Clinical Diagnosis

The diagnosis of GATA1-related cytopenia is suggested in males with the following:

• Thrombocytopenia and/or anemia ranging from mild to severe (including fetal hydrops)
• One or more of the following:
  • Platelet dysfunction
  • Mild β-thalassemia
  • Neutropenia
  • Congenital erythropoietic porphyria (CEP)
• Family history consistent with X-linked inheritance
• No evidence of Wiskott-Aldrich syndrome (WAS), an X-linked disorder of microthrombocytopenia that can present with or without immunodeficiency

The diagnosis of GATA1-related cytopenia is established when a GATA1 disease-causing mutation is detected..

Note: (1) Hematologic findings in GATA1-related cytopenia are variable and usually nonspecific (i.e., seen in numerous conditions and thus by themselves not indicative of a specific diagnosis). (2) Females may be affected but usually have milder symptoms.

Testing

Diagnostic laboratory findings in males with GATA1-related cytopenia include the following:

• Complete blood count
  • Platelet counts are usually low (11-82 x 10³/µL), but vary considerably with specific mutations. Normal counts have also been reported (150-400 x 10³/µL). The platelets are typically larger than normal (macrothrombocytopenia).
  • Anemia (hematocrit 16%-35%; normal: 35%-45%) may be present; the severity is associated with the specific mutation. Red cell indices are normochromic but may be mildly microcytic (75-79 fL) or macrocytic (101-103 fL) (normal: 80-99 fL).
  • Significant persistent neutropenia (0.5-2.8 x 10³/µL; normal 1.9-8.0 x 10³/µL) was observed in one family with a specific GATA1 mutation [Hollanda et al 2006].

Note: Thrombocytopenia, anemia, and neutropenia are usually defined as two standard deviations below values observed in the normal population.

• Peripheral blood smear may show the following:
  • Some platelets that are larger and more spherical than the typical discoid morphology. Platelets may be pale, reflecting reduced granularity.
  • Variation in erythrocyte size and shape and hypochromia, reflecting low hemoglobin content
  • Decreased neutrophils with abnormal morphology; this rare finding was reported in one family with an unusual germline mutation that results in exclusive production of truncated GATA-1 (erythroid transcription factor) protein (GATA-1s) [Hollanda et al 2006].
• Bone marrow biopsy may show the following:
  • Hyper- or hypocellularity
  • Increased or decreased numbers of megakaryocytes
  • Small, dysplastic megakaryocytes with signs of incomplete maturation
  • Dyserythropoiesis
  • Hypocellularity of erythroid and granulocytic lineages
• Platelet function abnormalities. Defects in platelet aggregation in response to agonists, such as ristocetin, adenosine diphosphate, epinephrine or collagen occur in some cases [Thompson et al 1977, Freson et al 2001, Balduini et al 2004, Hollanda et al 2006]. These studies can be normal in some affected individuals.
• Electron microscopy. Findings in some cases include reduced numbers of platelet alpha granules and dysplastic features in megakaryocytes and platelets.
• In subtypes associated with globin chain imbalance, findings consistent with mild hemolysis, including mild reticulocytosis, elevated LDH, and low haptoglobin, may be present. In addition, HbA2 and HbF may be elevated.

Note: In female carriers, two distinct platelet morphologies can be observed on peripheral blood smear, reflecting mosaicism secondary to random X-chromosome inactivation.

Definitions of terms used to describe this disorder

• Thrombocytopenia: reduced platelet count
• Macrothrombocytopenia: thrombocytopenia with large platelets
• Dyserythropoiesis: impaired production and maturation of erythrocytes (red blood cells)
• Thalassemia: an inherited form of anemia associated with unbalanced globin chain synthesis
• Hemoglobin: the oxygen-carrying compound of red blood cells, made up of heme, α-globin, and β-globin. β-thalassemia is associated with decreased β-globin synthesis in red blood cells.

Molecular Genetic Testing

Gene. GATA1 is the only gene in which mutation is known to be associated with GATA1-related cytopenia.

Clinical testing

• Sequence analysis. Most GATA1 mutations identified in GATA1-related cytopenias have been missense mutations. One germline mutation predicting a splicing abnormality that results in the loss of the first 83 coding amino acids of GATA-1 has been reported [Hollanda et al 2006].
• Deletion/duplication analysis. Some laboratories offer deletion/duplication analysis of GATA1; however, no exonic or whole-gene deletions or duplications have been reported as a cause of GATA1-related cytopenia. Complete loss of GATA1 through deletion is expected to be embryonic lethal in males. This could be maintained in carrier females but has not been seen. Copy number variation of GATA1 could be detected by a variety of methods (Table 1).

Table 1. Summary of Molecular Genetic Testing Used in GATA1-Related Cytopenias

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1		Test Availability
			Affected Males	Carrier Females
GATA1	Sequence analysis	Sequence variants 2	>95% 3	>95% 4	Clinical
	Deletion/duplication analysis 5	Deletion/ duplication of one or more exons or the whole gene	Unknown; none reported 6	Unknown; none reported 6

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Lack of amplification by PCRs prior to sequence analysis can suggest a putative deletion of one or more exons or the entire X-linked gene in a male; confirmation may require additional testing by deletion/duplication analysis.

4. Sequence analysis of genomic DNA cannot detect deletion or duplication of one or more exons or the entire X-linked gene in a heterozygous female.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

6. No deletions or duplications involving GATA1 as causative of GATA1-related cytopenia have been reported. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband. Initial testing should include complete blood count, examination of the blood smear, and bone marrow aspirate and biopsy to confirm that cytopenia results from ineffective hematopoiesis rather than peripheral destruction or sequestration. The diagnosis should be confirmed by molecular genetic testing as the hematologic abnormalities can be seen with other disorders.

Platelet function studies or electron microscopy may also be informative, as specific abnormalities are reported in some affected individuals.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: (1) Carriers are heterozygotes for this X-linked disorder and may develop clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by methods to detect gross structural abnormalities.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Two hematopoietic disorders in children with Down syndrome (DS) associated with acquired (somatic) mutations in exon 2 of GATA1 are transient myeloproliferative disorder (TMD) and acute megakaryoblastic leukemia (M7 subtype, DS-AMKL) [Wechsler et al 2002, Elagib et al 2003, Waltzer et al 2003, Ahmed et al 2004, Creutzig et al 2005, Crispino 2005a, Crispino 2005b, Muntean et al 2006, Roy et al 2009].

Transient myeloproliferative disorder (TMD), found in up to 10% of infants with DS, usually resolves spontaneously; however, TMD confers a markedly increased risk for DS-AMKL [Wechsler et al 2002, Ahmed et al 2004, Crispino 2005a, Crispino 2005b, Hitzler & Zipursky 2005]. The acquired exon 2 mutations lead to premature arrest of translation and reinitiation of protein synthesis at the downstream methionine codon at position 83, and result in the production of GATA-1 short isoform (GATA-1s) that lacks the amino-terminal activation domain. Some splice site mutations also result in generation of GATA-1s. How GATA1 mutations synergize with trisomy 21 to promote DS-AMKL is unknown.

‘Grey platelet syndrome’ (GPS) is a term that has been used to describe a genetically heterogeneous group of congenital disorders in which the platelets are large and have a grey appearance on light microscopy (Wright-stained slides) and the platelet alpha granules are either absent or reduced in numbers on electron microscopy. Most cases of GPS are simplex (i.e., a single occurrence in a family), but sibships with unaffected, often consanguineous parents consistent with an autosomal recessive mode of inheritance and families with apparent autosomal dominant or X-linked transmission have been reported [reviewed in Nurden & Nurden 2007]. A locus for an autosomal recessive GPS was recently mapped [Gunay-Aygun et al 2010], but the responsible gene has not been identified. One family with an c.647G>A mutation was reported to have GPS [Tubman et al 2007]; however, in general, GPS is not associated with a GATA1 mutation.

Natural History

Males. GATA1-related thrombocytopenia typically presents in infancy as a bleeding disorder. Affected individuals have easy bruising and mucosal bleeding, such as epistaxis. Physical examination may reveal petechiae, ecchymoses, or splenomegaly. Excessive hemorrhage and/or bruising can occur either spontaneously or after trauma or surgery. Some affected individuals may be recognized only after incidental findings of mild to moderate cytopenias on blood count analysis.

Anemia, the other major clinical problem in males with GATA1-related cytopenia, ranges from minimal with only mild dyserythropoiesis [Freson et al 2001] to severe hydrops fetalis requiring in utero transfusions [Nichols et al 2000]. Anemia can be so severe that affected males are red blood cell transfusion-dependent after birth [Freson et al 2002].

Variable mild to moderate neutropenia with macrocytic anemia and normal platelet counts was reported in one extended family (with a germline mutation leading to exclusive GATA-1s production) in which those individuals with severe neutropenia were predisposed to infection [Hollanda et al 2006].

In one family, moderately severe anemia was associated with congenital erythropoietic porphyria (CEP) [Phillips et al 2005]. The affected individual also had bullous skin lesions associated with porphyria.

The long-term course depends on disease severity. At the extreme end of the clinical spectrum, severe hemorrhage and/or erythrocyte transfusion dependence are life long. At the milder end, the risk for bleeding decreases spontaneously with age, despite continued thrombocytopenia [Mehaffey et al 2001, Del Vecchio et al 2005].

Splenomegaly is commonly present in one form of GATA1-related disease (see Genotype-Phenotype Correlations).

Typically, no other physical anomalies are present.

Carrier females. Females who carry a GATA1 mutation may manifest platelet abnormalities [White 2007] and mild to moderate symptoms such as menorrhagia, presumably related to the proportion of relevant cells that contain the mutant GATA1 allele on the active X chromosome [Nichols et al 2000; Raskind et al 2000; Balduini et al 2004; Del Vecchio et al 2005; Raskind, unpublished observations].

Of note, females who carry a GATA1 mutation may have normal platelet counts or be mildly to moderately thrombocytopenic [Nichols et al 2000]. This may depend on the nature of the mutation or other modifiers either genetic or environmental. Morphologic abnormalities of platelets can be detected by electron microscopy (mutation c.622_623delinsTC, p.Gly208Ser) [White 2007] and in some instances on peripheral blood smears (mutation c.647G>A, p.Arg216Gln) [Tubman et al 2007].

Genotype-Phenotype Correlations

To a large extent, disease severity depends on the nature of the GATA1 mutation. GATA-1 (erythroid transcription factor) is a transcription factor containing two zinc fingers. The carboxyl terminal finger (C-f) is essential for binding to DNA at most or all target genes. The amino terminal finger (N-f) stabilizes GATA-1 binding to a subset of DNA target sites and also participates in critical protein interactions. Most importantly, the N-f is required for interaction with the critical essential GATA-1 cofactor FOG-1.

Most GATA1 mutations associated with inherited thrombocytopenia/anemia occur within the N-f and affect DNA binding, FOG-1 interactions, or perhaps both. The extent to which these functions are impaired can be linked to clinical severity.

For example, two different amino acid substitutions occur at GATA-1 amino acid position 218:

• An aspartic acid-to-glycine missense mutation (p.Asp218Gly, c.653A>G) results in a mild phenotype characterized by macrothrombocytopenia without anemia [Freson et al 2001].
• A tyrosine substitution at the same position (p.Asp218Tyr, c.652G>T) results in a severe phenotype with profound anemia and thrombocytopenia [Freson et al 2002].

In four families, two different mutations are described at amino acid position 216, which forms part of the DNA binding face of GATA-1. The phenotypic variability observed between different families illustrates how different mutations in GATA-1 protein could selectively impair its ability to recognize specific elements in cis configuration.

• Substitution c.647G>A (p.Arg216Gln) causes macrothrombocytopenia with mild anemia and mild β-thalassemia [Raskind et al 2000, Yu et al 2002, Balduini et al 2004].
• The missense mutation c.646C>T (p.Arg216Trp) causes more severe symptoms, including anemia and CEP [Phillips et al 2005]. Apparently, this particular mutation causes porphyria by impairing transcription of the gene encoding the heme synthetic enzyme uroporphyrinogen III synthase, a known GATA-1 target gene [Solis et al 2001].

Specific genotype-phenotype correlations are illustrated further by the family described by Hollanda et al [2006], in which a germline splice mutation results in the exclusive production of the amino terminal truncated GATA-1s protein. Affected individuals exhibit a unique phenotype that includes macrocytic anemia, variable neutropenia, and trilineage dysplasia in the bone marrow. Hence, generation of the neutrophil lineage appears to be selectively affected (directly or indirectly) by loss of the GATA-1 amino terminus.

Nomenclature

Until GATA1 mutations were shown to underlie this heterogeneous disorder, a variety of terms were coined for the different clinical presentations. The first term used was X-linked thrombocytopenia with thalassemia (XLTT) [Raskind et al 2000]. Other terms used in the past and still in the current literature are "familial dyserythropoietic anemia and thrombocytopenia" [Nichols et al 2000, Del Vecchio et al 2005] and "X-linked macrothrombocytopenia" [Freson et al 2001].

Prevalence

GATA1-related cytopenia is rare; the prevalence is not known. To date, hematopoietic disease caused by inherited mutations in GATA1 has been reported in ten families [Nichols et al 2000; Freson et al 2001; Mehaffey et al 2001; Freson et al 2002; Yu et al 2002; Balduini et al 2004; Del Vecchio et al 2005; Phillips et al 2005; Hollanda et al 2006; Raskind, unpublished observation].

GATA1 mutations may be more common than previously appreciated, particularly in persons with mild, unexplained thrombocytopenia/"grey platelet syndrome" present since birth [Tubman et al 2007].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with GATA1-related cytopenia, the following are recommended:

• Complete blood count and examination of the peripheral smear to assess the degree of cytopenia(s)
• Detailed history of age at which hematologic disease was manifest
• Documentation of abnormal/unexpected bleeding episodes and platelet counts obtained at the time of the episodes to help determine whether platelet function is abnormal and whether disease severity has changed over time
  
  Note: Platelet aggregation studies may also be useful to identify functional abnormalities that predict a greater risk of bleeding for any given platelet count, but can be difficult to interpret when platelet counts are lower than 100,000/μL.

Treatment of Manifestations

Individuals with GATA1-related cytopenia are treated supportively.

Thrombocytopenia. Individuals with moderate to severe epistaxis, gingival bleeding, or gastrointestinal bleeding should receive platelet transfusions. Transfusion requirements vary from person to person as bleeding can be related to quantitative and/or qualitative platelet defects.

For individuals with thrombocytopenia and/or platelet aggregation defects, DDAVP treatment may be helpful for short-term management of mild to moderate bleeding.

Individuals who are only mildly symptomatic (easy bruisability without mucosal or more severe bleeding) do not require specific treatment.

There is no evidence that splenectomy is beneficial in people with GATA1-related disease, although this treatment may be considered if splenomegaly is severe. Although splenectomy may improve the cytopenias, platelet dysfunction will not be improved.

Anemia. Erythrocyte transfusions are indicated when anemia is symptomatic (fatigue, tachycardia). Iron overload and the development of alloantibodies may limit chronic transfusion therapy. Extended pretransfusion red blood cell phenotyping and matching for minor erythrocyte antigens in individuals receiving frequent transfusions can reduce the risk of alloimmunization.

Neutropenia. Patients with neutropenia who present with fever should be evaluated promptly with a physical examination, complete blood count, and blood culture and should receive appropriate parenteral antibiotics.

Bone marrow transplantation (BMT). For severe cases, BMT can be curative [Phillips et al 2005, Hollanda et al 2006]. BMT should be considered in individuals with severe phenotypes of GATA1-related cytopenia, particularly if an HLA-matched donor is available. While BMT may offer a cure, clinical experience with BMT in this disease is limited and families must be counseled on the significant risks and morbidity associated with BMT.

Prevention of Primary Manifestations

The only definitive cure for GATA1-related disease is bone marrow transplantation (BMT).

Prevention of Secondary Complications

Individuals with thrombocytopenia and/or platelet aggregation defects should receive a platelet transfusion prior to surgical or invasive dental procedures.

Individuals with neutropenia should be counseled regarding their increased risk of infection. They should avoid crowds and contact with individuals who have communicable diseases. When febrile, patients who are severely neutropenic (absolute neutrophil count <500) should seek medical attention; typically blood cultures are obtained and parenteral antibiotics are administered to avoid the possibility of life-threatening sepsis.

Surveillance

Depending on the phenotype of the disease, complete blood counts should be monitored so that supportive care can be provided as needed.

Individuals undergoing repeated erythrocyte transfusions should be monitored for iron overload and managed appropriately with iron chelation therapy.

Agents/Circumstances to Avoid

Individuals with thrombocytopenia should avoid antiplatelet agents including aspirin and nonsteroidal anti-inflammatory agents (NSAIDs) (e.g., ibuprofen).

Individuals with thrombocytopenia and/or platelet aggregation defects should be advised to avoid contact sports or activities with a high risk of trauma.

Individuals with significant splenomegaly should avoid contact sports, which involve increased risk for traumatic splenic rupture.

Individuals with significant neutropenia should avoid crowds and avoid close contact with persons who have a communicable disease to minimize risk of infection.

Testing of Relatives at Risk

If a GATA1 mutation has been identified in the family, molecular genetic testing of at-risk relatives can be offered.

At-risk relatives who choose not to have molecular genetic testing should have a screening complete blood count to evaluate for thrombocytopenia, anemia, or neutropenia as these conditions have implications for their medical care. However, normal results do not rule out GATA1-related disease as platelet, erythrocyte, and neutrophil counts can vary significantly in individuals with GATA1 mutations.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

In the future, this disorder may be treatable by adoptive gene therapy approaches to restore GATA-1 activity in hematopoietic cells.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Unlike immune-mediated platelet disorders such as ITP, GATA1-related thrombocytopenia does not respond to steroid or immunoglobulin therapy.

Supplemental erythropoietin therapy is unlikely to be effective because the anemia is secondary to ineffective erythropoiesis, not erythropoietin deficiency.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

GATA1-related cytopenia is inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

• The father of an affected male will not have the disease nor will he be a carrier of the mutation.
• In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
• If pedigree analysis reveals that the proband is the only affected family member, the mother may be a carrier or the affected male may have a de novo gene mutation, in which case the mother is not a carrier.
  • Because very few families with GATA1 mutations have been described to date, the frequency of de novo mutations is not known.
  • Evidence of germline mosaicism has not been observed.
• If a woman has more than one affected son and the disease-causing mutation cannot be detected in her DNA, she has germline mosaicism.
• When an affected male is the only affected individual in the family; several possibilities regarding his mother's carrier status need to be considered:
  • He has a de novo disease-causing mutation in GATA1, in which case his mother is not a carrier.
  • His mother has a de novo disease-causing mutation in GATA1, either (a) as a "germline mutation" (i.e., present at the time of her conception and therefore in every cell of her body); or (b) as "germline mosaicism" (i.e., present in some of her germ cells only).
  • His mother has a disease-causing mutation that she inherited from a maternal female ancestor.

Sibs of a proband

• The risk to sibs depends on the carrier status of the mother.
• If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%.
  • Male sibs who inherit the mutation will be affected.
  • Female sibs who inherit the mutation will be carriers and will usually not be affected, but may have reduced hematocrits and platelet counts to a variable degree. Large platelets may also be present and carriers of the XLTT subtype may have splenomegaly and slightly decreased β-globin synthesis.
• If the disease-causing mutation cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because, although not yet observed, the possibility of germline mosaicism exists.

Offspring of a proband. Males will pass the disease-causing mutation to all of their daughters and none of their sons.

Other family members of a proband. The proband's maternal aunts and their offspring may be at risk of being carriers or of being affected (depending on their gender and family relationship and the carrier status of the proband's mother).

Carrier Detection

Carrier testing for at-risk family members is available on a clinical basis once the mutation has been identified in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

If the GATA1 mutation has been identified in a family member, prenatal testing is possible for pregnancies at increased risk. The usual procedure is to determine fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation or by amniocentesis usually performed at about 15 to 18 weeks' gestation. If the karyotype is 46,XY, DNA from fetal cells can be analyzed for the known disease-causing mutation.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

1. Ahmed M, Sternberg A, Hall G, Thomas A, Smith O, O'Marcaigh A, Wynn R, Stevens R, Addison M, King D, Stewart B, Gibson B, Roberts I, Vyas P. Natural history of GATA1 mutations in Down syndrome. Blood. 2004;103:2480–9. [PubMed: 14656875]
2. Balduini CL, Savoia A. Inherited thrombocytopenias: molecular mechanisms. Semin Thromb Hemost. 2004;30:513–23. [PubMed: 15497094]
3. 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. Effects of the R216Q mutation of GATA-1 on erythropoiesis and megakaryocytopoiesis. Thromb Haemost. 2004;91:129–40. [PubMed: 14691578]
4. Creutzig U, Reinhardt D, Diekamp S, Dworzak M, Stary J, Zimmermann M. AML Patients with Down syndrome have a high cure rate with AML-BFM therapy with reduced dose intensity. Leukemia. 2005;19:1355–60. [PubMed: 15920490]
5. Crispino JD. GATA1 in normal and malignant hematopoiesis. Semin Cell Dev Biol. 2005a;16:137–47. [PubMed: 15659348]
6. Crispino JD. GATA1 mutations in Down syndrome: implications for biology and diagnosis of children with transient myeloproliferative disorder and acute megakaryoblastic leukemia. Pediatr Blood Cancer. 2005b;44:40–44. [PubMed: 15390312]
7. Del Vecchio GC, Giordani L, De Santis A, De Mattia D. Dyserythropoietic anemia and thrombocytopenia due to a novel mutation in GATA-1. Acta Haematol. 2005;114:113–6. [PubMed: 16103636]
8. Drachman JG. Inherited thrombocytopenia: when a low platelet count does not mean ITP. Blood. 2004;103:390–8. [PubMed: 14504084]
9. Elagib KE, Racke FK, Mogass M, Khetawat R, Delehanty LL, Goldfarb AN. RUNX1 and GATA-1 coexpression and cooperation in megakaryocytic differentiation. Blood. 2003;101:4333–41. [PubMed: 12576332]
10. Ferreira R, Ohneda K, Yamamoto M, Philipsen S. GATA1 function, a paradigm for transcription factors in hematopoiesis. Mol Cell Biol. 2005;25:1215–27. [PMC free article: PMC548021] [PubMed: 15684376]
11. Fox AH, Liew C, Holmes M, Kowalski K, Mackay J, Crossley M. Transcriptional cofactors of the FOG family interact with GATA proteins by means of multiple zinc fingers. EMBO J. 1999;18:2812–22. [PMC free article: PMC1171362] [PubMed: 10329627]
12. Freson K, Devriendt K, Matthijs G, Van Hoof A, De Vos R, Thys C, Minner K, Hoylaerts MF, Vermylen J, Van Geet C. Platelet characteristics in patients with X-linked macrothrombocytopenia because of a novel GATA1 mutation. Blood. 2001;98:85–92. [PubMed: 11418466]
13. Freson K, Matthijs G, Thys C, Marien P, Hoylaerts MF, Vermylen J, Van Geet C. 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. 2002;11:147–52. [PubMed: 11809723]
14. Ged C, Moreau-Gaudry F, Richard E, Robert-Richard E, de Verneuil H. Congenital erythropoietic porphyria: mutation update and correlations between genotype and phenotype. Cell Mol Biol (Noisy-le-grand). 2009;55:53–60. [PubMed: 19268002]
15. Grossfeld PD, Mattina T, Lai Z, Favier R, Jones KL, Cotter F, Jones C. The 11q terminal deletion disorder: a prospective study of 110 cases. Am J Med Genet A. 2004;129:51–61. [PubMed: 15266616]
16. Gunay-Aygun M, Zivony-Elboum Y, Gumruk F. et al. Gray platelet syndrome: natural history of a large patient cohort and locus assignment to chromosome 3p. Blood. 2010;116:4990–5001. [PMC free article: PMC3012593] [PubMed: 20709904]
17. Hindmarsh JT. The porphyrias: recent advances. Clin Chem. 1986;32:1255–63. [PubMed: 3521939]
18. Hitzler JK, Zipursky A. Origins of leukaemia in children with Down syndrome. Nat Rev Cancer. 2005;5:11–20. [PubMed: 15630411]
19. Hollanda LM, Lima CS, Cunha AF, Albuquerque DM, Vassallo J, Ozelo MC, Joazeiro PP, Saad ST, Costa FF. An inherited mutation leading to production of only the short isoform of GATA-1 is associated with impaired erythropoiesis. Nat Genet. 2006;38:807–12. [PubMed: 16783379]
20. Hughan SC, Senis Y, Best D, Thomas A, Frampton J, Vyas P, Watson SP. Selective impairment of platelet activation to collagen in the absence of GATA1. Blood. 2005;105:4369–76. [PubMed: 15701726]
21. Kratz CP, Niemeyer CM, Karow A, Volz-Fleckenstein M, Schmitt-Gräff A, Strahm B. Congenital transfusion-dependent anemia and thrombocytopenia with myelodysplasia due to a recurrent GATA1(G208R) germline mutation. Leukemia. 2008;22:432–4. [PubMed: 17713552]
22. Li Z, Godinho FJ, Klusmann JH, Garriga-Canut M, Yu C, Orkin SH. Developmental stage-selective effect of somatically mutated leukemogenic transcription factor GATA1. Nat Genet. 2005;37:613–9. [PubMed: 15895080]
23. Lindeboom F, Gillemans N, Karis A, Jaegle M, Meijer D, Grosveld F, Philipsen S. A tissue-specific knockout reveals that Gata1 is not essential for Sertoli cell function in the mouse. Nucleic Acids Research. 2003;31:5405–12. [PMC free article: PMC203309] [PubMed: 12954777]
24. Lopez JA, Andrews RK, Afshar-Kharghan V, Berndt MC. Bernard-Soulier syndrome. Blood. 1998;91:4397–418. [PubMed: 9616133]
25. Lowry JA, Mackay JP. GATA-1: one protein, many partners. Int J Biochem Cell Biol. 2006;38:6–11. [PubMed: 16095949]
26. Mehaffey MG, Newton AL, Gandhi MJ, Crossley M, Drachman JG. X-linked thrombocytopenia caused by a novel mutation of GATA-1. Blood. 2001;98:2681–8. [PubMed: 11675338]
27. Muntean AG, Ge Y, Taub JW, Crispino JD. Transcription factor GATA-1 and Down syndrome leukemogenesis. Leuk Lymphoma. 2006;47:986–97. [PubMed: 16840187]
28. Nichols KE, Crispino JD, Poncz M, White JG, Orkin SH, Maris JM, Weiss MJ. Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1. Nat Genet. 2000;24:266–70. [PubMed: 10700180]
29. Noris P, Pecci A, Di Bari F, Di Stazio MT, Di Pumpo M, Ceresa IF, Arezzi N, Ambaglio C, Savoia A, Balduini CL. Application of a diagnostic algorithm for inherited thrombocytopenias to 46 consecutive patients. Haematologica. 2004;89:1219–25. [PubMed: 15477207]
30. Nurden AT, Nurden P. The gray platelet syndrome: Clinical spectrum of the disease. Blood Rev. 2007;21:21–36. [PubMed: 16442192]
31. Ohneda K, Yamamoto M. Roles of hematopoietic transcription factors GATA-1 and GATA-2 in the development of red blood cell lineage. Acta Haematol. 2002;108:237–45. [PubMed: 12432220]
32. Phillips JD, Steensma DP, Pulsipher MA, Spangrude GJ, Kushner JP. Congenital erythropoietic porphyria due to a mutation in GATA1: the first trans-acting mutation causative for a human porphyria. Blood. 2007;109:2618–21. [PMC free article: PMC1852202] [PubMed: 17148589]
33. Phillips JD, Steensma DP, Spangrude GJ, Kushner JP. Congenital erythropoietic porphyria, beta-thalassemia intermedia and thrombocytopenia due to a GATA1 mutation. Blood. 2005;106:515.
34. Raskind WH, Niakan KK, Wolff J, Matsushita M, Vaughan T, Stamatoyannopoulos G, Watanabe C, Rios J, Ochs HD. Mapping of a syndrome of X-linked thrombocytopenia with Thalassemia to band Xp11-12: further evidence of genetic heterogeneity of X-linked thrombocytopenia. Blood. 2000;95:2262–8. [PubMed: 10733494]
35. Seri M, Pecci A, Di Bari F, Cusano R, Savino M, Panza E, Nigro A, Noris P, Gangarossa S, Rocca B, Gresele P, Bizzaro N, Malatesta P, Koivisto PA, Longo I, Musso R, Pecoraro C, Iolascon A, Magrini U, Rodriguez Soriano J, Renieri A, Ghiggeri GM, Ravazzolo R, Balduini CL, Savoia A. MYH9-related disease: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness. Medicine (Baltimore). 2003;82:203–15. [PubMed: 12792306]
36. Roy A, Roberts I, Norton A, Vyas P. Acute megakaryoblastic leukaemia (AMKL) and transient myeloproliferative disorder (TMD) in Down syndrome: a multi-step model of myeloid leukaemogenesis. British Journal of Haematology. 2009;147:3–12. [PubMed: 19594743]
37. Solis C, Aizencang GI, Astrin KH, Bishop DF, Desnick RJ. Uroporphyrinogen III synthase erythroid promoter mutations in adjacent GATA1 and CP2 elements cause congenital erythropoietic porphyria. J Clin Invest. 2001;107:753–62. [PMC free article: PMC208941] [PubMed: 11254675]
38. Sullivan KE. The clinical, immunological, and molecular spectrum of chromosome 22q11.2 deletion syndrome and DiGeorge syndrome. Curr Opin Allergy Clin Immunol. 2004;4:505–12. [PubMed: 15640691]
39. Thompson AR, Wood WG, Stamatoyannopoulos G. X-linked syndrome of platelet dysfunction, thrombocytopenia, and imbalanced globin chain synthesis with hemolysis. Blood. 1977;50:303–16. [PubMed: 871527]
40. Tsai SF, Strauss E, Orkin SH. Functional analysis and in vivo footprinting implicate the erythroid transcription factor GATA-1 as a positive regulator of its own promoter. Genes Dev. 1991;5:919–31. [PubMed: 2044960]
41. Tsang AP, Visvader JE, Turner CA, Fujiwara Y, Yu C, Weiss MJ, Crossley M, Orkin SH. FOG, a multitype zinc finger protein, acts as a cofactor for transcription factor GATA-1 in erythroid and megakaryocytic differentiation. Cell. 1997;90:109–19. [PubMed: 9230307]
42. Tubman VN, Levine JE, Campagna DR, Fleming MD, Neufeld EJ. X-linked gray platelet syndrome due to a GATA1 Arg261Gln mutation. Blood. 2007;109:3297–9. [PubMed: 17209061]
43. Waltzer L, Ferjoux G, Bataille L, Haenlin M. Cooperation between the GATA and RUNX factors Serpent and Lozenge during Drosophila hematopoiesis. EMBO J. 2003;22:6516–6525. [PMC free article: PMC291817] [PubMed: 14657024]
44. Wechsler J, Greene M, McDevitt MA, Anastasi J, Karp JE, Le Beau MM, Crispino JD. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet. 2002;32:148–52. [PubMed: 12172547]
45. White JG. Platelet pathology in carriers of the X-linked GATA-1 macrothrombocytopenia. Platelets. 2007;18:620–7. [PubMed: 18041654]
46. White JG, Nichols WL, Steensma DP. Platelet pathology in sex-linked GATA-1 dyserythropoietic macrothrombocytopenia II. Cytochemistry. Platelets. 2007;18:436–50. [PubMed: 17763153]
47. Yu C, Niakan KK, Matsushita M, Stamatoyannopoulos G, Orkin SH, Raskind WH. X-linked thrombocytopenia with thalassemia from a mutation in the amino finger of GATA-1 affecting DNA binding rather than FOG-1 interaction. Blood. 2002;100:2040–5. [PMC free article: PMC2808424] [PubMed: 12200364]

Suggested Reading

1. Balduini CL, De Candia E, Savoia A. Why the disorder induced by GATA1 Arg216Gln mutation should be called "X-linked thrombocytopenia with thalassemia" rather than "X-linked gray platelet syndrome". Blood. 2007;110:2770–1. [PMC free article: PMC1988927] [PubMed: 17881640]
2. Ciovacco WA, Raskind WH, Kacena MA. Human phenotypes associated with GATA-1 mutations. Gene. 2008;427:1–6. [PMC free article: PMC2601579] [PubMed: 18930124]
3. de Waele L, Freson K, Louwette S, Thys C, Wittevrongel C, de Vos R, Debeer A, van Geet C. Severe gastrointestinal bleeding and thrombocytopenia in a child with an anti-GATA1 autoantibody. Pediatr Res. 2010;67:314–9. [PubMed: 19924028]
4. Hamlett I, Draper J, Strouboulis J, Iborra F, Porcher C, Vyas P. Characterization of megakaryocyte GATA1-interacting proteins: the corepressor ETO2 and GATA1 interact to regulate terminal megakaryocyte maturation. Blood. 2008;112:2738–49. [PMC free article: PMC2556610] [PubMed: 18625887]

Author History

Stella T Chou, MD (2006-present)
Melissa A Kacena, PhD (2006-present)
Jessica Kirk, BS; Yale University School of Medicine (2006-2011)
Wendy H Raskind, MD, PhD (2006-present)
Mitchel J Weiss, MD, PhD (2006-present)

Acknowledgments

This work was supported in part by the Indiana Center for Translational and Clinical Sciences Institute, in part by NIH grants NCRR RR025760 and RR025761 (MAK), a pilot and feasibility award from the Yale Center of Excellence in Molecular Hematology/NIH DK0724429 (MAK), and by NIH grant NIAMS R03 AR055269 (MAK).

Revision History

• 22 March 2011 (me) Comprehensive update posted live
• 30 March 2007 (cd) Revision: prenatal testing clinically available
• 21 February 2007 (cd) Revision: clinical testing available
• 22 November 2006 (me) Review posted to live Web site
• 10 August 2006 (whr) Original submission