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 residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
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-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex-d ...
in both species.
GATA1 regulates the
expression
Expression may refer to:
Linguistics
* Expression (linguistics), a word, phrase, or sentence
* Fixed expression, a form of words with a specific meaning
* Idiom, a type of fixed expression
* Metaphorical expression, a particular word, phrase, o ...
(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 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 mammals, all of t ...
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 BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...
and
heme
Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver.
In biochemical terms, heme is a coordination complex "consisti ...
. GATA1 plays a similarly critical role in the maturation of blood
platelets
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
from
megakaryoblast
A megakaryoblast is a precursor cell to a promegakaryocyte, which in turn becomes a megakaryocyte during haematopoiesis. It is the beginning of the thrombocytic series.
Development
The megakaryoblast derives from a CFU-Meg colony unit of pluripot ...
s,
promegakaryocyte
A promegakaryocyte is a precursor cell for a megakaryocyte. It arises from a megakaryoblast, into a promegakaryocyte and then into a megakaryocyte, which will eventually break off and become a platelet.
The developmental stages of the megakaryoc ...
s, and
megakaryocyte
A megakaryocyte (''mega-'' + '' karyo-'' + '' -cyte'', "large-nucleus cell") is a large bone marrow cell with a lobated nucleus responsible for the production of blood thrombocytes (platelets), which are necessary for normal blood clotting. In hum ...
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
Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...
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
Acute megakaryoblastic leukemia (AMKL) is life-threatening leukemia in which malignant megakaryoblasts proliferate abnormally and injure various tissues. Megakaryoblasts are the most immature precursor cells in a platelet-forming lineage; they matu ...
occurring in
Down syndrome
Down syndrome or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. It is usually associated with physical growth delays, mild to moderate intellectual dis ...
,
Diamond–Blackfan anemia
Diamond–Blackfan anemia (DBA) is a congenital erythroid aplasia that usually presents in infancy. DBA causes low red blood cell counts (anemia), without substantially affecting the other blood components (the platelets and the white blood cells) ...
, and various combined
anemia
Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...
-
thrombocytopenia
Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients an ...
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 growth of abnormal cells in the bone marrow. ...
, i.e. a malignant disease that involves the replacement of bone marrow cells by fibrous tissue and
extramedullary hematopoiesis
Extramedullary hematopoiesis (EMH or sometimes EH) refers to hematopoiesis occurring outside of the medulla of the bone (bone marrow). It can be physiologic or pathologic.
Physiologic EMH occurs during embryonic and fetal development; during this ...
, i.e. the extension of blood cell-forming cells to sites outside of the
bone marrow
Bone marrow is a semi-solid tissue found within the 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 is composed of hematopoietic ce ...
.
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-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex-d ...
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 ...
, 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 hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
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+) in order to stabilize the fold. It was originally coined to describe the finger-like appearance of a hypothesized struct ...
structural motif
In a polymer, chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a common Biomolecular structure#Tertiary structure, three-dimensional structure that appears in a variety of different, evolutionarily unrel ...
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), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
s and
platelets
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
but also
eosinophil
Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. A ...
s,
basophil
Basophils are a type of white blood cell. Basophils are the least common type of granulocyte, representing about 0.5% to 1% of circulating white blood cells. However, they are the largest type of granulocyte. They are responsible for inflammator ...
s,
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 par ...
s, and
dendritic cell
Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their 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
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...
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, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
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, a precursor cell, also called a blast cell or simply blast, is a partially differentiated cell, usually referred to as a unipotent cell that has lost most of its stem cell properties. A precursor cell is also known as a pro ...
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' "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 stimulated by decrea ...
(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 growth of abnormal cells in the bone marrow. ...
.
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, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
zinc finger) binds to DNA-specific
nucleic acid sequence
A nucleic acid sequence is a succession of Nucleobase, bases signified by a series of a set of five different letters that indicate the order of nucleotides forming alleles within a DNA (using GACT) or RNA (GACU) molecule. By convention, sequence ...
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 ami ...
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
Zinc finger protein ZFPM1 (FOG-1) also known as friend of GATA protein 1 is a protein that in humans is encoded by the ''ZFPM1'' gene.
It is a cofactor of the GATA1 transcription factor
In molecular biology, a transcription factor (TF) (or s ...
'', 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
In the field of molecular biology, the Mi-2/NuRD (Nucleosome Remodeling Deacetylase) complex, is a group of associated proteins with both ATP-dependent chromatin remodeling and histone deacetylase activities. , Mi-2/NuRD was the only known protei ...
(a
chromatin remodeler) and
CTBP1
C-terminal-binding protein 1 also known as CtBP1 is a protein that in humans is encoded by the ''CTBP1'' gene. CtBP1 is one of two CtBP proteins, the other protein being CtBP2.
Function
The CtBP1 protein was originally identified as a human prote ...
(a
histone deacetylase) and three gene expression-regulating proteins,
SET8 (a GATA1-inhibiting
histone methyltransferase
Histone methyltransferases (HMT) are histone-modifying enzymes (e.g., histone-lysine N-methyltransferases and histone-arginine N-methyltransferases), that catalyze the transfer of one, two, or three methyl groups to lysine and arginine residues of ...
),
BRG1
Transcription activator BRG1 also known as ATP-dependent chromatin remodeler SMARCA4 is a protein that in humans is encoded by the ''SMARCA4'' gene.
Function
The protein encoded by this gene is a member of the SWI/SNF family of proteins and i ...
(a
transcription activator
A transcriptional activator is a protein (transcription factor) that increases transcription of a gene or set of genes. Activators are considered to have ''positive'' control over gene expression, as they function to promote gene transcription and, ...
), and
Mediator
Mediator may refer to:
*A person who engages in mediation
*Business mediator, a mediator in business
* Vanishing mediator, a philosophical concept
* Mediator variable, in statistics
Chemistry and biology
*Mediator (coactivator), a multiprotein ...
(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 proteins and resembles thread wrapped around a spool. The nucleosome is the fundamen ...
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 famil ...
(binds acetylated lysine residues in DNA-associated histone to regulate gene accessibility),
FLI1
Friend leukemia integration 1 transcription factor (FLI1), also known as transcription factor ERGB, is a protein that in humans is encoded by the ''FLI1'' gene, which is a proto-oncogene.
Function
Fli-1 is a member of the ETS transcription fa ...
(a transcription factor that blocks erythroid differentiation),
HDAC1
Histone deacetylase 1 (HDAC1) is an enzyme that in humans is encoded by the ''HDAC1'' gene.
Function
Histone acetylation and deacetylation, catalyzed by multisubunit complexes, play a key role in the regulation of eukaryotic gene expression. T ...
(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.
Function
LMO2 encodes a cysteine- ...
(regulator of erythrocyte development),
ZBTB16 (transcription factor regulating
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
progression),
TAL1
__NOTOC__
T-cell acute lymphocytic leukemia protein 1 (i.e. TAL1 but also termed stem cell leukemia/T-cell acute leukemia 1 .e. SCL/TAL1 is a protein that in humans is encoded by the ''TAL1'' gene.
The protein encoded by TAL1 is a basic helix-lo ...
(a transcription factor),
FOG2 (a transcription factor regulator),
and
GATA2
GATA2 or GATA-binding factor 2 is a transcription factor, i.e. a nuclear protein which regulates the expression of genes. It regulates many genes that are critical for the embryonic development, self-renewal, maintenance, and functionality of bl ...
(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.
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 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 mammals, all of t ...
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 is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. ...
of
hemoglobin
Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...
s and
heme
Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver.
In biochemical terms, heme is a coordination complex "consisti ...
, 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
megakaryoblast
A megakaryoblast is a precursor cell to a promegakaryocyte, which in turn becomes a megakaryocyte during haematopoiesis. It is the beginning of the thrombocytic series.
Development
The megakaryoblast derives from a CFU-Meg colony unit of pluripot ...
s to mature ultimately to
megakaryocyte
A megakaryocyte (''mega-'' + '' karyo-'' + '' -cyte'', "large-nucleus cell") is a large bone marrow cell with a lobated nucleus responsible for the production of blood thrombocytes (platelets), which are necessary for normal blood clotting. In hum ...
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 Meaning (linguistic), 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 ...
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 growth of abnormal cells in the bone marrow. ...
, 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 that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells o ...
and
osteoblasts
Osteoblasts (from the Greek language, Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cell (biology), cells with a single Cell nucleus, nucleus that synthesize bone. However, in the p ...
. Based on mouse studies, low GATA1 levels are also thought to promote the development of splenic
enlargement and
extramedullary hematopoiesis
Extramedullary hematopoiesis (EMH or sometimes EH) refers to hematopoiesis occurring outside of the medulla of the bone (bone marrow). It can be physiologic or pathologic.
Physiologic EMH occurs during embryonic and fetal development; during this ...
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
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
, 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 inherited blood disorders characterized by decreased hemoglobin production. Symptoms depend on the type and can vary from none to severe. Often there is mild to severe anemia (low red blood cells or hemoglobin). Anemia can result ...
-type and
porphyria
Porphyria is a group of liver disorders in which substances called porphyrins build up in the body, negatively affecting the skin or nervous system. The types that affect the nervous system are also known as acute porphyria, as symptoms are ra ...
-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 48 million base pairs (the building material of DNA) representing about 1.5 percent of the total DNA in cells. M ...
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
Acute megakaryoblastic leukemia (AMKL) is life-threatening leukemia in which malignant megakaryoblasts proliferate abnormally and injure various tissues. Megakaryoblasts are the most immature precursor cells in a platelet-forming lineage; they matu ...
.
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, mi ...
s are associated with the development of various
genetic disorders
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic 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 inherited blood disorders characterized by decreased hemoglobin production. Symptoms depend on the type and can vary from none to severe. Often there is mild to severe anemia (low red blood cells or hemoglobin). Anemia can result ...
,
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
A birth defect, also known as a congenital disorder, 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 r ...
, 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 growth of abnormal cells in the bone marrow. ...
.
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
frameshift
Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during translation that results in the production of multiple, unique proteins from a single mRNA. The process can ...
s 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 metaphase 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 disce ...
(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 48 million base pairs (the building material of DNA) representing about 1.5 percent of the total DNA in cells. M ...
) 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
megakaryoblast
A megakaryoblast is a precursor cell to a promegakaryocyte, which in turn becomes a megakaryocyte during haematopoiesis. It is the beginning of the thrombocytic series.
Development
The megakaryoblast derives from a CFU-Meg colony unit of pluripot ...
s, 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 unipoten ...
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. They hav ...
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 normal blood cell production. Symptoms may includ ...
).
Phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
analyses indicate that these blasts belong to the megakaryoblast series. Abnormal findings include the frequent presence of excessive
blast cell
In cell biology, a precursor cell, also called a blast cell or simply blast, is a partially differentiated cell, usually referred to as a unipotent cell that has lost most of its stem cell properties. A precursor cell is also known as a proge ...
numbers, reduced platelet and red blood cell levels, increased circulating
white blood cell
White blood cells, also called leukocytes or leucocytes, are the cell (biology), cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and de ...
levels, and infiltration of platelet-precursor cells into the bone marrow, liver, heart, pancreas, and skin.
The disorder is thought to develop
in utero
''In Utero'' is the third and final studio album by American rock band Nirvana. It was released on September 21, 1993, by DGC Records. After breaking into the mainstream with their second album, ''Nevermind'' (1991), Nirvana hired Steve Albini t ...
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
A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may ...
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
Down syndrome or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. It is usually associated with physical growth delays, mild to moderate intellectual dis ...
. The disease in Down syndrome occurs in 20% to 30% of individuals who previously had transient myeloproliferative disorder. Their ''GATA1'' mutations are
frameshift
Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during translation that results in the production of multiple, unique proteins from a single mRNA. The process can ...
s 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 protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often ...
,
RUNX1
Runt-related transcription factor 1 (RUNX1) also known as acute myeloid leukemia 1 protein (AML1) or core-binding factor subunit alpha-2 (CBFA2) is a protein that in humans is encoded by the ''RUNX1'' gene.
RUNX1 is a transcription factor that re ...
,
FLT3
Cluster of differentiation antigen 135 (CD135) also known as fms like tyrosine kinase 3 (FLT-3), receptor-type tyrosine-protein kinase FLT3, or fetal liver kinase-2 (Flk2) is a protein that in humans is encoded by the ''FLT3'' gene. FLT3 is a cyto ...
,
ERG
The erg is a unit of energy equal to 10−7joules (100 nJ). It originated in the Centimetre–gram–second system of units (CGS). It has the symbol ''erg''. The erg is not an SI unit. Its name is derived from (), a Greek word meaning 'work' o ...
,
DYRK1A
Dual specificity tyrosine-phosphorylation-regulated kinase 1A is an enzyme that in humans is encoded by the ''DYRK1A'' gene. Alternative splicing of this gene generates several transcript variants differing from each other either in the Five prime ...
,
CHAF1B,
HLCS
Holocarboxylase synthetase (biotin—(propionyl-Coenzyme A-carboxylase (ATP-hydrolysing)) ligase)), also known as protein—biotin ligase, is a family of enzymes ({{{EnzExplorer, 6.3.4.10). This enzyme is important for the effective use of bi ...
,
CTCF
Transcriptional repressor CTCF also known as 11-zinc finger protein or CCCTC-binding factor is a transcription factor that in humans is encoded by the ''CTCF'' gene. CTCF is involved in many cellular processes, including transcriptional regulatio ...
,
STAG2
Cohesin subunit SA-2 (SA2) is a protein that in humans is encoded by the ''STAG2'' gene. SA2 is a subunit of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. In somatic cells cohesin is form ...
,
RAD21,
SMC3
Structural maintenance of chromosomes protein 3 (SMC3) is a protein that in humans is encoded by the SMC3 gene. SMC3 is a subunit of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. Cohesi ...
,
SMC1A
Structural maintenance of chromosomes protein 1A (SMC1A) is a protein that in humans is encoded by the ''SMC1A'' gene. SMC1A is a subunit of the cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. ...
,
NIPBL
Nipped-B-like protein (NIPBL), also known as SCC2 or delangin is a protein that in humans is encoded by the ''NIPBL'' gene. NIPBL is required for the association of cohesin with DNA and is the major subunit of the cohesin loading complex. Heterozy ...
,
SUZ12
Polycomb protein SUZ12 is a protein that in humans is encoded by the ''SUZ12'' gene.
Function
This zinc finger gene has been identified at the breakpoints of a recurrent chromosomal translocation reported in endometrial stromal sarcoma. Recomb ...
,
PRC2
PRC2 (polycomb repressive complex 2) is one of the two classes of polycomb-group proteins or (PcG). The other component of this group of proteins is PRC1 (Polycomb Repressive Complex 1).
This complex has histone methyltransferase activity and pr ...
,
JAK1
JAK1 is a human tyrosine kinase protein essential for signaling for certain type I and type II cytokines. It interacts with the common gamma chain (γc) of type I cytokine receptors, to elicit signals from the IL-2 receptor family (e.g. IL-2R, I ...
,
JAK2
Janus kinase 2 (commonly called JAK2) is a non-receptor tyrosine kinase. It is a member of the Janus kinase family and has been implicated in signaling by members of the type II cytokine receptor family (e.g. interferon receptors), the GM-CSF rece ...
,
JAK3
Tyrosine-protein kinase JAK3 is a tyrosine kinase enzyme that in humans is encoded by the ''JAK3'' gene.
Janus kinases
Janus kinase 3 is a tyrosine kinase that belongs to the janus family of kinases. Other members of the Janus family include ...
,
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 cell ...
,
NRAS,
SH2B3
SH2B adapter protein 3 (SH2B3), also known as lymphocyte adapter protein (LNK), is a protein that in humans is encoded by the ''SH2B3'' gene on chromosome 12.
SH2B adapter protein 3 is a protein that in humans is encoded by the SH2B3 gene on chrom ...
'', and ''MIR125B2'' which is the gene for
microRNA
MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miRN ...
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
An infant or baby is the very young offspring of human beings. ''Infant'' (from the Latin word ''infans'', meaning 'unable to speak' or 'speechless') is a formal or specialised synonym for the common term ''baby''. The terms may also be used to ...
or, less commonly, later childhood as
aplastic anemia
Aplastic anemia is a cancer in which the body fails to make blood cells in sufficient numbers. Blood cells are produced in the bone marrow by stem cells that reside there. Aplastic anemia causes a deficiency of all blood cell types: red blood ...
and the circulation of abnormally enlarged
red blood cell
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
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, also known as a congenital disorder, 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 ...
.
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 effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
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 an ...
s. About 90% of the latter mutations occur in 6 ribosomal protein genes viz., ''
RPS19
40S ribosomal protein S19 is a protein that in humans is encoded by the ''RPS19'' gene.
Function
Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are c ...
,
RPL5
60S ribosomal protein L5 is a protein that in humans is encoded by the ''RPL5'' gene.
Function
Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are compo ...
,
RPS26,
RPL11
60S ribosomal protein L11 is a protein that in humans is encoded by the ''RPL11'' gene.
Function
Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits a ...
,
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. The ...
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''-inactivatng 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 deprotonat ...
; M=
methionine
Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical ro ...
; 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 (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
; 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 − form un ...
, 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. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...
; 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 non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
, R=
arginine
Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...
; 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 aromatic ...
, 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 thalassemias (β thalassemias) are a group of inherited blood disorders. They are forms of thalassemia caused by reduced or absent synthesis of the beta chains of hemoglobin that result in variable outcomes ranging from severe anemia to cli ...
-type disease, i.e.
microcytic anemia
Microcytic anaemia is any of several types of anemia characterized by smaller than normal red blood cells (called microcytes). The normal mean corpuscular volume (abbreviated to MCV on full blood count results, and also known as mean cell volume) ...
, absence of
hemoglobin B, and
hereditary persistence of fetal hemoglobin
Hereditary persistence of fetal hemoglobin (HPFH) is a benign condition in which increased fetal hemoglobin (hemoglobin F, HbF) production continues well into adulthood, disregarding the normal shutoff point after which only adult-type hemoglobin s ...
; symptoms of
congenital erythropoietic porphyria
A birth defect, also known as a congenital disorder, 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 r ...
; 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, 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 sufficiently lar ...
(rs113966884
) in which the
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...
adenine
Adenine () ( symbol A or Ade) is a nucleobase (a purine derivative). It is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The three others are guanine, cytosine and thymine. Its derivati ...
replaces
guanine
Guanine () ( symbol G or Gua) is one of the four main nucleobases 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 is called ...
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
*Standing start, and rolling start, in an auto race
Acronyms
*St ...
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 granules that perform different functions, and include alpha granules, dense granules, and lysosomes. ...
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
Neurobeachin-like 2 is a protein that in humans is encoded by the ''NBEAL2'' gene.
Function
The protein encoded by this gene contains a beige and Chediak-Higashi (BEACH) domain and multiple WD40 domains, and may play a role in megakaryocyte ...
'' 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 almost 200 million base pairs (the building material of DNA) and represents about 6.5 percent of the total DNA in ...
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 effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
inheritance, causes a mild to moderate bleeding tendency, and may be accompanied by a defect in the secretion of the granule contents in
neutrophils
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...
. 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'' (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 effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
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
Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients an ...
) 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 inherited blood disorders characterized by decreased hemoglobin production. Symptoms depend on the type and can vary from none to severe. Often there is mild to severe anemia (low red blood cells or hemoglobin). Anemia can result ...
-like disorder due to unbalanced hemoglobin production, and/or a
porphyria
Porphyria is a group of liver disorders in which substances called porphyrins build up in the body, negatively affecting the skin or nervous system. The types that affect the nervous system are also known as acute porphyria, as symptoms are ra ...
-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
Extramedullary hematopoiesis (EMH or sometimes EH) refers to hematopoiesis occurring outside of the medulla of the bone (bone marrow). It can be physiologic or pathologic.
Physiologic EMH occurs during embryonic and fetal development; during this ...
(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
A megakaryocyte (''mega-'' + '' karyo-'' + '' -cyte'', "large-nucleus cell") is a large bone marrow cell with a lobated nucleus responsible for the production of blood thrombocytes (platelets), which are necessary for normal blood clotting. In hum ...
in the bone marrow. Ultimately, the disease may progress to
leukemia
Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in 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
Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transl ...
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
Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...
transformation.
References
Further reading
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*
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External links
GenecardsGeneReviews/NCBI/NIH/UW entry on GATA1-Related X-Linked CytopeniaGeneatlasNextbio*
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.
[{{cite journal , vauthors = Katsumura KR, Bresnick EH , title = The GATA factor revolution in hematology , journal = Blood , volume = 129 , issue = 15 , pages = 2092–2102 , date = April 2017 , pmid = 28179282 , pmc = 5391619 , doi = 10.1182/blood-2016-09-687871 ]
Transcription factors