C, Orkin S . Developmental stage-selective effect of somatically mutated leukemogenic transcription factor GATA1. Nat Genet. 2005; 37(6):613-9. DOI: 10.1038/ng1566. View

13.

Gazda H, Sheen M, Vlachos A, Choesmel V, ODonohue M, Schneider H . Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients. Am J Hum Genet. 2008; 83(6):769-80. PMC: 2668101. DOI: 10.1016/j.ajhg.2008.11.004. View

14.

Sankaran V, Orkin S, Walkley C . Rb intrinsically promotes erythropoiesis by coupling cell cycle exit with mitochondrial biogenesis. Genes Dev. 2008; 22(4):463-75. PMC: 2238668. DOI: 10.1101/gad.1627208. View

15.

McDevitt M, Shivdasani R, Fujiwara Y, Yang H, Orkin S . A "knockdown" mutation created by cis-element gene targeting reveals the dependence of erythroid cell maturation on the level of transcription factor GATA-1. Proc Natl Acad Sci U S A. 1997; 94(13):6781-5. PMC: 21235. DOI: 10.1073/pnas.94.13.6781. View

16.

Hollanda L, Lima C, Cunha A, Albuquerque D, Vassallo J, Ozelo M . An inherited mutation leading to production of only the short isoform of GATA-1 is associated with impaired erythropoiesis. Nat Genet. 2006; 38(7):807-12. DOI: 10.1038/ng1825. View

17.

Tsai S, Martin D, Zon L, DAndrea A, Wong G, Orkin S . Cloning of cDNA for the major DNA-binding protein of the erythroid lineage through expression in mammalian cells. Nature. 1989; 339(6224):446-51. DOI: 10.1038/339446a0. View

18.

Boria I, Garelli E, Gazda H, Aspesi A, Quarello P, Pavesi E . The ribosomal basis of Diamond-Blackfan Anemia: mutation and database update. Hum Mutat. 2010; 31(12):1269-79. PMC: 4485435. DOI: 10.1002/humu.21383. View

19.

Kuramitsu M, Sato-Otsubo A, Morio T, Takagi M, Toki T, Terui K . Extensive gene deletions in Japanese patients with Diamond-Blackfan anemia. Blood. 2012; 119(10):2376-84. DOI: 10.1182/blood-2011-07-368662. View

20.

Narla A, Ebert B . Ribosomopathies: human disorders of ribosome dysfunction. Blood. 2010; 115(16):3196-205. PMC: 2858486. DOI: 10.1182/blood-2009-10-178129. View