Congenital transfusion-dependent anemia and thrombocytopenia with myelodysplasia due to a recurrent GATA1(G208R) germline mutation.
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ABSTRACT: Most heritable anemias are caused by mutations in genes encoding globins, red blood cell (RBC) membrane proteins or enzymes in the glycolytic and hexose monophosphate shunt pathways. A less common class of genetic anemia is caused by mutations that alter the functions of erythroid transcription factors (TFs). Many TF mutations associated with heritable anemia cause truncations or amino acid substitutions, resulting in the production of functionally altered proteins. Characterization of these mutant proteins has provided insights into mechanisms of gene expression, hematopoietic development and human disease. Mutations within promoter or enhancer regions that disrupt TF binding to essential erythroid genes also cause anemia and heritable variations in RBC traits, such as fetal hemoglobin content. Defining the latter may have important clinical implications for de-repressing fetal hemoglobin synthesis to treat sickle cell anemia and β thalassemia. Functionally important alterations in genes encoding TFs or their cognate cis elements are likely to occur more frequently than currently appreciated, a hypothesis that will soon be tested through ongoing genome wide association studies and the rapidly expanding use of global genome sequencing for human diagnostics. Findings obtained through such studies of RBCs and associated diseases are likely generalizable to many human diseases and quantitative traits.Blood 03/2014; · 9.78 Impact Factor
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ABSTRACT: GATA-1, an X-linked gene, encodes a transcription factor that plays a role in erythropoiesis and megakaryopoiesis. GATA-1 mutations have been associated with various diseases, such as X-linked thrombocytopenia. ALAS2 is an X-linked erythroid-specific isoenzyme expressed during erythropoiesis. Mutations of ALAS2 were associated with X-linked sideroblastic anemia. We report a case of newborn twin boy with anemia and thrombocytopenia at birth. A bone marrow biopsy at 4 months of age showed marked dyserythropoiesis, dysmegakaryopoiesis, and rare ringed sideroblasts. Gene sequencing study showed a previously reported mutation in GATA-1 at c.622G>A location (G208R) and a novel ALAS2 mutation at c.1436G>A location (R479Q).American journal of blood research. 01/2014; 4(1):41-5.
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Center, Nagoya; Toyohashi Municipal Hospital, Toyohashi;
Hospital, Toyoake; Komaki City Hospital, Komaki; Yokkaichi
Central Hospital, Yamanashi; Okazaki City Hospital, Okazaki,
Hospital, Nagoya;Fujita HealthUniversity
Congenital transfusion-dependent anemia and thrombocytopenia with myelodysplasia
due to a recurrent GATA1G208Rgermline mutation
Leukemia (2008) 22, 432–434; doi:10.1038/sj.leu.2404904;
published online 23 August 2007
The X-linked gene GATA1 encodes a 414-amino-acid hemato-
poietic transcription factor that controls erythroid and mega-
karyocytic differentiation. Virtually all cases of transient
myeloproliferative disease and acute megakaryoblastic leuke-
mia in children with Down syndrome harbor somatic GATA1
mutations typically affecting exon 2 and leading to expression of
the short isoform, GATA-1s, which lacks the transcriptional
activation domain. Moreover, germline missense mutations in
exon 4 of GATA1 that predict alterations of amino acids Val205,
Gly208, Arg216 or Asp218 of the N-terminal zinc-finger domain
(residues 204–228) have been reported in nine families.1–9One
additional family has been found to harbor a germline mutation,
GATA1 c.322G4C, which leads to expression of GATA-1s.10
Consistent with X-linked inheritance and full penetrance,
germline GATA1 mutations disrupt hematopoiesis in males
who harbor a hemizygous mutant GATA1 allele. In contrast,
female heterozygous carriers have no or minor hematopoietic
defects such as mild chronic thrombocytopenia.1–10
spectrum of abnormalities caused by different GATA1 mutations
probably depends on the function of the predicted mutant
protein such as the ability to associate with cofactor FOG-1.9
Hematologic abnormalities include dyserythropoietic anemia
and thrombocythemia (V205M, G208R, D218Y and GATA-
congenital erythropoietic porphyria (R216W),7
and gray platelet syndrome (R216Q).6Splenomegaly is noted
in some cases5,7and is likely to be due to ineffective and
consecutive extramedullary hematopoiesis. To date, only the
GATA1R216Qmutation has been identified in more than one
family,4–6hampering phenotype–genotype correlation.
We identified a second family with a GATA1G208Rmutation.
The index patient was a male neonate born at term to healthy
European non-consanguineous parents. Family history was
unremarkable and the mother previously gave birth to a healthy
boy. At birth, petechiae and ecchymoses on skin and mucosa as
well as enlargement of liver and spleen were noted. Hemoglobin
measured 8.9g/dl, leukocytes 54900/ml and thrombocytes
54000/ml. Repeated platelet and packed red blood cell transfu-
sions were administered. A bone marrow smear revealed
dyserythropoiesis (Figure 1) and dysmegakaryopoiesis but no
increase in blasts. A liver biopsy taken at the age of 16 days
revealed siderosis, cholestasis and extramedullary hematopoi-
esis. Mutation analysis with published methods,1,10uncovered a
hemizygous G to A transition at nucleotide position c.622 in
exon 4 of GATA1 predicting a p.G208R change in the highly
conserved N-terminal zinc-finger domain of GATA-1. The
patient inherited this allele from his heterozygous mother
(Figure 1), who had a hemoglobin level of 11.3g/dl, mean
erythrocyte volume 81fl, leukocytes 12700/ml and thrombocytes
172000/ml. At the time of this report, the patient was 6 months of
age and was in stable condition requiring platelet transfusions
every week and red packed cell transfusions every second to
third week. To obtain the option of hematopoietic stem cells
transplantation (HSCT) a donor search has been initiated. The
same mutation, GATA1G208Rhas been described in another
individual with dyserythropoietic anemia and thrombocytopenia
who was found to have anemia and thrombocytopenia at birth
requiring transfusions.3This patient received his last red packed
cell transfusion at 5 years of age and the frequency of mucosal
and severe bleeding decreased in adulthood. At the age of 17
years he had a hemoglobin level of 9.6g/dl, mean erythrocyte
volume 103fl and thrombocytes 12000/ml.3Notably, this
patient’s mother was mildly thrombocytopenic with platelets
measuring 140000/ml.3The similar clinical presentation with
transfusion-dependent cytopenia at birth underscores the notion
Letters to the Editor
of a genotype–phenotype relationship of different GATA1
defects. However, in addition to dyserythropoietic anemia and
thrombocytopenia, our patient presented with marked organo-
megaly. Although bleeding complications in patients with
germline GATA1 mutations may decrease with age,3this
disorder may lead to early death.2,9Notably, in one family with
a GATA1D218Yallele, six affected boys died before the age of 2
years.9In cases of GATA1 defects with significant thrombo-
cytopenia and severe bleeding diathesis, HSCT may be warranted.
Indeed, related or unrelated HSCT has been performed in a small
number of cases.1,7,10In conclusion, we describe the second
family with a GATA1G208Rallele causing congenital dyserythro-
poietic anemia and thrombocytopenia. Additionally, the affected
male showed marked organomegaly. Besides GATA1G216Q, the
GATA1G208Rallele is the only mutation that has been identified in
more than one family. The identification of a larger number of
families with these rare mutations that lead to a spectrum of mild
to severe hematologic defects will help to perform phenotype–
genotype correlations that eventually will facilitate treatment
decisions and patient care.
We thank Cornelia Klein for technical assistance.
CP Kratz1, CM Niemeyer1, A Karow1, M Volz-Fleckenstein2,
A Schmitt-Gra ¨ff3and B Strahm1
1Department of Pediatrics and Adolescent Medicine, Pediatric
Hematology/Oncology, University of Freiburg, Freiburg,
2Krankenhaus Barmherzige Bru ¨der Regensburg, Klinik St
Hedwig/Pa ¨diatrische Onkologie und Ha ¨matologie,
Regensburg, Germany and
3Department of Pathology, University of Freiburg, Freiburg,
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N terminal zinc finger
GATA1 mutation, c.622G4A, is detected in the patient’s mother. The patient harbors a hemizygous mutant allele (a). This alteration in exon 4
predicts a G208R change in the N-terminal zinc finger (N) of the protein (TD: transcriptional activation domain; C: C-terminal zinc finger). This
mutation locates near residues that are altered by other known germline mutations (red) (b). A bone marrow slide shows severe dyserythropoietic
changes (arrows) (c).
The recurrent GATA1G208Rmutation causes congenital dyserythropoietic anemia and thrombocytopenia. A heterozygous germline
Letters to the Editor
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et al. Platelet characteristics in patients with X-linked macro-
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and anemia andare associated
A simple FISH assay for the detection of 3q26 rearrangements in myeloid malignancy
Leukemia (2008) 22, 434–437; doi:10.1038/sj.leu.2404906;
published online 13 September 2007
In myeloid malignancy, a number of recurrent and sporadic
rearrangements of 3q26 are associated with transcriptional
activation of EVI1 and/or EVI1 chimaeric genes.1Recurrent
rearrangements include the inv(3)(q21q26) and its variants
t(3;3)(q21;q26) and ins(3;3)(q26;q21q26), as well as transloca-
tions involving other chromosomes such as the t(3;21)(q26;q22).
In general, 3q26 rearrangements are associated with a poor
Given the unfavourable outcome of 3q26 rearrangements,
methods for establishing their presence at diagnosis and during
treatment or disease progression are highly desirable, particu-
larly when chromosome banding analysis is hampered by low
quality or insufficient metaphase cells. To date, however, the
wide 3q26 breakpoint region has precluded development of a
single fluorescent in situ hybridization (FISH) probe sensitive
enough to monitor residual disease. We describe a novel dual-
colour FISH probe designed to span the entire 3q26 breakpoint
region in a single hybridization, which allowed successful
detection and quantification of the level of leukaemic cells in 11
patients with 3q26 rearrangements. Physical mapping data
obtained with this probe further support the notion of a degree of
rearrangement-specific breakpoint clustering within cytogenetic
subgroups of 3q26 abnormality.
The dual-colour EVI1 FISH probe was designed to comprise
two differentially labelled DNA contigs flanking the common
3q26 breakpoint region (Figure 1). Expected signal patterns from
differentially labelled contigs specific for the 3q26 locus (Kreatech Biotechnologies, Amsterdam, The Netherlands). The most centromeric contig,
labelled in green fluorochrome, hybridizes to a region extending 460kb from the centromeric (30) end of the EVI1 gene. The second, most
telomeric contig, labelled with a red fluorochrome, is specific for a region beginning approximately 500kb 30of EVI1 and extends 370kb in a
telomeric direction. The distance between the hybridization regions of the two contigs is 530kb. The breakpoint region associated with 3q26
abnormalities is indicated. The lower portion of the figure shows the principle of the EVI1 break-apart FISH assay with the expected normal and
abnormal hybridization patterns. For simplicity, an inv(3)(q21q26) is depicted in the scheme, however, the principles of this approach apply to all
3q26 rearrangements. (i) Expected hybridization pattern on normal chromosome 3 and corresponding interphase nuclei. Two red-green fusion
signals are produced (2F). (ii) Expected pattern on metaphase chromosomes and in interphases with a 3q26 rearrangement involving a breakpoint
mapping 30of EVI1, within the hybridization region of the green probe component (indicated by the first square bracket). Interphase cells show a
pattern of one green and two fusion signals (1G2F). (iii) Hybridization pattern expected in cells with a more centromeric 3q26 breakpoint, up to
500kb 50of EVI1 between the hybridization regions of the two probe contigs (middle square bracket). Interphase cells show one red, one green and
one fusion signal (1R1G1F). (iv) Pattern expected in cells with a 3q26 breakpoint more than 500kb 50of EVI1 (third square bracket), resulting in a
split red signal and an interphase pattern of one red and two fusion signals (1G2F).
Structure and principle of the EVI1 break-apart fluorescent in situ hybridization (FISH) probe system. The probe is composed of two
Letters to the Editor