Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by the presence in the patient's hematopoietic system of a large cell population with a mutation in the X-linked PIG-A gene. Although this abnormal cell population is often found to be monoclonal, it is not unusual that 2 or even several PIG-A mutant clones coexist in the same patient. Therefore, it has been suggested that the PIG-A gene may be hypermutable in PNH. By a method we have recently developed for measuring the intrinsic rate of somatic mutations (mu) in humans, in which PIG-A itself is used as a sentinel gene, we have found that in 5 patients with PNH, mu ranged from 1.24 x 10(-7) to 11.2 x 10(-7), against a normal range of 2.4 x 10(-7) to 29.6 x 10(-7) mutations per cell division. We conclude that genetic instability of the PIG-A gene is not a factor in the pathogenesis of PNH.
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PMID:The mutation rate in PIG-A is normal in patients with paroxysmal nocturnal hemoglobinuria (PNH). 1654 65

Attachment to the plasma membrane by linkage to a glycosylphosphatidylinositol (GPI) anchor is a mode of protein expression highly conserved from protozoa to mammals. As a clinical entity, deficiency of GPI has been recognized as paroxysmal nocturnal hemoglobinuria, an acquired clonal disorder associated with somatic mutations of the X-linked PIGA gene in hematopoietic cells. We have identified a novel disease characterized by a propensity to venous thrombosis and seizures in which deficiency of GPI is inherited in an autosomal recessive manner. In two unrelated kindreds, a point mutation (c --> g) at position -270 from the start codon of PIGM, a mannosyltransferase-encoding gene, disrupts binding of the transcription factor Sp1 to its cognate promoter motif. This mutation substantially reduces transcription of PIGM and blocks mannosylation of GPI, leading to partial but severe deficiency of GPI. These findings indicate that biosynthesis of GPI is essential to maintain homeostasis of blood coagulation and neurological function.
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PMID:Hypomorphic promoter mutation in PIGM causes inherited glycosylphosphatidylinositol deficiency. 1676

The microwave spectra of (methylamino)thiophosphoryl difluoride, CH(3)NHP(=S)F(2), and two deuterated species, CH(3)NDP(=S)F(2) and CD(3)NHP(=S)F(2), have been investigated in the region from 26.5 to 39.0 GHz. The rotational constants of the ground vibrational state have been determined and have been shown to be only consistent with the trans conformer (CH(3) group antiperiplanar to the P=S bond) with C(s) symmetry. The a-type R branch transitions have been assigned for the trans conformer for the three isotopomers on the basis of the rigid rotor model. Near-trans and near-cis forms without molecular planes of symmetry are predicted by all ab initio calculations with the near-trans form being more stable. However, the double-well potentials governing the interchange between the two enantiomeric near-trans as well as the two near-cis forms are too shallow to accommodate the zero-point energies of the nu(24) asymmetric torsion. Thus, the trans conformation with C(s) symmetry may be more accurate in explaining the microwave experimental data. The "adjusted" r(0) structural parameters have been obtained by systematically adjusting the ab initio MP2(full)/6-311+G(d,p) structure of the trans conformer with C(s) symmetry to fit the microwave rotational constants. The determined heavy atom distances are r(C-N) = 1.459(5), r(P-N) = 1.621(5), r(P=S) = 1.879(5), and r(P-F) = 1.550(5) A, and the heavy atom angles are angleCNP = 124.7(5) degrees , angleNPS = 118.3(5) degrees , angleNPF = 103.2(5) degrees , angleFPS = 117.0(5) degrees , and angleFPF = 94.6(5) degrees . The adjusted r(0) parameters have also been obtained for aminodifluorophosphine, H(2)NPF(2), with a slightly pyramidal -PNH(2) moiety. The results indicate that the previously reported short distance of 0.981(5) A for the N-H(o)(outer) bond from the microwave study is too short, and the adjusted r(0) value of 1.007(3) A is obtained from the combined data. Adjusted r(0) parameters are also reported for (dimethylamino)difluorophosphine, (CH(3))(2)NPF(2), with C(s) symmetry with the PNC(2) portion of the molecule being planar. The previously reported C-H distances from the electron diffraction study are too long, and the anglePNC(i) and angleC(o)NC(i) angles are also found to be in error. These results provide a reasonable explanation why the microwave and electron diffraction results differ for the structures of these latter two molecules.
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PMID:Microwave spectra, ab initio calculations, and r0 structural parameters for (methylamino)thiophosphoryl difluoride. 1680 89

PIG-A is an X-linked gene that is essential for the first step in the biosynthesis of glycosylphosphatidyl-inositol (GPI) anchors. A rare clonal hematopoietic stem cell disease, paroxysmal nocturnal hemoglobinuria (PNH), is caused by mutations in the PIG-A gene. PNH is an acquired disease that may arise de novo or emanate from aplastic anemia. PNH blood cells have an absence or marked deficiency of all GPI anchored proteins. Interestingly, rare GPI anchor deficient blood and marrow cells that harbor PIG-A mutations can also be found in most healthy controls. This review examines the clinical and biological relevance of PIG-A mutations in PNH, aplastic anemia and healthy controls.
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PMID:PIG-A mutations in paroxysmal nocturnal hemoglobinuria and in normal hematopoiesis. 1692 49

Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon intravascular hemolytic anemia that results from the clonal expansion of hematopoietic stem cells harboring somatic mutations in an X-linked gene, termed PIG-A. PIG-A mutations block glycosylphosphatidylinositol (GPI) anchor biosynthesis, resulting in a deficiency or absence of all GPI-anchored proteins on the cell surface. CD55 and CD59 are GPI-anchored complement regulatory proteins. Their absence on PNH red cells is responsible for the complement-mediated intravascular hemolysis. Intravascular hemolysis leads to release of free hemoglobin, which contributes to many of the clinical manifestations of PNH including fatigue, pain, esophageal spasm, erectile dysfunction and possibly thrombosis. Interestingly, rare PIG-A mutations can be found in virtually all healthy control subjects, leading to speculation that PIG-A mutations in hematopoietic stem cells are common benign events. However, negative selection of PIG-A mutant colony-forming cells with proaerolysin, a toxin that targets GPI-anchored proteins, reveals that most of these mutations are not derived from stem cells. Recently, a humanized monoclonal antibody directed against the terminal complement protein C5 has been shown to reduce hemolysis and greatly improve symptoms and quality of life for PNH patients.
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PMID:New insights into paroxysmal nocturnal hemoglobinuria. 1712 35

Until recently, there has been no specific therapy for PNH with clinical management mainly supportive in terms of cytopenias and control of thrombotic risk. Currently, the only curative procedure for PNH is bone marrow transplantation although for the majority of patients the associated risks are too great to justify transplantation. The pioneering use of the therapeutic monoclonal antibody eculizumab, which binds to and prevents the activation of the complement protein C5, represents a significant advance in treatment for patients with PNH and is set to become the future standard therapy for hemolytic PNH. In both an initial pilot study and two phase III clinical trials, eculizumab has been shown to dramatically reduce intravascular hemolysis, hemoglobinuria, and transfusion requirements thus improving the quality of life in patients with PNH. As a clinical entity, PNH is synonymous with glycosylphosphatidylinositol (GPI) deficiency, and is an acquired clonal disorder associated with somatic mutations of the X-linked PIGA gene in hematopoietic stem cells. A recent study identified a novel autosomal recessively inherited form of GPI-deficiency involving a mutation in a promotor component of the pig-m gene and characterized by a thrombotic tendency and seizures. In both these developments, flow cytometry played a critical role. In the first instance, in monitoring direct response to a new therapeutic agent; second, in demonstrating the phenotypic/genotypic link in a new form of GPI deficiency.
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PMID:Recent advances in the diagnosis, monitoring, and management of patients with paroxysmal nocturnal hemoglobinuria. 1754 42

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired haemopoietic stem cell disorder arising from somatic mutation of the X-linked PIG-A gene which leads to deficiency of the glycosylphosphatidylinositol (GP1) membrane anchor proteins such as CD 59 (MIRL: membrane inhibitor of reactive lysis) and CD 55 (DAF: decay accelerating factor). Allogeneic peripheral blood stem cell transplant (PBSCT) is a curative mode of treatment in symptomatic PNH patients. Assessment of donor chimerism for PBSCT can be performed by various methods including short tandem repeat loci (STR) and variable number of tandem repeats (VNTR). Flow cytometry, which is much cheaper and faster, also can be used to assess engraftment in patients with PNH. Engrafted patients will show the presence of CD 55 and CD 59 on their red cells and white cells. We describe here the usefulness of flow cytometry in the assessment of donor chimerism following allogeneic PBSCT, in a case of PNH.
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PMID:Assessing donor chimerism using flow cytometry in paroxysmal nocturnal haemoglobinuria after stem cell transplantation--a case report. 1837

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia caused by the expansion of a hematopoietic progenitor cell that has acquired a mutation in the X-linked PIGA gene. PNH occurs on the background of bone marrow failure. Bone marrow failure and the presence of the abnormal cells account for the clinical phenotype of patients with PNH including hemolysis, cytopenia, and thrombophilia. PIGA is essential for the synthesis of glycosyl phosphatidylinositol (GPI) anchor molecules. PNH blood cells are therefore deficient in all proteins that use such an anchor molecule for attachment to the cell membrane. Two of these proteins regulate complement activation on the cell surface. Their deficiency therefore explains the exquisite sensitivity of PNH red blood cells to complement-mediated lysis. Complement-mediated lysis of red blood cells is intravascular, and intravascular hemolysis contributes significantly to the morbidity and mortality in patients with this condition. PNH is an outstanding example of how an increased understanding of pathophysiology may directly improve the diagnosis, care, and treatment of disease.
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PMID:The pathophysiology of disease in patients with paroxysmal nocturnal hemoglobinuria. 1907 66

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disorder of hematopoietic stem cells. PNH is related to a somatic mutation in the phosphatidylinositol glycan class A (PIG-A), X-linked gene, responsible for a deficiency in glycosylphosphatidylinositol-anchored proteins (GPI-AP). The lack of one of the GPI-AP complement regulatory proteins (CD59) leads to haemolysis. The disease is diagnosed with haemolytic anemia, marrow failure or episodes of venous thrombosis. The diagnosis is based on flow cytometry, which allowed direct quantification of the GPI-AP-deficient cells. From earlier descriptions, the clinical polymorphism of PNH has been recognized by two presentations; one form, predominantly haemolytic without overt marrow failure, referred to classic PNH and the other one, with marrow failure, was often described as the aplastic anemia PNH syndrome (AA-PNH). Thromboses remain a major life threatening complication affecting outcomes in both disease subcategories. Thrombotic events are characterized by involvement of unusual sites (hepatic, mesenteric, cerebral, dermal veins). In classic PNH, recent studies have focused on inhibiting the complement cascade with encouraging clinical results using eculizumab, a C5-inhibitor humanized monoclonal antibody. Concerning the AA-PNH syndrome, bone marrow transplantation (BMT) is the reference treatment in young patients with a sibling donor. Immunosuppressive therapy remains an important treatment modality in this subcategory for patients without a donor or ineligible for BMT. Recurrent thrombotic events remains even now associated with bad prognosis, whatever the form of the disease.
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PMID:[Paroxysmal nocturnal hemoglobinuria]. 1930 77

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal non-malignant hematological disease characterized by the expansion of hematopoietic stem cells (HSCs) and progeny mature cells, whose surfaces lack all the proteins linked through the glycosyl-phosphatidyl inositol anchor. This defect arises from an acquired somatic mutation in the X-linked phosphatidylinositol glycan class A gene, with subsequent clonal expansion of the mutated HSCs as a result of a concomitant, likely immune-mediated, selective pressure. The disease is characterized by complement-mediated chronic intravascular hemolysis, resulting in hemolytic anemia and hemosiderinuria; capricious exacerbations lead to recurrent gross hemoglobinuria. Additional cardinal manifestations of PNH are a variable degree of bone marrow failure and an intrinsic propensity to thromboembolic events. The disease is markedly invalidating, with chronic symptoms requiring supportive therapy - usually including periodical transfusions; possible life-threatening complications may also ensue. The biology of PNH has been progressively elucidated in the past few years, but therapeutic strategies remained unsatisfactory for decades, the only exception being stem cell transplantation, which is restricted to selected patients and retains significant morbidity and mortality. Recently, a biological agent to treat PNH has been developed - the terminal complement inhibitor eculizumab - which has been tested in a number of clinical trials, with exciting results. All the data from worldwide clinical trials confirm that eculizumab radically modifies the symptoms, the biology, and the natural history of PNH, strongly improving the quality of life of PNH patients.
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PMID:Paroxysmal nocturnal hemoglobinuria: pathophysiology, natural history and treatment options in the era of biological agents. 1970 55


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