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Journal of Thrombosis and Haemostasis :... Nov 2013GFI1B is a transcription factor important for erythropoiesis and megakaryocyte development but previously unknown to be associated with human disease.
BACKGROUND
GFI1B is a transcription factor important for erythropoiesis and megakaryocyte development but previously unknown to be associated with human disease.
METHODS
A family with a novel bleeding disorder was identified and characterized. Genetic linkage analysis and massively parallel sequencing were used to localize the mutation causing the disease phenotype on chromosome 9. Functional studies were then performed in megakaryocytic cell lines to determine the biological effects of the mutant transcript.
RESULTS
We have identified a family with an autosomal dominant bleeding disorder associated with macrothrombocytopenia, red cell anisopoikilocytosis, and platelet dysfunction. The severity of bleeding is variable with some affected individuals experiencing spontaneous bleeding while other family members exhibit only abnormal bleeding with surgery. A single nucleotide insertion was identified in GFI1B that predicts a frameshift mutation in the fifth zinc finger DNA-binding domain. This mutation alters the transcriptional activity of the protein, resulting in a reduction in platelet α-granule content and aberrant expression of key platelet proteins.
CONCLUSIONS
GFI1B mutation represents a novel human bleeding disorder, and the described phenotype identifies GFI1B as a critical regulator of platelet shape, number, and function.
Topics: Adult; Aged; Aged, 80 and over; Blood Platelet Disorders; Blood Platelets; Erythrocytes; Female; Frameshift Mutation; Genetic Linkage; Humans; Male; Megakaryocytes; Middle Aged; Mutation; Phenotype; Polymorphism, Single Nucleotide; Proto-Oncogene Proteins; Repressor Proteins; Sequence Analysis, DNA; Transfection; Young Adult
PubMed: 23927492
DOI: 10.1111/jth.12368 -
Annales de Biologie Clinique 2012We report on a case of hereditary pyropoïkilocytosis fortuitously diagnosed in a 34-year old woman issued from Benin. Laboratory tests indicated a moderate haemolytic...
We report on a case of hereditary pyropoïkilocytosis fortuitously diagnosed in a 34-year old woman issued from Benin. Laboratory tests indicated a moderate haemolytic anaemia with a marked microcytosis. Blood film examination revealed a striking anisopoikilocytosis characterized by elliptocytes, numerous red blood cells (RBC) fragments and microspherocytes. The histogram of RBC volume distribution showed two populations of RBC: a normocytic and a very microcytic population, this later corresponding to the RBC fragmentation. These features strongly suggested a membrane disorder, particularly an hereditary pyropoïkilocytosis (HPP). The thermal unstability of the cytoskeleton was demonstrated by enhanced red cell fragmentation after in vitro exposure to heat which occurs at a lower temperature as compared to normal red cells. The diagnosis of HPP was confirmed by specialized investigations (osmotic gradient ektacytometry and erythrocytic membrane proteins electrophoresis). HPP is considered as a severe form of hereditary elliptocytosis characterized by jaundice and a severe haemolytic anaemia which usually appears during the neonatal period and the childhood. Our report is intriguing because of the delayed diagnosis of HPP in a patient who presented moderate clinical manifestations.
Topics: Adult; Delayed Diagnosis; Elliptocytosis, Hereditary; Female; Humans; Incidental Findings; Pregnancy; Pregnancy, Ectopic
PubMed: 22796621
DOI: 10.1684/abc.2012.0710 -
Indian Pediatrics Mar 2009A 14 year male adolescent born of 2nd degree consanguineous marriage presented with asymptomatic proteinuria and severe anemia. He had leucopenia, anisopoikilocytosis,...
A 14 year male adolescent born of 2nd degree consanguineous marriage presented with asymptomatic proteinuria and severe anemia. He had leucopenia, anisopoikilocytosis, megaloblastic erythropoiesis, megakaryocytes with low serum B12 level. His younger sibling was similarly affected. This combination suggested Imerslund-Grasbeck syndrome. The hemoglobin levels improved with injection of vitamin B12 but proteinuria persisted. During follow-up, he developed ketoacidosis due to insulin dependent diabetes mellitus. This rare combination has not been reported in the Indian literature.
Topics: Adolescent; Anemia, Megaloblastic; Child; Diabetes Mellitus, Type 1; Failure to Thrive; Humans; Hyperpigmentation; Intestinal Absorption; Malabsorption Syndromes; Male; Mutation, Missense; Prevalence; Risk Factors; Syndrome; Vitamin B 12; Vitamin B 12 Deficiency
PubMed: 19346573
DOI: No ID Found -
Journal of Laboratory Physicians Jan 2009To assess the efficacy of a peripheral smear examination as a screening tool for β-thalassemia trait.
OBJECTIVE
To assess the efficacy of a peripheral smear examination as a screening tool for β-thalassemia trait.
MATERIALS AND METHODS
17 623 Leishman-stained peripheral smears were evaluated during the period from July 2006 to September 2007. The following parameters were studied: hemoglobin, red blood cell count, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration and red cell distribution width. All the cases that showed microcytosis, hypochromia, erythrocytosis and absence of anisopoikilocytosis were suspected of having the thalassemia trait (TT), and all these cases were further evaluated with Alkaline Hemoglobin Electrophoresis for confirmation.
RESULTS
Of the 17 623 smears examined, 60 cases were considered suspicious of having TT. Alkaline hemoglobin electrophoresis carried out on all these cases revealed an elevated HbA(2) (Mean = 7.5%). Five cases evaluated were found to have other hemoglobinopathies (1 Sickle cell trait, 3 Hb-E, 1 thalassemia intermedia).
CONCLUSION
Careful screening of peripheral smear is an invaluable screening tool for thalassemia trait (PPV - 95%). There must be awareness among the peripheral centers about the importance of peripheral smear screening and the affected persons should be counseled.
PubMed: 21938243
DOI: 10.4103/0974-2727.54802 -
Annales de Biologie Clinique 2007We report the case of a 59 year old man presenting a regenerative microcytic hypochromic anaemia. The investigations revealed the presence of haemoglobin H, suggesting...
We report the case of a 59 year old man presenting a regenerative microcytic hypochromic anaemia. The investigations revealed the presence of haemoglobin H, suggesting abnormalities in the alpha-globin chains synthesis. Alpha-thalassemia was thus suspected. The patient had no personal or familial history. The association with aniso-poïkilocytosis and a marked iron overload (ferritinemia > 1,500 microg/L) suggested a myelodysplastic syndrome, which was confirmed with a bone marrow aspiration. The pattern was consistent with the Acquired alpha-Thalassemia-Myelodysplastic Syndrome (ATMDS). About a hundred cases are listed worldwidely and collected in an international registry. The causes of ATMDS are ignored, but recent reports indicate that the ATRX gene may be implicated in the pathogenesis. ATRX is a chromatin-associated protein, involved in the transcription of several genes. The alpha globin genes could be one of the targets of the ATRX protein.
Topics: Anemia, Refractory; Erythrocytes; Hemochromatosis; Humans; Male; Middle Aged; Myelodysplastic Syndromes; alpha-Thalassemia
PubMed: 17627922
DOI: No ID Found -
Immunity Feb 2003Basal complement activity presents a potential danger for "self" cells that are tightly protected by complement regulators including CD59. Mice express two Cd59 genes...
Basal complement activity presents a potential danger for "self" cells that are tightly protected by complement regulators including CD59. Mice express two Cd59 genes (mCd59a and mCd59b); mCd59b has approximately a 6-fold higher specific activity than mCd59a. Consistently, mCd59b knockout mice present a strong phenotype characterized by hemolytic anemia with increased reticulocytes, anisopoikilocytosis, echinocytosis, schistocytosis, free hemoglobin in plasma, hemoglobinuria with hemosiderinuria, and platelet activation. Remarkably, mCd59b(-/-) males express a progressive loss of fertility associated with immobile dysmorphic and fewer sperm cells after 5 months of age. This work indicates that mCd59b is a key complement regulator in mice and that CD59 is critical in protecting self cells; it also provides a novel model to study complement regulation in human diseases.
Topics: Anemia, Hemolytic; Animals; CD59 Antigens; Humans; Infertility, Male; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Platelet Activation; Sperm Motility; Spermatozoa
PubMed: 12594949
DOI: 10.1016/s1074-7613(03)00022-0 -
American Journal of Hematology Nov 2000Of the numerous beta-thalassemic mutations linked or unlinked to the beta-globin gene, all invariably cause a decrease in or an absence of structurally normal...
Of the numerous beta-thalassemic mutations linked or unlinked to the beta-globin gene, all invariably cause a decrease in or an absence of structurally normal beta-globin mRNA when assayed. Here we report an anemic patient with an elevated alpha-/beta globin synthesis ratio of 2.0 in his reticulocytes. The patient's blood film showed marked red cell anisopoikilocytosis, microcytosis, and hypochromia, consistent with a typical beta-thalassemic trait phenotype. Acid-eluted erythrocytes contained numerous Heinz bodies. Molecular analysis of the patient's reticulocyte mRNA indicated that, compared to normal controls, there was a 3-fold elevation of beta-globin mRNA when assayed by RT-PCR and a 1.5-fold elevation of beta-globin mRNA when assayed by RNA slot blotting. The level of alpha-globin mRNA was normal when compared to that of normal adult controls. Extensive structural analysis of the beta-globin mRNA and gene by sequencing of RT-PCR and PCR products, respectively, did not detect any mutations. Tryptic mapping of purified beta-globin chains also did not show any abnormal tryptic fragments. These data indicated that a relative insufficiency of structurally normal beta-globin mRNA was not a cause of this beta-thalassemic phenotype. Therefore, the lesion that caused this particular thalassemic phenotype is not linked to the beta-globin allele.
Topics: Anemia; Child, Preschool; Globins; Humans; Male; Phenotype; RNA, Messenger; Reticulocytes; beta-Thalassemia
PubMed: 11074543
DOI: 10.1002/1096-8652(200011)65:3<243::aid-ajh12>3.0.co;2-6 -
British Journal of Haematology Mar 1999The purpose of this work was to develop a definition of myelofibrosis with myeloid metaplasia (MMM) using diagnostic criteria that would remain valid within the set of... (Review)
Review
The purpose of this work was to develop a definition of myelofibrosis with myeloid metaplasia (MMM) using diagnostic criteria that would remain valid within the set of patients with chronic myeloproliferative disorders or myelodysplastic syndromes. A list of 12 names for the disease and 37 diagnostic criteria were proposed to a Consensus Panel of 12 Italian experts who ranked them in order so as to identify a core set of criteria. The Panel was then asked to score the diagnosis of 46 patient profiles as appropriate or not appropriate for MMM. Using the experts' consensus as the gold standard, the performance of 90 possible definitions of the disease obtained through the core set was evaluated. 'Myelofibrosis with myeloid metaplasia' ranked as the preferred name of the disease. Necessary criteria consisted of 'diffuse bone marrow fibrosis' and 'absence of Philadelphia chromosome or BCR-ABL rearrangement in peripheral blood cells'. The six optional criteria in the core set consisted of: splenomegaly of any grade; anisopoikilocytosis with tear-drop erythrocytes; the presence of circulating immature myeloid cells; the presence of circulating erythroblasts: the presence of clusters of megakaryoblasts and anomalous megakaryocytes in bone marrow sections; myeloid metaplasia. The definition of the disease with the highest final score was as follows: necessary criteria plus any other two criteria when splenomegaly is present or any four when splenomegaly is absent. The use of this definition will help to standardize the conduct and reporting of clinical studies and should help practitioners in clinical practice.
Topics: Humans; Primary Myelofibrosis; Terminology as Topic
PubMed: 10192432
DOI: 10.1046/j.1365-2141.1999.01262.x -
Internal Medicine (Tokyo, Japan) Nov 1993Three subjects in a family with microcytic and hypochromic anemia were studied; red blood cell morphology indicated aniso-poikilocytosis and hypochromasia. Target and...
Three subjects in a family with microcytic and hypochromic anemia were studied; red blood cell morphology indicated aniso-poikilocytosis and hypochromasia. Target and tear-drop cells were also noted. In all three cases evaluated, there was an increase in HbA2 levels and a decline in the beta/alpha synthesis ratio. Direct cloning and DNA sequencing identified a point mutation (G-->T) at position 1 of intervening sequence I. The resulting reduction of beta-globin chain synthesis is considered to give rise to beta 0-thalassemia phenotype. This point mutation is to our knowledge, the first case in Japan.
Topics: Base Sequence; DNA; Female; Globins; Heterozygote; Humans; Introns; Japan; Male; Middle Aged; Molecular Sequence Data; Pedigree; Point Mutation; RNA Splicing; beta-Thalassemia
PubMed: 8012089
DOI: 10.2169/internalmedicine.32.865 -
Internal Medicine (Tokyo, Japan) Feb 1992A 26-year-old Chinese-Malaysian female patient with beta-thalassemia is presented. The main hematological values found in this patient were as follows: 1) normocytic...
A 26-year-old Chinese-Malaysian female patient with beta-thalassemia is presented. The main hematological values found in this patient were as follows: 1) normocytic hypochromic anemia (RBC 444 x 10(4)/microliters, Hb 11.8 g/dl) with marked anisopoikilocytosis, 2) erythroid hyperplasia, and 3) increased HbF (HbA 41.4%, HbA2 2.9%, HbF 48.9%). DNA obtained from peripheral leukocytes was analyzed using dot blot hybridization of the polymerase chain reaction (PCR)-amplified DNA with allele-specific oligonucleotide probes. A C----T substitution at position 654 of the second intervening sequence (IVS-2) was detected in her beta-globin clone.
Topics: Adult; Base Sequence; DNA; DNA Mutational Analysis; Female; Globins; Glomerulonephritis, IGA; Humans; Introns; Molecular Sequence Data; Pedigree; RNA Splicing; RNA, Messenger; Thalassemia
PubMed: 1600278
DOI: 10.2169/internalmedicine.31.269