GATA-binding factor 1 or GATA-1 (also termed Erythroid transcription factor) is the founding member of the
GATA family of transcription factors. This
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
is widely expressed throughout vertebrate species. In humans and mice, it is encoded by the ''GATA1'' and ''Gata1'' genes, respectively. These genes are located on the
X chromosome
The X chromosome is one of the two sex chromosomes in many organisms, including mammals, and is found in both males and females. It is a part of the XY sex-determination system and XO sex-determination system. The X chromosome was named for its u ...
in both species.
GATA1 regulates the
expression (i.e. formation of the genes' products) of an ensemble of genes that mediate the development of red blood cells and platelets. Its critical roles in red blood cell formation include promoting the
maturation of precursor cells, e.g.
erythroblast
A nucleated red blood cell (NRBC), also known by #Nomenclature, several other names, is a red blood cell that contains a cell nucleus. Almost all vertebrate organisms have hemoglobin-containing cells in their blood, and with the exception of mamm ...
s, to red blood cells and stimulating these cells to erect their
cytoskeleton
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
and
biosynthesize their oxygen-carrying components viz.,
hemoglobin
Hemoglobin (haemoglobin, Hb or Hgb) is a protein containing iron that facilitates the transportation of oxygen in red blood cells. Almost all vertebrates contain hemoglobin, with the sole exception of the fish family Channichthyidae. Hemoglobin ...
and
heme
Heme (American English), or haem (Commonwealth English, both pronounced /Help:IPA/English, hi:m/ ), is a ring-shaped iron-containing molecule that commonly serves as a Ligand (biochemistry), ligand of various proteins, more notably as a Prostheti ...
. GATA1 plays a similarly critical role in the maturation of blood
platelets
Platelets or thrombocytes () are a part of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a blood clot. Platelets have no cell nucleus; they are fragments of cyto ...
from
megakaryoblasts,
promegakaryocytes, and
megakaryocyte
A megakaryocyte () is a large bone marrow cell with a lobation, lobated nucleus that produces blood platelets (thrombocytes), which are necessary for normal blood coagulation, clotting. In humans, megakaryocytes usually account for 1 out of 10,00 ...
s; the latter cells then shed membrane-enclosed fragments of their cytoplasm, i.e. platelets, into the blood.
In consequence of the vital role that GATA1 has in the proper maturation of red blood cells and platelets,
inactivating mutations in the ''GATA1'' gene (i.e. mutations that result in the production of no, reduced levels of, or a less active GATA1) cause
X chromosome-linked anemic and/or
bleeding diseases due to the reduced formation and functionality of red blood cells and/or platelets, respectively, or, under certain circumstances, the pathological proliferation of megakaryoblasts. These diseases include
transient myeloproliferative disorder occurring in Down syndrome,
acute megakaryoblastic leukemia occurring in
Down syndrome,
Diamond–Blackfan anemia, and various combined
anemia
Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availabl ...
-
thrombocytopenia
In hematology, thrombocytopenia is a condition characterized by abnormally low levels of platelets (also known as thrombocytes) in the blood. Low levels of platelets in turn may lead to prolonged or excessive bleeding. It is the most common coag ...
syndromes including a
gray platelet syndrome
Gray platelet syndrome (GPS), or platelet alpha-granule deficiency, is a rare congenital autosomal recessive bleeding disorder caused by a reduction or absence of alpha-granules in blood platelets, and the release of proteins normally contained in ...
-type disorder.
Reduced levels of GATA1 due to reductions in the translation of GATA1
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
into its transcription factor product are associated with promoting the progression of
myelofibrosis
Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is activation and growth of mutated cells in ...
, i.e. a malignant disease that involves the replacement of bone marrow cells by fibrous tissue and
extramedullary hematopoiesis, i.e. the extension of blood cell-forming cells to sites outside of the
bone marrow
Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...
.
Gene
The human ''GATA1'' gene is located on the short (i.e. "p") arm of the
X chromosome
The X chromosome is one of the two sex chromosomes in many organisms, including mammals, and is found in both males and females. It is a part of the XY sex-determination system and XO sex-determination system. The X chromosome was named for its u ...
at position 11.23. It is 7.74
kilobases in length, consists of 6
exons
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence i ...
, and codes for a full-length protein, GATA1, of 414
amino acids
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...
as well as a shorter one, GATA1-S. GATA1-S lacks the first 83 amino acids of GATA1 and therefore consists of only 331 amino acids.
''GATA1'' codes for two
zinc finger
A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) which stabilizes the fold. The term ''zinc finger'' was originally coined to describe the finger-like appearance of a ...
structural motif
In a chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a common three-dimensional structure that appears in a variety of different, evolutionarily unrelated molecules. A structural motif does not have t ...
s, C-ZnF and N-ZnF, that are present in both GATA1 and GATA1-S proteins. These motifs are critical for both transcription factors' gene-regulating actions. N-ZnF is a frequent site of disease-causing mutations. Lacking the first 83 amino acids and therefore one of the two activation domains of GATA1, GATA1-S has significantly less gene-regulating activity than GATA1.
Studies in ''Gata1''-
knockout mice
A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
, i.e. mice lacking the ''Gata1'' gene, indicate that this gene is essential for the development and maintenance of blood-based and/or tissue-based hematological cells, particularly
red blood cell
Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...
s and
platelets
Platelets or thrombocytes () are a part of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a blood clot. Platelets have no cell nucleus; they are fragments of cyto ...
but also
eosinophils,
basophils,
mast cell
A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a p ...
s, and
dendritic cell
A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...
s. The knock-out mice die by day 11.5 of their
embryonic development
In developmental biology, animal embryonic development, also known as animal embryogenesis, is the developmental stage of an animal embryo. Embryonic development starts with the fertilization of an egg cell (ovum) by a sperm, sperm cell (spermat ...
due to severe anemia that is associated with absence of cells of the red blood cell lineage, excessive numbers of malformed platelet-precursor cells, and an absence of
platelet
Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...
s. These defects reflect the essential role of Gata-1 in stimulating the development, self-renewal, and/or maturation of red blood cell and platelet
precursor cell
In cell biology, precursor cells—also called blast cells—are partially differentiated, or intermediate, and are sometimes referred to as progenitor cells. A precursor cell is a stem cell with the capacity to differentiate into only one cell ...
s. Studies using mice depleted of their ''Gata1'' gene during adulthood show that: 1) Gata1 is required for the stimulation of
erythropoiesis
Erythropoiesis (from Greek ''erythro'', meaning ''red'' and ''poiesis'', meaning ''to make'') is the process which produces red blood cells (erythrocytes), which is the development from erythropoietic stem cell to mature red blood cell.
It is s ...
(i.e. increase in red blood cell formation) in response to stress and 2) ''Gata1''-deficient adult mice invariably develop a form of
myelofibrosis
Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is activation and growth of mutated cells in ...
.
GATA1 proteins
In both GATA1 and GATA1-S, C-ZnF (i.e.
C-terminus
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein
Proteins are large biomolecules and macromolecules that comp ...
zinc finger) binds to DNA-specific
nucleic acid sequence
A nucleic acid sequence is a succession of Nucleobase, bases within the nucleotides forming alleles within a DNA (using GACT) or RNA (GACU) molecule. This succession is denoted by a series of a set of five different letters that indicate the orde ...
s sites viz., (T/A(GATA)A/G), on the expression-regulating sites of its target genes and in doing so either stimulates or suppresses the expression of these target genes. Their N-ZnF (i.e.
N-terminus
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
zinc fingers) interacts with an essential transcription factor-regulating nuclear protein,
FOG1. FOG1 powerfully promotes or suppresses the actions that the two transcription factors have on most of their target genes. Similar to the knockout of ''Gata1'', knockout of the mouse gene for FOG1, ''
Zfpm1'', causes total failure of red blood cell development and embryonic lethality by day 11.5. Based primarily on mouse studies, it is proposed that the GATA1-FOG1 complex promotes human erythropoiesis by recruiting and binding with at least two gene expression-regulating complexes,
Mi-2/NuRD complex (a
chromatin remodeler) and
CTBP1 (a
histone deacetylase) and three gene expression-regulating proteins,
SET8 (a GATA1-inhibiting
histone methyltransferase),
BRG1 (a
transcription activator), and
Mediator (a
transcription co-activator). Other interactions include those with:
BRD3 (remodels DNA
nucleosome
A nucleosome is the basic structural unit of DNA packaging in eukaryotes. The structure of a nucleosome consists of a segment of DNA wound around eight histone, histone proteins and resembles thread wrapped around a bobbin, spool. The nucleosome ...
s),
BRD4
Bromodomain-containing protein 4 is a protein that in humans is encoded by the ''BRD4'' gene.
BRD4 is a member of the BET (bromodomain and extra terminal domain) family, which also includes BRD2, BRD3, and BRDT. BRD4, similar to other BET fam ...
(binds acetylated lysine residues in DNA-associated histone to regulate gene accessibility),
FLI1 (a transcription factor that blocks erythroid differentiation),
HDAC1 (a
histone deacetylase),
LMO2
LIM domain only 2 (rhombotin-like 1), also known as LMO2, RBTNL1, RBTN2, RHOM2, LIM Domain Only Protein 2, TTG2, and T-Cell Translocation Protein 2, is a protein which in humans is encoded by the ''LMO2'' gene.
Structure
LMO2 is characterized ...
(regulator of erythrocyte development),
ZBTB16 (transcription factor regulating
cell cycle
The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...
progression),
TAL1 (a transcription factor),
FOG2 (a transcription factor regulator),
and
GATA2 (Displacement of GATA2 by GATA1, i.e. the "GATA switch", at certain gene-regulating sites is critical for red blood development in mice and, presumably, humans).
GATA1-FOG1 and GATA2-FOG1 interactions are critical for platelet formation in mice and may similarly be critical for this in humans.
Other types of ''GATA2'' mutations cause the over-expression of the GATA2 transcription factor. This overexpression is associated with the development of non-familial AML. Apparently, the ''GATA2'' gene's expression level must be delicately balanced between deficiency and excess in order to avoid life-threatening disease.
Physiology and Pathology
GATA1 was first described as a transcription factor that activates the
hemoglobin B gene in the red blood cell precursors of chickens. Subsequent studies in mice and isolated human cells found that GATA1 stimulates the expression of genes that promote the maturation of precursor cells (e.g.
erythroblast
A nucleated red blood cell (NRBC), also known by #Nomenclature, several other names, is a red blood cell that contains a cell nucleus. Almost all vertebrate organisms have hemoglobin-containing cells in their blood, and with the exception of mamm ...
s) to red blood cells while silencing genes that cause these precursors to proliferate and thereby to
self-renew.
GATA1 stimulates this maturation by, for example, inducing the expression of genes in erythroid cells that contribute to the formation of their
cytoskeleton
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
and that make enzymes necessary for the
biosynthesis
Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...
of
hemoglobin
Hemoglobin (haemoglobin, Hb or Hgb) is a protein containing iron that facilitates the transportation of oxygen in red blood cells. Almost all vertebrates contain hemoglobin, with the sole exception of the fish family Channichthyidae. Hemoglobin ...
s and
heme
Heme (American English), or haem (Commonwealth English, both pronounced /Help:IPA/English, hi:m/ ), is a ring-shaped iron-containing molecule that commonly serves as a Ligand (biochemistry), ligand of various proteins, more notably as a Prostheti ...
, the oxygen-carrying components of red blood cells. GATA1-inactivating mutations may thereby result in a failure to produce sufficient numbers of and/or fully functional red blood cells.
Also based on mouse and isolated human cell studies, GATA1 appears to play a similarly critical role in the maturation of platelets from their precursor cells. This
maturation involves the stimulation of
megakaryoblasts to mature ultimately to
megakaryocyte
A megakaryocyte () is a large bone marrow cell with a lobation, lobated nucleus that produces blood platelets (thrombocytes), which are necessary for normal blood coagulation, clotting. In humans, megakaryocytes usually account for 1 out of 10,00 ...
s which cells shed membrane-enclosed fragments of their cytoplasm, i.e. platelets, into the blood. GATA1-inactivating mutations may thereby result in reduced levels of and/or dysfunctional blood platelets.
Reduced levels of GATA1 due to defective
translation
Translation is the communication of the semantics, meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The English la ...
of GATA1
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
in human megakaryocytes is associated with
myelofibrosis
Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is activation and growth of mutated cells in ...
, i.e. the replacement of bone marrow cells by fibrous tissue. Based primarily on mouse and isolated human cell studies, this myelofibrosis is thought to result from the accumulation of platelet precursor cells in the bone marrow and their release of excessive amounts of cytokines that stimulate bone marrow
stromal cells to become fiber-secreting
fibroblasts
A fibroblast is a type of biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibrobla ...
and
osteoblasts. Based on mouse studies, low GATA1 levels are also thought to promote the development of splenic
enlargement and
extramedullary hematopoiesis in human myelofibrosis disease. These effects appear to result directly from the over-proliferation of abnormal platelet precursor cells.
The clinical features associated with inactivating ''GATA1'' mutations or other causes of reduced GATA1 levels vary greatly with respect not only to the types of disease exhibited but also to disease severity. This variation depends on at least four factors. First, inactivating mutations in ''GATA1'' cause
X-linked recessive diseases. Males, with only one ''GATA1'' gene, experience the diseases of these mutations while women, with two GATA1 genes, experience no or extremely mild evidence of these diseases unless they have inactivating mutations in both genes or their mutation is
dominant negative, i.e. inhibiting the good gene's function. Second, the extent to which a mutation reduces the cellular levels of fully functional GATA1 correlates with disease severity. Third, inactivating ''GATA1'' mutations can cause different disease manifestations. For example, mutations in GATA1's N-ZnF that interfere with its interaction with FOG1 result in reduced red blood cell and platelet levels whereas mutations in N-ZnF that reduce its binding affinity to target genes cause a reduction in red blood cells plus
thalassemia
Thalassemias are a group of Genetic disorder, inherited blood disorders that manifest as the production of reduced hemoglobin. Symptoms depend on the type of thalassemia and can vary from none to severe, including death. Often there is mild to ...
-type and
porphyria
Porphyria ( or ) is a group of disorders in which substances called porphyrins build up in the body, adversely affecting the skin or nervous system. The types that affect the nervous system are also known as Porphyria#Acute porphyrias, acute p ...
-type symptoms. Fourth, the genetic background of individuals can impact the type and severity of symptoms. For example, ''GATA1''-inactivating mutations in individuals with the extra
chromosome 21
Chromosome 21 is one of the 23 pairs of chromosomes in humans. Chromosome 21 is both the smallest human autosome and chromosome, with 46.7 million base pairs (the building material of DNA) representing about 1.5 percent of the total DNA in cell ...
of Down syndrome exhibit a proliferation of megakaryoblasts that infiltrate and consequentially directly damage liver, heart, marrow, pancreas, and skin plus secondarily life-threatening damage to the lungs and kidneys. These same individuals can develop secondary mutations in other genes that results in
acute megakaryoblastic leukemia.
Genetic disorders
''GATA1'' gene
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
s are associated with the development of various
genetic disorders which may be familial (i.e. inherited) or newly acquired. In consequence of its X chromosome location, GATA1 mutations generally have a far greater physiological and clinical impact in men, who have only one X chromosome along with its ''GATA1'' gene, than woman, who have two of these chromosomes and genes: GATA1 mutations lead to
X-linked diseases occurring predominantly in males.
Mutations in the activation domain of GATA1 (GATA1-S lacks this domain) are associated with the transient myeloproliferative disorder and acute megakaryoblastic leukemia of Down syndrome while mutations in the N-ZnF motif of GATA1 and GATA1-S are associated with diseases similar to congenital dyserythropoietic anemia, congenital thrombocytopenia, and certain features that occur in
thalassemia
Thalassemias are a group of Genetic disorder, inherited blood disorders that manifest as the production of reduced hemoglobin. Symptoms depend on the type of thalassemia and can vary from none to severe, including death. Often there is mild to ...
,
gray platelet syndrome
Gray platelet syndrome (GPS), or platelet alpha-granule deficiency, is a rare congenital autosomal recessive bleeding disorder caused by a reduction or absence of alpha-granules in blood platelets, and the release of proteins normally contained in ...
,
congenital erythropoietic porphyria, and
myelofibrosis
Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is activation and growth of mutated cells in ...
.
Down syndrome-related disorders
Transient myeloproliferative disorder
Acquired inactivating mutations in the activation domain of GATA1 are the apparent cause of the transient myeloproliferative disorder that occurs in individuals with Down syndrome. These mutations are
frameshifts in exon 2 that result in the failure to make GATA1 protein, continued formation of GATA1-S, and therefore a greatly reduced ability to regulate GATA1-targeted genes. The presence of these mutations is restricted to cells bearing the trisomy 21
karyotype
A karyotype is the general appearance of the complete set of chromosomes in the cells of a species or in an individual organism, mainly including their sizes, numbers, and shapes. Karyotyping is the process by which a karyotype is discerned by de ...
(i.e. extra
chromosome 21
Chromosome 21 is one of the 23 pairs of chromosomes in humans. Chromosome 21 is both the smallest human autosome and chromosome, with 46.7 million base pairs (the building material of DNA) representing about 1.5 percent of the total DNA in cell ...
) of Down syndrome: GATA1 inactivating mutations and trisomy 21 are necessary and sufficient for development of the disorder.
Transient myeloproliferative disorder consists of a relatively mild but pathological proliferation of platelet-precursor cells, primarily
megakaryoblasts, which often show an abnormal morphology that resembles immature
myeloblasts (i.e.
unipotent
In mathematics, a unipotent element ''r'' of a ring ''R'' is one such that ''r'' − 1 is a nilpotent element; in other words, (''r'' − 1)''n'' is zero for some ''n''.
In particular, a square matrix ''M'' is a unipote ...
stem cells which differentiate into
granulocytes
Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear, that ...
and are the malignant proliferating cell in
acute myeloid leukemia
Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with haematopoiesis, normal blood cell production. Sympt ...
).
Phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...
analyses indicate that these blasts belong to the megakaryoblast series. Abnormal findings include the frequent presence of excessive
blast cell
In cell biology, precursor cells—also called blast cells—are partially differentiated, or intermediate, and are sometimes referred to as progenitor cells. A precursor cell is a stem cell with the capacity to differentiate into only one cell t ...
numbers, reduced platelet and red blood cell levels, increased circulating
white blood cell
White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...
levels, and infiltration of platelet-precursor cells into the bone marrow, liver, heart, pancreas, and skin.
The disorder is thought to develop
in utero and is detected at birth in about 10% of individuals with Down syndrome. It resolves totally within ~3 months but in the following 1–3 years progresses to acute megakaryoblastic leukemia in 20% to 30% of these individuals: transient myeloprolierative disorder is a
clonal (abnormal cells derived from single parent cells), pre-leukemic condition and is classified as a
myelodysplastic syndrome disease.
Acute megakaryoblastic leukemia
Acute megakaryoblastic leukemia is a subtype of acute myeloid leukemia that is extremely rare in adults and, although still rare, more common in children. The childhood disease is classified into two major subgroups based on its occurrence in individuals with or without
Down syndrome. The disease in Down syndrome occurs in 20% to 30% of individuals who previously had transient myeloproliferative disorder. Their ''GATA1'' mutations are
frameshifts in exon 2 that result in the failure to make GATA1 protein, continued formation of GATA1-S, and thus a greatly reduced ability to regulate GATA1-targeted genes. Transient myeloproliferative disorder is detected at or soon after birth and generally resolves during the next months but is followed within 1–3 years by acute megakaryoblastic leukemia.
During this 1-3 year interval, individuals accumulate multiple
somatic mutations in cells bearing inactivating GATA1 mutations plus trisomy 21. These mutations are thought to result from the uncontrolled proliferation of blast cells caused by the ''GATAT1'' mutation in the presence of the extra chromosome 21 and to be responsible for progression of the transient disorder to leukemia. The mutations occur in one or, more commonly, multiple genes including: ''
TP53
p53, also known as tumor protein p53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory transcription factor protein that is often mutated in human cancers. The p53 proteins (originally thou ...
,
RUNX1
Runt-related transcription factor 1 (RUNX1) also known as acute myeloid leukemia 1 protein (AML1) or core-binding factor subunit alpha-2 (CBFA2) and it is a protein that is encoded by the ''RUNX1'' gene, in humans.
RUNX1 is a transcription facto ...
,
FLT3,
ERG
The erg is a unit of energy equal to 10−7joules (100Nano-, nJ). It is not an SI unit, instead originating from the centimetre–gram–second system of units (CGS). Its name is derived from (), a Greek language, Greek word meaning 'work' or ' ...
,
DYRK1A,
CHAF1B,
HLCS,
CTCF,
STAG2,
RAD21
Double-strand-break repair protein rad21 homolog is a protein that in humans is encoded by the ''RAD21'' gene. ''RAD21'' (also known as ''Mcd1'', ''Scc1'', ''KIAA0078'', ''NXP1'', ''HR21''), an essential gene, encodes a DNA repair#Double-strand b ...
,
SMC3,
SMC1A,
NIPBL,
SUZ12,
PRC2,
JAK1,
JAK2,
JAK3,
MPL,
KRAS
''KRAS'' ( Kirsten rat sarcoma virus) is a gene that provides instructions for making a protein called K-Ras, a part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the ce ...
,
NRAS,
SH2B3'', and ''MIR125B2'' which is the gene for
microRNA
Micro ribonucleic acid (microRNA, miRNA, μRNA) are small, single-stranded, non-coding RNA molecules containing 21–23 nucleotides. Found in plants, animals, and even some viruses, miRNAs are involved in RNA silencing and post-transcr ...
MiR125B2.
Diamond–Blackfan anemia
Diamond–Blackfan anemia is a familial (i.e. inherited) (45% of cases) or acquired (55% of cases) genetic disease that presents in
infancy
In common terminology, a baby is the very young offspring of adult human beings, while infant (from the Latin word ''infans'', meaning 'baby' or 'child') is a formal or specialised synonym. The terms may also be used to refer to juveniles of ...
or, less commonly, later childhood as
aplastic anemia and the circulation of abnormally enlarged
red blood cell
Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...
s. Other types of blood cell and platelets circulate at normal levels and appear normal in structure. About half of affected individuals have various
birth defects
A birth defect is an abnormal condition that is present at birth, regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can range from mild to severe. Birth de ...
.
The disease is regarded as a uniformly genetic disease although the genes causing it have not been identified in ~30% of cases. In virtually all the remaining cases,
autosomal recessive
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
inactivating mutations occur in any one of 20 of the 80 genes encoding
ribosomal protein
A ribosomal protein (r-protein or rProtein) is any of the proteins that, in conjunction with rRNA, make up the ribosomal subunits involved in the cellular process of translation. ''E. coli'', other bacteria and Archaea have a 30S small subunit ...
s. About 90% of the latter mutations occur in 6 ribosomal protein genes viz., ''
RPS19,
RPL5,
RPS26,
RPL11,
RPL35A'', and ''
RPS24''.
However, several cases of familial Diamond–Blackfan anemia have been associated with ''GATA1'' gene mutations in the apparent absence of a mutation in ribosomal protein genes. These ''GATA1'' mutations occur in an exon 2 splice site or the
start codon
The start codon is the first codon of a messenger RNA (mRNA) transcript translated by a ribosome. The start codon always codes for methionine in eukaryotes and archaea and a ''N''-formylmethionine (fMet) in bacteria, mitochondria and plastids.
...
of GATA1, cause the production of the GATA1-S in the absence of the GATA1 transcription factor, and therefore are gene-inactivating in nature. It is proposed that these ''GATA1'' mutations are a cause for Diamond Blackfan anemia.
Combined anemia-thrombocytopenia syndromes
Certain ''GATA1''-inactivating mutations are associated with familial or, less commonly, sporadic X-linked disorders that consist of anemia and thrombocytopenia due to a failure in the maturation of red blood cell and platelet precursors plus other hematological abnormalities. These ''GATA1'' mutations are identified by an initial letter identifying the normal amino acid followed by a number giving the position of this amino acid in GATA1, followed by a final letter identifying the amino acid substituted for the normal one. The amino acids are identified as V=
valine
Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deproton ...
; M=
methionine
Methionine (symbol Met or M) () is an essential amino acid in humans.
As the precursor of other non-essential amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine play ...
; G=
glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (G ...
; S=
serine
Serine
(symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...
, D=
aspartic acid
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. The L-isomer of aspartic acid is one of the 22 proteinogenic amino acids, i.e., the building blocks of protei ...
; Y=
tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...
, R=
arginine
Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidinium, guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) a ...
; W=
tryptophan
Tryptophan (symbol Trp or W)
is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromat ...
, Q=
glutamine
Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...
). These mutations and some key abnormalities they cause are:
* V205M: familial disease characterized by severe anemia in fetuses and newborns; bone marrow has increased numbers of malformed platelet and red blood cell precursors.
* G208S and D218G: familial disease characterized by severe bleeding, reduced number of circulating platelets which are malformed (i.e. enlarged), and mild anemia.
* D218Y: familial disease similar to but more severe that the disease cause by G209S and D218G mutations.
* R216W: characterized by a
beta thalassemia
Beta-thalassemia (β-thalassemia) is an genetic disorder, inherited hemoglobinopathy, blood disorder, a form of thalassemia resulting in variable outcomes ranging from clinically asymptomatic to severe anemia individuals. It is caused by reduce ...
-type disease, i.e.
microcytic anemia, absence of
hemoglobin B, and
hereditary persistence of fetal hemoglobin; symptoms of
congenital erythropoietic porphyria; mild to moderately severe thrombocytopenia with features of the gray platelet syndrome.
* R216Q: familial disease characterized by mild anemia with features of heterozygous rather than homozygous (i.e. overt) beta thalassemia; mild thrombocytopenia with features of the gray platelet syndrome.
* G208R: disease characterized by mild anemia and severe thrombocytopenia with malformed erythroblasts and megakaryoblasts in the bone marrow. Structural features of these cells were similar to those observed in congenital dyserythropoietic anemia.
*-183G>A: rare
Single-nucleotide polymorphism
In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a ...
(rs113966884
) in which the
nucleotide
Nucleotides are Organic compound, organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both o ...
adenine
Adenine (, ) (nucleoside#List of nucleosides and corresponding nucleobases, symbol A or Ade) is a purine nucleotide base that is found in DNA, RNA, and Adenosine triphosphate, ATP. Usually a white crystalline subtance. The shape of adenine is ...
replaces
guanine
Guanine () (symbol G or Gua) is one of the four main nucleotide bases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine ( uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside ...
in DNA at the position 183 nucleotides upstream of the
start
Start can refer to multiple topics:
* Takeoff, the phase of flight where an aircraft transitions from moving along the ground to flying through the air
* Starting lineup in sports
* Track and field#Starts use in race, Starts use in sport race
* S ...
of ''GATA1''; disorder characterized as mild anemia with structural features in bone marrow red cell precursors similar to those observed in congenital dyserythropoietic anemia.
The
Gray platelet syndrome
Gray platelet syndrome (GPS), or platelet alpha-granule deficiency, is a rare congenital autosomal recessive bleeding disorder caused by a reduction or absence of alpha-granules in blood platelets, and the release of proteins normally contained in ...
is a rare congenital bleeding disorder caused by reductions or absence of
alpha-granules
Alpha granules, (α-granules) also known as platelet alpha-granules are a cellular component of platelets. Platelets contain different types of Granule (cell biology), granules that perform different functions, and include alpha granules, dense gr ...
in platelets. Alpha-granules contain various factors which contribute to blood clotting and other functions. In their absence, platelets are defective. The syndrome is commonly considered to result solely from mutations in the ''
NBEAL2'' gene located on human
chromosome 3
Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans more than 201 million base pairs (the building material of DNA) and represents about 6.5 percent of the total DNA ...
at position p21. In these cases, the syndrome follows
autosomal recessive
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
inheritance, causes a mild to moderate bleeding tendency, and may be accompanied by a defect in the secretion of the granule contents in
neutrophils. There are other causes for a congenital platelet alpha-granule-deficient bleeding disorder viz., the autosomal recessive disease of
Arc syndrome caused by mutations in either the ''
VPS33B'' (on human chromosome 15 at q26) or ''
VIPAS39
Spermatogenesis-defective protein 39 homolog is a protein that in humans is encoded by the ''VIPAS39'' gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucl ...
'' (on chromosome 14 at q34); the
autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
disease of GFI1B-related syndrome caused by mutations in ''
GFI1B'' (located on human chromosome 9 at q34); and the disease caused by R216W and R216Q mutations in GATA1. The GATA1 mutation-related disease resembles the one caused by ''NBEAL2'' mutations in that it is associated with the circulation of a reduced number (i.e.
thrombocytopenia
In hematology, thrombocytopenia is a condition characterized by abnormally low levels of platelets (also known as thrombocytes) in the blood. Low levels of platelets in turn may lead to prolonged or excessive bleeding. It is the most common coag ...
) of abnormally enlarged (i.e. macrothrombocytes), alpha-granule deficient platelets. It differs from the ''NBEAL2''-induced disease in that it is X chromosome-linked, accompanied by a moderately severe bleeding tendency, and associated with abnormalities in red blood cells (e.g. anemia, a
thalassemia
Thalassemias are a group of Genetic disorder, inherited blood disorders that manifest as the production of reduced hemoglobin. Symptoms depend on the type of thalassemia and can vary from none to severe, including death. Often there is mild to ...
-like disorder due to unbalanced hemoglobin production, and/or a
porphyria
Porphyria ( or ) is a group of disorders in which substances called porphyrins build up in the body, adversely affecting the skin or nervous system. The types that affect the nervous system are also known as Porphyria#Acute porphyrias, acute p ...
-like disorder.
A recent study found that GATA1 is a strong enhancer of ''NBEAL2'' expression and that the R216W and R216Q inactivating mutations in ''GATA1'' may cause the development of alpha granule-deficient platelets by failing to stimulate the expression of NBDAL2 protein.
Given these differences, the ''GATA1'' mutation-related disorder appears better classified as clinically and pathologically different than the gray platelet syndrome.
GATA1 in myelofibrosis
Myelofibrosis is a rare hematological malignancy characterized by progressive fibrosis of the bone marrow,
extramedullary hematopoiesis (i.e. formation of blood cells outside of their normal site in the bone marrow), variable reductions in the levels of circulating blood cells, increases in the circulating levels of the precursors to the latter cells, abnormalities in platelet precursor cell maturation, and the clustering of grossly malformed
megakaryocytes in the bone marrow. Ultimately, the disease may progress to
leukemia
Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...
. Recent studies indicate that the megakaryocytes but not other cell types in rare cases of myelofibrosis have greatly reduced levels of GATA1 as a result of a ribosomal deficiency in
translating GATA1
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
into GATA1 transcription factor. The studies suggest that these reduced levels of GATA1 contribute to the progression of myelofibrosis by leading to an impairment in platelet precursor cell maturation, by promoting extramedullary hematopoiesis, and, possibly, by contributing to its
leukemic transformation.
References
Further reading
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External links
GenecardsGeneReviews/NCBI/NIH/UW entry on GATA1-Related X-Linked CytopeniaGeneatlas
Nextbio*
{{Transcription factors and intracellular receptors, g2
Transcription factors