Main pathogenetic mechanisms of inherited thrombocytopenias
| Disease . | Gene . | Function of the defective gene/pathogenetic mechanisms of thrombocytopenia . |
|---|---|---|
| Defects in megakaryocyte differentiation | ||
| Congenital amegakaryocytic thrombocytopenia39 | MPL | MPL encodes for the receptor for THPO. MPL biallelic mutations abrogate THPO-MPL signaling, which is essential for the commitment differentiation of multipotent hematopoietic stem cells to MKs since birth and the self-renewal and maintenance of the multipotent stem cell compartment in postnatal hematopoiesis. |
| Thrombocytopenia-absent radius syndrome32 | RBM8A | RBM8A encodes for Y14, a component of the ubiquitous exon-junction complex, which is involved in RNA processing. Thrombocytopenia-absent radius syndrome is caused by compound inheritance of a low-frequency noncoding SNP and a rare null allele in RBM8A that significantly reduces Y14 expression. It has been hypothesized that Y14 deficiency affects MK differentiation by impairing the signaling downstream MPL. |
| Radioulnar synostosis with amegakaryocytic thrombocytopenia36 | HOXA11 | HOXA11 encodes for a member of the Homeobox family of DNA-binding proteins involved in the regulation of early hematopoiesis. Mutation of HOXA11 responsible for RUSAT affects MK differentiation in vitro. |
| MECOM | MECOM encodes the oncoprotein EVI1, a transcription factor involved in homeostasis of the hematopoietic stem cell compartment and MK differentiation. Missense pathogenetic variants of EVI1 may reduce its interaction with DNA and/or other transcription factors. | |
| Defects in megakaryocyte maturation | ||
| Familial platelet disorder with propensity to acute myelogenous leukemia40 | RUNX1 (AML1, CBFA2) | RUNX1 encodes for the DNA-binding α subunit of the CBF transcription complex, which transactivates multiple hematopoiesis-specific genes. Pathogenetic variants induce profound defects in MK maturation and platelet functional abnormalities deriving from dysregulated expression of several genes involved in MK development. Moreover, they affect the clonogenic potential and self-renewal capacities of the hematopoietic myeloid progenitors. |
| ANKRD26-related thrombocytopenia41 | ANKRD26 | ANKRD26 is downregulated during MK maturation by binding of RUNX1 and FLI1 to the 5′ UTR of the gene. Pathogenetic mutations abolish this binding, resulting in ANKRD26 overexpression in MKs, which, in turn, induces unbalanced activation of kinases downstream the MPL receptor, especially the MAPK/ERK 1/2 pathway. This mechanism induces altered MK maturation and reduced proplatelet extension. |
| Paris-Trousseau thrombocytopenia/Jacobsen syndrome29 | Deletions in 11q23 | Contiguous gene deletion syndrome. Different sizes and breakpoints of deletions are responsible for heterogeneity of the clinical picture. Thrombocytopenia derives from the deletion of FLI1, a transcription factor that promotes platelet production by transactivation of several genes associated with MK development, such as MPL, GP6, GP9, GP1BA, ITGA2B, and PF4. FLI1 haploinsufficiency results in altered MK maturation and dysmorphic and dysfunctional platelets. |
| FLI1-related thrombocytopenia24 | FLI1 | A homozygous missense mutation of FLI1 (see above) results in impaired DNA binding of the transcription factor and causes a phenotype similar to that of Paris-Trousseau thrombocytopenia. |
| ETV6-related thrombocytopenia9 | ETV6 | ETV6 encodes an ETS transcription factor that was initially identified as a tumor suppressor. ETV6 is involved in the balance between proliferation and differentiation of early hematopoietic progenitors and in late MK development. Mutations cause thrombocytopenia by affecting MK maturation. |
| GATA1-related diseases42 | GATA1 | GATA1 is a transcription factor regulating several genes with a key role in megakaryopoiesis, as GP1BA, GP1BB, ITGA2B, PF4, MPL, and NFE2, and in erythropoiesis, as HBB, ALAS1, and BCL2L1. Mutations affect MK maturation, resulting in thrombocytopenia and the production of dysmorphic and dysfunctional platelets. |
| GFI1b-related thrombocytopenia5 | GFI1B | GFI1B is a transcription factor regulating homeostasis of hematopoietic stem cells and development of the MK and erythroid lineages. Mutations cause defective MK maturation with defective expression of several platelet proteins, α granule deficiency, and variable alterations of platelet function. |
| Gray platelet syndrome43 | NBEAL2 | NBEAL2 encodes neurobeachin-like protein 2, which is involved in protein-protein interactions, membrane dynamics, and vesicle trafficking. Mutations result in defective MK maturation, severe deficiency of platelet α granules, and variable defects of platelet function. |
| SLFN14-related thrombocytopenia8 | SLFN14 | The role of SLFN14 protein is poorly known. Possible role as an endoribonuclease, regulating rRNA, and ribosome-associated mRNA cleavage. Mutations induce reduced SLFN14 expression in platelets. Patients’ platelets have defective dense granule formation and ATP secretion and heterogeneous functional defects. Some observations suggested that thrombocytopenia derives from reduced MK maturation and proplatelet formation. |
| FYB-related thrombocytopenia7 | FYB | The FYB protein (ADAP) is a candidate linker between cell membrane activation signals and intracellular events regulating actin organization. Because of immature MKs in bone marrow and activated platelets in blood, it has been hypothesized that thrombocytopenia derives from defective maturation of MKs and clearance of activated platelets. |
| SRC-related thrombocytopenia11 | SRC | SRC encodes for a tyrosine kinase, with a key role in several MK and platelet signaling pathways. Thrombocytopenia is caused by a gain-of-function missense mutation, resulting in a constitutive kinase activation, which causes increased overall tyrosine phosphorylation. Some observations suggest that thrombocytopenia derives from defective MK maturation and reduced proplatelet formation. |
| Defects in platelet release | ||
| MYH9-related disease43 | MYH9 | The MYH9 gene encodes for the heavy chain of non-muscle myosin IIA, a cytoplasmic myosin involved in processes requiring the generation of a chemomechanical force by the actin cytoskeleton. Mutations cause macrothrombocytopenia by inducing multiple defects of proplatelet formation and possible premature, ectopic release of platelets within the bone marrow. |
| ACTN1-related thrombocytopenia19 | ACTN1 | The ACTN1 protein (α1 actinin) stabilizes the actin cytoskeleton by crosslinking actin filaments in bundles. Mutations cause macrothrombocytopenia by inducing multiple defects of proplatelet formation. |
| FLNA-related thrombocytopenia30 | FLNA | The FLNA protein (filamin A) stabilizes the actin cytoskeleton and connects it to the plasma membrane. In MKs, filamin A binds the intracytoplasmatic domain of GPIbα to the actin filament network. It has been suggested that mutations result in defective proplatelet formation. |
| Bernard-Soulier syndrome | ||
| Biallelic43 | GP1BA GPIBB GP9 | These genes encode for components of the GPIb-IX-V complex in platelets and MKs. Mutations result in defective expression of the complex in the plasma membrane and cause thrombocytopenia by hampering proplatelet formation. |
| Monoallelic43 | ||
| ITGA2B/ITGB3-related thrombocytopenia44 | ITGA2B ITGB3 | ITGA2B and ITGB3 encode for the components of the GPIIb-IIIa complex. Mutations responsible for macrothrombocytopenia cause constitutive activation of the complex, which affects actin cytoskeleton reorganization. Proplatelet formation and proplatelet conversion to platelets are defective. |
| TUBB1-related thrombocytopenia22 | TUBB1 | The TUBB1 protein (β1 tubulin) is a component of microtubules expressed only in mature MKs and platelets. Mutations disrupt microtubule assembly and result in defective proplatelet formation. |
| TRPM7-related thrombocytopenia26 | TRPM7 | TRPM7 is a cation channel regulating calcium and magnesium homeostasis and a kinase that modulates the activity of non-muscle myosin IIA. Mutations induce macrothrombocytopenia deriving from altered acto-myosin cytoskeletal reorganization, which, in turn, impairs proplatelet formation. |
| TPM4-related thrombocytopenia17 | TPM4 | Tropomyosins are cytoskeletal proteins that regulate multiple functions of the acto-myosin cytoskeleton. TPM4 encodes 2 tropomyosin isoforms that are abundantly expressed in MKs and platelets. Mutations cause TPM4 insufficiency, which induces macrothrombocytopenia by altering actin cytoskeleton reorganization and eventually proplatelet formation. |
| CYCS-related thrombocytopenia45 | CYCS | CYCS encodes cytochrome c, a ubiquitous mitochondrial protein involved in mitochondrial respiration and initiation of the intrinsic pathway of apoptosis. Data suggest that mutations cause thrombocytopenia by inducing ectopic, premature release of platelets by a proplatelet-independent mechanism. |
| DIAPH1-related thrombocytopenia10 | DIAPH1 | DIAPH1 encodes a conserved member of the formin protein family, which mediates ρ GTPase-dependent assembly of filamentous actin and microtubule regulation during cytoskeletal remodeling. Mutation causes constitutive activation of the protein, which affects proplatelet formation by inducing abnormalities of cytoskeletal and microtubule function. |
| PRKACG-related thrombocytopenia4 | PRKACG | PRKACG encodes the γ isoform of the catalytic subunit of cAMP-dependent protein kinase A. Mutations affect proplatelet formation and platelet activation. |
| Shortened platelet survival | ||
| Platelet-type von Willebrand disease20 | GP1BA | The gene GP1BA encodes GPIbα, whose extracellular domain binds to vWF. The disorder derives from gain-of-function mutations that increase the affinity of GPIbα for von Willebrand factor. Reduced platelet survival derives from platelet clumping within the circulation. |
| Wiskott-Aldrich syndrome27 | WAS | The WAS protein plays a key role in the polymerization of actin in hematopoietic cells. Mutations result in increased clearance of platelets by the reticuloendothelial system and premature, ectopic platelet release of platelets in the bone marrow. The observation that splenectomy normalizes or significantly increases platelet counts in patients with WAS/XLT suggests that increased platelet clearance is the key mechanism of thrombocytopenia. |
| X-linked thrombocytopenia27 | ||
| Unknown defect | ||
| Stormorken syndrome/York platelet syndrome6,35 | STIM1 | STIM1 encodes for a protein of the endoplasmic reticulum that regulates Ca2+ influx to cells through the Ca2+ release-activated Ca2+ channels of the plasma membrane in many cell types. The causative variants are gain-of-function monoallelic mutations, resulting in constitutive Ca2+ influx from the extracellular space to the cytoplasm. Platelets have several in vitro defects of aggregation, activation, and δ granule secretion. |
| Disease . | Gene . | Function of the defective gene/pathogenetic mechanisms of thrombocytopenia . |
|---|---|---|
| Defects in megakaryocyte differentiation | ||
| Congenital amegakaryocytic thrombocytopenia39 | MPL | MPL encodes for the receptor for THPO. MPL biallelic mutations abrogate THPO-MPL signaling, which is essential for the commitment differentiation of multipotent hematopoietic stem cells to MKs since birth and the self-renewal and maintenance of the multipotent stem cell compartment in postnatal hematopoiesis. |
| Thrombocytopenia-absent radius syndrome32 | RBM8A | RBM8A encodes for Y14, a component of the ubiquitous exon-junction complex, which is involved in RNA processing. Thrombocytopenia-absent radius syndrome is caused by compound inheritance of a low-frequency noncoding SNP and a rare null allele in RBM8A that significantly reduces Y14 expression. It has been hypothesized that Y14 deficiency affects MK differentiation by impairing the signaling downstream MPL. |
| Radioulnar synostosis with amegakaryocytic thrombocytopenia36 | HOXA11 | HOXA11 encodes for a member of the Homeobox family of DNA-binding proteins involved in the regulation of early hematopoiesis. Mutation of HOXA11 responsible for RUSAT affects MK differentiation in vitro. |
| MECOM | MECOM encodes the oncoprotein EVI1, a transcription factor involved in homeostasis of the hematopoietic stem cell compartment and MK differentiation. Missense pathogenetic variants of EVI1 may reduce its interaction with DNA and/or other transcription factors. | |
| Defects in megakaryocyte maturation | ||
| Familial platelet disorder with propensity to acute myelogenous leukemia40 | RUNX1 (AML1, CBFA2) | RUNX1 encodes for the DNA-binding α subunit of the CBF transcription complex, which transactivates multiple hematopoiesis-specific genes. Pathogenetic variants induce profound defects in MK maturation and platelet functional abnormalities deriving from dysregulated expression of several genes involved in MK development. Moreover, they affect the clonogenic potential and self-renewal capacities of the hematopoietic myeloid progenitors. |
| ANKRD26-related thrombocytopenia41 | ANKRD26 | ANKRD26 is downregulated during MK maturation by binding of RUNX1 and FLI1 to the 5′ UTR of the gene. Pathogenetic mutations abolish this binding, resulting in ANKRD26 overexpression in MKs, which, in turn, induces unbalanced activation of kinases downstream the MPL receptor, especially the MAPK/ERK 1/2 pathway. This mechanism induces altered MK maturation and reduced proplatelet extension. |
| Paris-Trousseau thrombocytopenia/Jacobsen syndrome29 | Deletions in 11q23 | Contiguous gene deletion syndrome. Different sizes and breakpoints of deletions are responsible for heterogeneity of the clinical picture. Thrombocytopenia derives from the deletion of FLI1, a transcription factor that promotes platelet production by transactivation of several genes associated with MK development, such as MPL, GP6, GP9, GP1BA, ITGA2B, and PF4. FLI1 haploinsufficiency results in altered MK maturation and dysmorphic and dysfunctional platelets. |
| FLI1-related thrombocytopenia24 | FLI1 | A homozygous missense mutation of FLI1 (see above) results in impaired DNA binding of the transcription factor and causes a phenotype similar to that of Paris-Trousseau thrombocytopenia. |
| ETV6-related thrombocytopenia9 | ETV6 | ETV6 encodes an ETS transcription factor that was initially identified as a tumor suppressor. ETV6 is involved in the balance between proliferation and differentiation of early hematopoietic progenitors and in late MK development. Mutations cause thrombocytopenia by affecting MK maturation. |
| GATA1-related diseases42 | GATA1 | GATA1 is a transcription factor regulating several genes with a key role in megakaryopoiesis, as GP1BA, GP1BB, ITGA2B, PF4, MPL, and NFE2, and in erythropoiesis, as HBB, ALAS1, and BCL2L1. Mutations affect MK maturation, resulting in thrombocytopenia and the production of dysmorphic and dysfunctional platelets. |
| GFI1b-related thrombocytopenia5 | GFI1B | GFI1B is a transcription factor regulating homeostasis of hematopoietic stem cells and development of the MK and erythroid lineages. Mutations cause defective MK maturation with defective expression of several platelet proteins, α granule deficiency, and variable alterations of platelet function. |
| Gray platelet syndrome43 | NBEAL2 | NBEAL2 encodes neurobeachin-like protein 2, which is involved in protein-protein interactions, membrane dynamics, and vesicle trafficking. Mutations result in defective MK maturation, severe deficiency of platelet α granules, and variable defects of platelet function. |
| SLFN14-related thrombocytopenia8 | SLFN14 | The role of SLFN14 protein is poorly known. Possible role as an endoribonuclease, regulating rRNA, and ribosome-associated mRNA cleavage. Mutations induce reduced SLFN14 expression in platelets. Patients’ platelets have defective dense granule formation and ATP secretion and heterogeneous functional defects. Some observations suggested that thrombocytopenia derives from reduced MK maturation and proplatelet formation. |
| FYB-related thrombocytopenia7 | FYB | The FYB protein (ADAP) is a candidate linker between cell membrane activation signals and intracellular events regulating actin organization. Because of immature MKs in bone marrow and activated platelets in blood, it has been hypothesized that thrombocytopenia derives from defective maturation of MKs and clearance of activated platelets. |
| SRC-related thrombocytopenia11 | SRC | SRC encodes for a tyrosine kinase, with a key role in several MK and platelet signaling pathways. Thrombocytopenia is caused by a gain-of-function missense mutation, resulting in a constitutive kinase activation, which causes increased overall tyrosine phosphorylation. Some observations suggest that thrombocytopenia derives from defective MK maturation and reduced proplatelet formation. |
| Defects in platelet release | ||
| MYH9-related disease43 | MYH9 | The MYH9 gene encodes for the heavy chain of non-muscle myosin IIA, a cytoplasmic myosin involved in processes requiring the generation of a chemomechanical force by the actin cytoskeleton. Mutations cause macrothrombocytopenia by inducing multiple defects of proplatelet formation and possible premature, ectopic release of platelets within the bone marrow. |
| ACTN1-related thrombocytopenia19 | ACTN1 | The ACTN1 protein (α1 actinin) stabilizes the actin cytoskeleton by crosslinking actin filaments in bundles. Mutations cause macrothrombocytopenia by inducing multiple defects of proplatelet formation. |
| FLNA-related thrombocytopenia30 | FLNA | The FLNA protein (filamin A) stabilizes the actin cytoskeleton and connects it to the plasma membrane. In MKs, filamin A binds the intracytoplasmatic domain of GPIbα to the actin filament network. It has been suggested that mutations result in defective proplatelet formation. |
| Bernard-Soulier syndrome | ||
| Biallelic43 | GP1BA GPIBB GP9 | These genes encode for components of the GPIb-IX-V complex in platelets and MKs. Mutations result in defective expression of the complex in the plasma membrane and cause thrombocytopenia by hampering proplatelet formation. |
| Monoallelic43 | ||
| ITGA2B/ITGB3-related thrombocytopenia44 | ITGA2B ITGB3 | ITGA2B and ITGB3 encode for the components of the GPIIb-IIIa complex. Mutations responsible for macrothrombocytopenia cause constitutive activation of the complex, which affects actin cytoskeleton reorganization. Proplatelet formation and proplatelet conversion to platelets are defective. |
| TUBB1-related thrombocytopenia22 | TUBB1 | The TUBB1 protein (β1 tubulin) is a component of microtubules expressed only in mature MKs and platelets. Mutations disrupt microtubule assembly and result in defective proplatelet formation. |
| TRPM7-related thrombocytopenia26 | TRPM7 | TRPM7 is a cation channel regulating calcium and magnesium homeostasis and a kinase that modulates the activity of non-muscle myosin IIA. Mutations induce macrothrombocytopenia deriving from altered acto-myosin cytoskeletal reorganization, which, in turn, impairs proplatelet formation. |
| TPM4-related thrombocytopenia17 | TPM4 | Tropomyosins are cytoskeletal proteins that regulate multiple functions of the acto-myosin cytoskeleton. TPM4 encodes 2 tropomyosin isoforms that are abundantly expressed in MKs and platelets. Mutations cause TPM4 insufficiency, which induces macrothrombocytopenia by altering actin cytoskeleton reorganization and eventually proplatelet formation. |
| CYCS-related thrombocytopenia45 | CYCS | CYCS encodes cytochrome c, a ubiquitous mitochondrial protein involved in mitochondrial respiration and initiation of the intrinsic pathway of apoptosis. Data suggest that mutations cause thrombocytopenia by inducing ectopic, premature release of platelets by a proplatelet-independent mechanism. |
| DIAPH1-related thrombocytopenia10 | DIAPH1 | DIAPH1 encodes a conserved member of the formin protein family, which mediates ρ GTPase-dependent assembly of filamentous actin and microtubule regulation during cytoskeletal remodeling. Mutation causes constitutive activation of the protein, which affects proplatelet formation by inducing abnormalities of cytoskeletal and microtubule function. |
| PRKACG-related thrombocytopenia4 | PRKACG | PRKACG encodes the γ isoform of the catalytic subunit of cAMP-dependent protein kinase A. Mutations affect proplatelet formation and platelet activation. |
| Shortened platelet survival | ||
| Platelet-type von Willebrand disease20 | GP1BA | The gene GP1BA encodes GPIbα, whose extracellular domain binds to vWF. The disorder derives from gain-of-function mutations that increase the affinity of GPIbα for von Willebrand factor. Reduced platelet survival derives from platelet clumping within the circulation. |
| Wiskott-Aldrich syndrome27 | WAS | The WAS protein plays a key role in the polymerization of actin in hematopoietic cells. Mutations result in increased clearance of platelets by the reticuloendothelial system and premature, ectopic platelet release of platelets in the bone marrow. The observation that splenectomy normalizes or significantly increases platelet counts in patients with WAS/XLT suggests that increased platelet clearance is the key mechanism of thrombocytopenia. |
| X-linked thrombocytopenia27 | ||
| Unknown defect | ||
| Stormorken syndrome/York platelet syndrome6,35 | STIM1 | STIM1 encodes for a protein of the endoplasmic reticulum that regulates Ca2+ influx to cells through the Ca2+ release-activated Ca2+ channels of the plasma membrane in many cell types. The causative variants are gain-of-function monoallelic mutations, resulting in constitutive Ca2+ influx from the extracellular space to the cytoplasm. Platelets have several in vitro defects of aggregation, activation, and δ granule secretion. |
CBF, core binding factor; ERK, extracellular signal-regulated kinase; Mk, megakaryocyte. Additional abbreviations are explained in Table 1.