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Sickle hemoglobin is the product of one mutated gene, but the disease phenotype is the product of many genes. Polymorphism among the genes responsible for the pleotropic effects can be epistatic (or modifier) genes contributing to interindividual variation that characterizes sickle cell anemia patients. Modulation in the hemoglobin F levels is associated with the beta-globin gene cluster haplotypes and to gender and chromosomal sites different from chromosome 11 influencing the severity of the disease. Coexistence of alpha thalassemia with sickle cell disease produces hematologic and clinical consequences that are beneficial in some complications but deleterious in others. There is little if any modulation of the phenotype of sickle cell anemia by coexistence of G6PD deficiency. Mutations that favor blood coagulation or thrombosis may influence the phenotype of the disease. Improved understanding of the influence of genes involved in modulating the complex pathophysiology of sickle cell disease may allow prediction of the phenotype of sickle cell patients and aid in management decisions.
Pediatr Pathol Mol Med
PMID:Role of epistatic (modifier) genes in the modulation of the phenotypic diversity of sickle cell anemia. 1267 37

alpha-Thalassemia is among the world's most common single gene disorders, which is most prevalent in the malaria belt. This geographic distribution has been attributed to a selective advantage of heterozygotes against this disease. Unexpectedly, we have found a high frequency of heterozygosity for deletional alpha-thalassemia (-alpha3.7) in Ashkenazi Jews (carrier frequency of 7.9%, allele frequency of 0.04). This population has resided in temperate climates for many centuries and was therefore not subjected to malarial selection pressure. In comparison, heterozygosity for beta-thalassemia, which is highly subject to malarial selection pressure, is very low (estimated <0.1%) in this group. It is possible that founder effect and genetic drift have contributed to the high frequency of deletional alpha-thalassemia in Ashkenazim, as may occur in closed populations. Alternatively, we hypothesize that positive selection pressure for an as yet unknown linked allele on chromosome 16 may be a significant factor leading to this high frequency.
Blood Cells Mol Dis
PMID:An unexpectedly high frequency of heterozygosity for alpha-thalassemia in Ashkenazi Jews. 1522 3

Phenotypic expression of sickle cell disease (SCD) is highly variable. We investigated red blood cells (RBCs) and reticulocytes using a laser light scattering method (ADVIA120, Bayer Diagnostics, Tarrytown, NY) in a series of patients with either sickle cell anemia (SS) or compound SC heterozygosity (SC), both groups with or without alpha thalassemia. Results were compared with those of a series of patients without hematological disease. Known data were consistently confirmed, namely heterogeneity in cell volume and hemoglobin (Hb) concentration, as well as the premature exit of "stress" reticulocytes from the bone marrow, mostly in SS patients. Specific changes were observed during maturation, including decreases in macrocytic and hypodense cells. Simultaneous viewing of the indices of the different RBC populations provided information on erythropoietic maturation by a rapid, reproducible, and cost-effective method.
Blood Cells Mol Dis
PMID:Automated analysis of mature red blood cells and reticulocytes in SS and SC disease. 1522 5

In this work, a ligation-independent, fully gene-specific, nested polymerase chain reaction (PCR) method for the elucidation of 5' cDNA sequence is described and demonstrated for the first time. Two manifestations of the method, rapid amplification of cDNA ends (RACE) by lariat-dependent nested PCR 5' (RACE LaNe), at least as simple to perform as conventional RACE, were successfully applied to the murine housekeeping genes phosphoglycerate kinase 1 (PGK1), beta-actin (beta-ACT), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the alpha thalassemia mental retardation Y homolog (ATRY) gene of the marsupial, Macropus eugenii. Significantly, a new murine GAPDH 5' exon, separated by 365 kb of intronic sequence from previously annotated GAPDH sequence, was discovered using 5'RACE LaNe.
Mol Biotechnol 2005 Jan
PMID:A new 5' terminal murine GAPDH exon identified using 5'RACE LaNe. 1566 18

There is clinical variability in the presentation of sickle cell disease among Indians. Vaso-occlusive crisis is common among non-tribal patients. Hydroxyurea, induces fetal hemoglobin (HbF) synthesis and reduces the clinical severity of sickle cell disease but individual patients have a variable response. This study was undertaken to investigate the efficacy and safety of hydroxyurea in Indians with severe manifestations where the beta(s) gene is linked to the Arab-Indian haplotype and is associated with higher HbF levels. Seventy-seven patients (29 adult sickle homozygous, 25 pediatric sickle homozygous, 23 adult sickle beta-thalassemia) selected for hydroxyurea therapy were evaluated for clinical, hematological, biochemical and genetic parameters and were followed for 24 months. Ninety-eight point seven percent of the sickle chromosomes were linked to the Arab-Indian haplotype, 27% of patients had associated alpha thalassemia and 65% were Xmn I +/+. Seventy-eight percent of the patients had no further crises after starting hydroxyurea. This effect was accompanied by a significant increase in HbF (p<0.001), but this increase was variable in individual cases. There was also an increase in gamma gene mRNA expression in the few cases so studied. Hemoglobin levels increased significantly (p<0.001) resulting in the cessation of blood transfusions. Leucopoenia was observed in one patient. Hydroxyurea was effective in reducing the clinical severity in Indian patients who initially had higher HbF levels and the presence of ameliorating factors, such as alpha-thalassemia and the Xmn I polymorphism. Hydroxyurea therapy with careful monitoring can thus change the quality of life of Indians with sickle cell disease.
Blood Cells Mol Dis
PMID:Hydroxyurea in sickle cell disease--a study of clinico-pharmacological efficacy in the Indian haplotype. 1895 99

Hemoglobinopathies were included in the Brazilian Neonatal Screening Program on June 6, 2001. Automated high-performance liquid chromatography (HPLC) was indicated as one of the diagnostic methods. The amount of information generated by these systems is immense, and the behavior of groups cannot always be observed in individual analyses. Three-dimensional (3-D) visualization techniques can be applied to extract this information, for extracting patterns, trends or relations from the results stored in databases. We applied the 3-D visualization tool to analyze patterns in the results of hemoglobinopathy based on neonatal diagnosis by HPLC. The laboratory results of 2520 newborn analyses carried out in 2001 and 2002 were used. The "Fast", "F1", "F" and "A" peaks, which were detected by the analytical system, were chosen as attributes for mapping. To establish a behavior pattern, the results were classified into groups according to hemoglobin phenotype: normal (N = 2169), variant (N = 73) and thalassemia (N = 279). 3-D visualization was made with the FastMap DB tool; there were two distribution patterns in the normal group, due to variation in the amplitude of the values obtained by HPLC for the F1 window. It allowed separation of the samples with normal Hb from those with alpha thalassemia, based on a significant difference (p < 0.05) between the mean values of the "Fast" and "A" peaks, demonstrating the need for better evaluation of chromatograms; this method could be used to help diagnose alpha thalassemia in newborns.
Genet Mol Res 2009 Mar 31
PMID:Three-dimensional visualization of human hemoglobin phenotypes with HPLC. 1944 Sep 71

From 362 thalassemia cases referred to adult thalassemia clinic of the Iranian blood transfusion organization (IBTO) for genotyping, 103 cases (28.5%) had a common primary disease factor, IVSII-1 mutation in homozygous state. 61 (59.2%) of these individuals represented thalassemia major and 42 (40.8%) thalassemia intermedia clinical phenotype. To re-evaluate our current diagnostic criteria, XmnI(G)gamma polymorphism and coexistence of alpha thalassemia mutations, frequently recalled as important factors modifying the clinical phenotype of homozygous beta zero thalassemia cases in our country, were examined in both groups. No statistically significant difference in the frequency of positive XmnI(G)gamma polymorphism was observed between thalassemia intermedia and thalassemia major patients. Double gene deletion --(Med) was observed in only one thalassemia major case, while -a(3.7) in heterozygous state (-a(3.7)/aa) was identified in 6 (9.8%) of thalassemia major and 8 (19%) of thalassemia intermedia patients. -a(4.2) was observed in only one thalassemia major case. No statistically significant difference in the frequency of coinheritance of alpha thalassemia was observed between the two groups. These results imply that other interacting mechanisms which modify the phenotype of thalassemia patients is still in the dark in our current diagnostic criteria of thalassemia.
Blood Cells Mol Dis
PMID:Frequency of positive XmnIGgamma polymorphism and coinheritance of common alpha thalassemia mutations do not show statistically significant difference between thalassemia major and intermedia cases with homozygous IVSII-1 mutation. 1989 74

alpha-Thalassemia is an inherited hemoglobin disorder that results from defective synthesis of alpha-globin protein. Couples who both carry the alpha-thalassemia-1 gene are at risk of having a fetus with Hb Bart's hydrops fetalis. Rapid and accurate screening for individuals carrying the alpha-thalassemia-1 gene is the most effective strategy to prevent and control this severe form of thalassemia. In this study, a new and accurate method for alpha-thalassemia diagnosis was developed by genotyping alpha-thalassemia-1, the Southeast Asian type (--(SEA)) and Thai type (--(THAI)) deletions, using multiplex PCR followed by a melting curve analysis. Primers were designed to specifically amplify two deletion fragments, the --(SEA) and --(THAI) deletions and two normal fragments, psizeta- and alpha2-globin gene. The primers were capable of distinguishing alpha-thalassemia 1 heterozygotes from alpha-thalassemia 2 homozygotes, which are unable to be diagnosed by standard hematological data and hemoglobin typing. The melting temperatures of the --(THAI), --(SEA), psizeta-globin, and alpha2-globin gene fragments were 79.9 +/- 0.2, 89.4 +/- 0.5, 92.8 +/- 0.2, and 85.0 +/- 0.2 degrees C, respectively. Melting curve analysis was performed in 130 subjects in parallel with conventional gap-PCR analysis, and results showed 100% concordance. This method eliminates the post-PCR electrophoresis process, which is laborious, and allows high throughput screening suitable for large population screening for prevention and control of thalassemia.
J Mol Diagn 2010 May
PMID:Rapid diagnosis of alpha-thalassemia by melting curve analysis. 2019 15

The aim of this study was to identify possible risk factors for albuminuria, an early marker of sickle cell anemia (SCA) glomerulopathy, in a cohort of 189 SCA adult patients followed at the Sickle Cell Center of Guadeloupe, a French Caribbean island. Biological parameters obtained at baseline, alpha-globin gene status, and beta(S) haplotypes were compared in patients stratified accordingly to graded albuminuria. Abnormal albumin excretion rate was detected in half of the studied adult patients and macroalbuminuria occurred in 21.6%. Graded albuminuria was associated with advanced age (p=0.006), systolic blood pressure (p=0.031), and worsened anemia, i.e. low hemoglobin rate (p<0.0001) and red blood cell count (p<0.0001). Alpha-thalassemia frequency was lower in microalbuminuric and macroalbuminuric patients than in normoalbuminuric patients, 12.5%, 13.75% and 26%, respectively (p=0.0057). Comparison of albuminuria-free survival curves in SCA patients without and with alpha-thalassemia showed that the median time of albuminuria onset was delayed in the later ones (p=0.021). In contrast, no association of albuminuria was detected with the Bantou beta(S) haplotype. Our results strongly suggest a protective effect of alpha-thalassemia against glomerulopathy in SCA adult patients which could be related to a decreased hemolytic rate.
Blood Cells Mol Dis 2010 Aug 15
PMID:Alpha-thalassemia is associated with a decreased occurrence and a delayed age-at-onset of albuminuria in sickle cell anemia patients. 2059 23

Alpha-thalassemia is an inherited hemoglobin disorder characterized by a microcytic hypochromic anemia caused by a quantitative reduction of the alpha-globin chain. The majority of the alpha-thalassemias is caused by deletions in the alpha-globin gene cluster. A deletion in the alpha-globin gene cluster, which was found in a Dutch family, was characterized by MLPA, long-range PCR and direct sequencing. We describe the molecular characterization of a novel 8.2kb deletion (--(AW)), involving both alpha-globin genes in cis. The deletion is caused by a non-homologous recombination event between an Alu and an L1-repeat sequence. This deletion is the third example of a non-homologous recombination event involving an Alu and an L1 repeat, and the first described in the human alpha-globin gene cluster. Because of a 25% risk of Hb Bart's with hydrops foetalis in the offspring when in combination with another alpha(0)-thalassemia allele, it is important to diagnose this deletion.
Blood Cells Mol Dis 2010 Aug 15
PMID:A new alpha(0)-thalassemia deletion found in a Dutch family (--(AW)). 2068 66


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