Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The bone marrow failure syndromes consist of a number of rare diseases, in which there is ineffective hematopoiesis by the bone marrow. Subsequently, absent or decreased production of a single cell line, single cytopenia, or of all cell lines, and pancytopenia, develops. The mechanisms of hematopoiesis and the defects that result in bone marrow failure are beginning to be better understood. This paper will review the genetic and molecular basis of several important bone marrow failure syndromes in children, Fanconi anemia, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, congenital amegakaryocytic thrombocytopenia, dyskeratosis congenita, and severe congenital neutropenia, and the recent discoveries that have enhanced our understanding of the pathogenesis of these diseases.
Mol Genet Metab
PMID:The genetic basis of bone marrow failure syndromes in children. 1612 92

Homeobox genes encode for regulatory proteins central to hematopoietic differentiation and proliferation. Previously, we identified an inherited syndrome of congenital amegakaryocytic thrombocytopenia and radio-ulnar synostosis that is associated with a point mutation in the third helix of HOXA11 homeodomain (HOXA11-DeltaH3). Here, we demonstrate that this mutation results in a significantly truncated protein with impaired DNA-binding efficiency. Electrophoretic mobility shift assays (EMSA) confirm that wild-type HOXA11 (HOXA11-WT) interacts in vitro with the DNA-binding consensus sequence for HOXA11, and that this interaction is most efficient when the TALE transcription factor, Meis1b, is also present. However, the binding between HOXA11-DeltaH3 and DNA is abrogated even in the presence of Meis1b, suggesting the point mutant causes a disruption in the DNA-binding capacity. We investigated whether the point mutation also affected the physical protein-protein interaction between HoxA11 and Meis1b. Using GST pulldown assays, we find Meis1b interactions with both HOXA11-WT and HOXA11-DeltaH3 in the presence of DNA. DNAse treatment decreased these interactions, suggesting that the interaction is a protein-protein association, and DNA may serve to stabilize this interaction. Stable expression of FLAG-HOXA11-WT or -DeltaH3 in K562 cells significantly impacts megakaryocytic differentiation. Staurosporine (STSP) induced K562 cells to differentiate into a megakaryocytic phenotype. Treatment leads to an increase in surface expression of the megakaryocytic/platelet-specific antigen, CD61, and causes morphological changes consistent with megakaryocytic differentiation. CD61 surface expression on STSP treated HOXA11-WT and -DeltaH3 expressing cells was significantly reduced as compared to untransfected K562 cells. Interestingly, we found only a slight difference in CD61 expression between wild-type and mutant HOXA11 K562. These data suggest that HoxA11 inhibition of differentiation may involve nonhomeodomain sequences. Finally, our laboratory has detected a small amount of HoxA11 mRNA in cells isolated from unfractionated human cord blood and murine ES cell culture cocultured on OP9 for 6 days in the absence of leukemia inhibitory factor (LIF). This finding suggests HoxA11 may be endogenously expressed in very early hematopoietic precursor cells. Taken together, these data begin to give us insight into the molecular mechanisms by which HoxA11 may be involved in regulating megakaryocytic differentiation.
Blood Cells Mol Dis
PMID:HOXA11 mutation in amegakaryocytic thrombocytopenia with radio-ulnar synostosis syndrome inhibits megakaryocytic differentiation in vitro. 1676 69

Signaling of the thrombopoietin (THPO) receptor MPL is critical for the maintenance of hematopoietic stem cells (HSCs) and megakaryocytic differentiation. Inherited loss-of-function mutations of MPL cause severe thrombocytopenia and aplastic anemia, a syndrome called congenital amegakaryocytic thrombocytopenia (CAMT). With the aim to assess the toxicity of retroviral expression of Mpl as a basis for further development of a gene therapy for this disorder, we expressed Mpl in a murine bone marrow transplantation (BMT) model. Treated mice developed a profound yet transient elevation of multilineage hematopoiesis, which showed morphologic features of a chronic myeloproliferative disorder (CMPD) with progressive pancytopenia. Ten percent of mice (3/27) developed erythroleukemia, associated with insertional activation of Sfpi1 and Fli1. The majority of transplanted mice developed a progressive pancytopenia with histopathological features of a myelodysplastic syndrome (MDS)-like disorder. To avoid these adverse reactions, improved retroviral vectors were designed that mediate reduced and more physiological Mpl expression. Self-inactivating gamma-retroviral vectors were constructed that expressed Mpl from the phosphoglycerate kinase (PGK) or the murine Mpl promoter. Mice that received BM cells expressing Mpl from the Mpl promoter were free of any previously observed adverse reactions.
Mol Ther 2010 Feb
PMID:Gene therapy of MPL deficiency: challenging balance between leukemia and pancytopenia. 1984 95

Congenital amegakaryocytic thrombocytopenia (MIM #604498) (CAMT) is a rare inherited disease presenting as severe thrombocytopenia in infancy. Untreated, many CAMT patients develop aplastic anemia within the first decade of life; the only effective treatment of CAMT is bone marrow transplantation. CAMT is the result of the presence of homozygous or compound heterozygous mutations in the thrombopoietin receptor-encoding gene, MPL. We report here the identification and characterization of a founder mutation in MPL in the Ashkenazi Jewish (AJ) population. This mutation, termed c.79+2T>A, is a T to A transversion in the invariant second base of the intron 1 donor splice site. Analysis of a random sample of 2018 individuals of AJ descent revealed a carrier frequency of approximately 1 in 75. Genotyping of six loci adjacent to the MPL gene in the proband and in the 27 individuals identified as carriers of the c.79+2T>A mutation revealed that the presence of this mutation in the AJ population is due to a single founder. The observed carrier frequency predicts an incidence of CAMT in the AJ population of approximately 1 in 22,500 pregnancies. The identification of this mutation will enable population carrier testing and will facilitate the identification and treatment of individuals homozygous for this mutation.
Blood Cells Mol Dis 2011 Jun 15
PMID:A founder mutation in the MPL gene causes congenital amegakaryocytic thrombocytopenia (CAMT) in the Ashkenazi Jewish population. 2148 38