H e m a t o lo g y E d u c a t io n - European Hematology Association

megarakaryoblastic leukemia (AMKL) associated with
trisomy 21, and anemia associated with the production
of GATA-1s. 45 GATA-1 has two zinc fingers essential for
normal function. The C-terminal finger is necessary for
DNA binding. The N-terminal finger mediates interaction
with FOG-1, a cofactor for GATA-1.
A family with X-linked dyserythropoietic anaemia
and thrombocytopenia due to a substitution of methionine
for valine at amino acid 205 of GATA-1 was
described. 46 This highly conserved valine is necessary for
interaction of the amino-terminal zinc finger of GATA-1
with its essential cofactor, FOG-1 (for friend of GATA-1).
They showed that the V205M mutation abrogates the
interaction between Gata-1 and Fog-1, inhibiting the
ability of GATA-1 to rescue erythroid differentiation in
an erythroid cell line deficient for GATA-1 (G1E). Their
findings underscore the importance of FOG-1:GATA-1
associations in both megakaryocyte and erythroid development,
and suggest that other X-linked anemias or
thrombocytopenias may be caused by defects in
GATA1. This mutation most closely resembles those of
mice with the ‘knockdown’ Gata1 mutation.
Another group described a family with a novel single
base mutation that results in an amino acid substitution
(Gly208Arg) within the highly conserved portion of the
GATA-1 N-terminal finger domain, leading to dyserythropoietic
anemia and macrothrombocytopenia. 47
In the 90s a 10-year-old female Danish case was
extensively described. 48-51 She showed severe anemia at
birth and required repeated transfusion during childhood.
The clinical characteristic exhibited by the patient
was persistent expression of ε and ζ embryonic globin,
an HbF level of 40%, novel intra-erythroblastic and
intra-erythrocytic inclusions and deficiency of erythroid
proteins CD44 and Aquaporin 1. The marrow aspirate
studies revealed active erythropoiesis with some
dyserythropoietic features. Blood grouping tests further
showed that the child has the very rare Co(a-b-) blood
group phenotype and is negative for the high incidence
antigen AnWj. 50
Only recently an erythroid transcriptional factor alteration
has been elucidated. It was the case of two
patients with a hitherto unclassified CDA in whom a
missense mutation in KLF1 has been identified. One of
these was a Danish patient previously described. The
first patient described showed a similar clinical phenotype
of Danish. KLF1 is an erythroid transcription factor,
and extensive studies in mouse models have shown that
it plays a critical role in the expression of globin genes,
but also in the expression of a wide spectrum of genes
potentially essential for erythropoiesis. 52-54 The unique
features of this CDA confirm the key role of KLF1 during
human erythroid differentiation. Sequencing of
KLF1 in both patients revealed the presence of de novo
c.973G>A (p.E325K) mutation that had never been
reported and was not present in 96 regular blood, suggesting
it was the disease-causing mutation. The
authors suggested that mutations in KLF1 cause a hitherto
unclassified CDA. 55
Finally, in recent months the case of a patient with
mevalonate kinase deficiency (MKD) and congenital
dyserythropoietic anemia has been described. The clinical
phenotype was variable, ranging from the hyperimmunoglobulinemia
D and periodic fever syndrome
(HIDS) to mevalonic aciduria (MA), a severe metabolic
disease. Genomic sequencing of the mevalonate kinase
gene revealed compound heterozygosity for a missense
mutation previously described in MA (V310M) and a
novel missense mutation (Y116H). In contrast, sequencing
of SEC23B gene revealed no mutations, suggesting
that the bone marrow abnormalities were causally related
to the MKD. 56
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