Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The presence of extra copies of alpha-globin gene has been shown to worsen the degree of anemia in beta-thalassemia heterozygotes. We describe the clinical phenotype of eight Chinese subjects with heterozygosity for both triplicated alpha-globin gene and a beta0-thalassemia allele. They were identified through genotyping of beta-thalassemia intermedia and major patients, and through community-based thalassemia screening program in Hong Kong. Standard molecular techniques were used in the determination of genotype. All subjects in this series showed five copies of alpha-globin genes (alphaalphaalpha/alphaalpha) in association with a beta0-thalassemia allele. Although genotypically identical, six subjects showed a beta-thalassemia intermedia phenotype while two were clinically indistinguishable from beta-thalassemia minor, implying the presence of genetic modifying factors that remained undefined. Triplication of alpha-globin gene and heterozygosity for beta0-thalassemia accounted for 15% of beta-thalassemia intermedia patients at our locality and was associated with a mild clinical phenotype. This genotype was not found among beta-thalassemia major patients. They presented in adulthood and were usually not transfusion dependent. When compared with simple beta-thalassemia heterozygotes, they showed obvious red cell abnormalities (hypochromasia, anisopoikilocytosis, circulating normoblasts), lower hemoglobin (Hb) and higher HbF levels. The presence of triplicated alpha-globin genes should always be considered in apparent beta-thalassemia carriers who were more symptomatic than expected, so that unnecessary investigations for the cause of anemia could be avoided. Finally, triplication of alpha-globin genes should be looked for in families with children affected by beta-thalassemia intermedia in which only one parent showed a picture of beta-thalassemia on Hb analysis.
Int J Mol Med 2001 Aug
PMID:Clinical phenotype of triplicated alpha-globin genes and heterozygosity for beta0-thalassemia in Chinese subjects. 1144 69

An RNA/DNA chimeric oligonucleotide was found to be effective in the targeted correction of point mutations in Escherichia coli, plant, and mammalian genomes. This strategy, named chimeraplasty, has the potential for gene therapy of many genetic diseases caused by point mutations. beta-Thalassemia is a very common human genetic disease and in most cases it is caused by point mutations. To test whether the chimeraplasty can be used to correct the point mutations responsible for beta-thalassemia, we introduced one mutated beta-globin gene, betaE, into MEL cells and successfully corrected the point mutation of the betaE gene with the highest correction efficiency of 1.9%. Furthermore, a targeted -202 C-->G mutation of the Ggamma-globin gene, which is associated with the elevated Ggamma-globin gene expression in the adult stage, was introduced into HeLa and CMK cells by an RNA/DNA oligonucleotide. These results indicated that the chimeraplasty has potential for human beta-thalassemia gene therapy.
Blood Cells Mol Dis
PMID:Targeted correction of the point mutations of beta-thalassemia and targeted mutagenesis of the nucleotide associated with HPFH by RNA/DNA oligonucleotides: potential for beta-thalassemia gene therapy. 1150 64

The ability to transduce non-dividing cells is a unique feature of lentiviruses which distinguishes them from simple retroviruses. This feature was the major incentive for the development of the lentivirus vector system. Lentivirus vectors can deliver and integrate > 8 kb of transgenic DNA into target cell genomes without inducing a host immune response against the transduced cells. Thus lentivirus vector-based gene delivery can be considered the most efficient method by which transgenes can be incorporated into the host cell genome and maintain long-term expression. This review describes the major developments in the lentivirus vector system, which significantly improve vector biosafety, vector production and transgene expression. The success and difficulties in reverting disease phenotypes by lentivirus vectors carrying therapeutic genes in various animal models including beta-thalassemia and Parkinson's disease and the implications of these studies for future gene therapy clinical trials are also discussed.
Curr Opin Mol Ther 2001 Aug
PMID:Lentivirus vectors: difficulties and hopes before clinical trials. 1152 55

We report on a generally useful, partially automated, human mutation detection method based upon printing moderate density oligonucleotide arrays using a biorobot on activated nylon membranes. The Beckman Biomek 2000 was adapted to this task through fabrication of aluminum membrane filter holders and the development of an addressable Tool Command Language (Tcl) program, which can be invoked through BioScript. During program execution, a robot arm is moved along the x, y, and z axes to expel liquid, without dripping, from disposable barrier pipette tips and then to touch the drops on preactivated membranes. Printed arrays consist of alternating rows of oligonucleotides containing normal and mutant sequences. Hybridization of biotin labeled polymerase chain reaction products derived from human patient genomic DNA samples are visualized using chemiluminescent or chromogenic indicators. This technique allows unequivocal genotyping of 32 mutations at the beta-thalassemia locus (11p15.5) and of 34 mutations and one polymorphism at the cystic fibrosis transconductance membrane regulator locus (7p35).
J Mol Diagn 2001 Nov
PMID:Robot printing of reverse dot blot arrays for human mutation detection. 1168 2

The transcription factor TFIIH is involved in both basal transcription and DNA repair. Mutations in the XPD helicase component of TFIIH can result in the diverse clinical features associated with xeroderma pigmentosum (XP) and trichothiodystrophy (TTD). It is generally believed that the multi-system abnormalities associated with TTD are the result of a subtle deficiency in basal transcription. However, to date, there has been no clear demonstration of a defect in expression of any specific gene in individuals with these syndromes. Here we show that the specific mutations in XPD that cause TTD result in reduced expression of the beta-globin genes in these individuals. Eleven TTD patients with characterized mutations in the XPD gene have the haematological features of beta-thalassaemia trait, and reduced levels of beta-globin synthesis and beta-globin mRNA. All these parameters were normal in three patients with XP. These findings provide the first evidence for reduced expression of a specific gene in TTD. They support the hypothesis that many of the clinical features of TTD result from inadequate expression of a diverse set of highly expressed genes.
Hum Mol Genet 2001 Nov 15
PMID:Mutations in the general transcription factor TFIIH result in beta-thalassaemia in individuals with trichothiodystrophy. 1173 44

GATA1 is the X-linked transcriptional activator required for megakaryocyte and erythrocyte differentiation. Missense mutations in the N-terminal zinc finger (Nf) of GATA1 result in abnormal hematopoiesis, as documented in four families: the mutation V205M leads to both severe macrothrombocytopenia and dyserythropoietic anemia, D218G to macrothrombocytopenia and mild dyserythropoiesis without anemia, G208S to macrothrombocytopenia and R216Q to macrothrombocytopenia with beta-thalassemia. The three first GATA1 mutants display a disturbed binding to their essential transcription cofactor FOG1, whereas the fourth mutant shows an abnormal direct DNA binding. In this study, we describe a new family with deep macrothrombocytopenia, marked anemia and early mortality, if untreated, due to a different GATA1 mutation (D218Y) in the same residue 218 also implicated in the above mentioned milder phenotype. Zinc finger interaction studies revealed a stronger loss of affinity of D218Y-GATA1 than of D218G-GATA1 for FOG1 and a disturbed GATA1 self-association. Comparison of the phenotypic characteristics of patients from both families revealed that platelet and erythrocyte morphology as well as expression levels of the platelet GATA1-target gene products were more profoundly disturbed for the hemizygote D218Y mutation. The D218Y allele (as opposed to the D218G allele) was not expressed in the platelets of a female carrier while her leukocytes showed a skewed X-inactivation pattern. We conclude that the nature of the amino acid substitution at position 218 of the Nf of GATA1 is of crucial importance in determining the severity of the phenotype in X-linked macrothrombocytopenia patients and possibly also in inducing skewed X inactivation.
Hum Mol Genet 2002 Jan 15
PMID:Different substitutions at residue D218 of the X-linked transcription factor GATA1 lead to altered clinical severity of macrothrombocytopenia and anemia and are associated with variable skewed X inactivation. 1180 23

Several X-linked mental retardation syndromes are caused by mutations in the ATRX gene. Common clinical features associated with ATRX mutations include severe mental retardation, characteristic facial anomalies and variable degrees of urogenital defects and alpha-thalassemia. Although the ATRX protein is a member of the SWI/SNF family of chromatin remodeling proteins, little is known about the biochemical activity of the ATRX protein or its in vivo function during development. Here we demonstrate that ATRX is part of a large multiprotein complex similar in size to the SWI/SNF complex. Furthermore, we have generated transgenic mice that overexpress ATRX as an initial model for studying the function of this protein during development. Misexpression of ATRX was associated with growth retardation, neural tube defects and a high incidence of embryonic death. Moreover, brains from E10.5 transgenic embryos displayed abnormal growth and organization of the ventricular zone that was highly convoluted in the most severely affected embryos. Transgenic mice that survived to birth exhibited a high incidence of perinatal death, as well as seizures, mild craniofacial anomalies and abnormal behavior. Our findings indicate that ATRX dosage is crucial for normal development and organization of the cortex, and emphasize the relevance of our model for the study of ATRX function and disease pathogenesis.
Hum Mol Genet 2002 Feb 01
PMID:Neurodevelopmental defects resulting from ATRX overexpression in transgenic mice. 1182 44

As a potential model for sickle cell trait (AS), we examined mice containing one normal mouse beta-globin allele in combination with a human hemoglobin S (h(alpha)beta(S)) transgene (m(beta)/hS). The mice segregated into two subpopulations containing low and high proportions of hemoglobin S (m(beta)/hS1 and m(beta)/hS2, respectively) that was associated with one or two human h(alpha)beta(S) transgenes. We noted striking kidney pathology (cortical cysts, hyperplastic tubules, and glomerulonephritis), increasing with age and with greater severity in m(beta)/hS1. mBeta/hS2 animals were largely tolerant to 5% O(2) for 1 h, whereas 80% of m(beta)/hS1 mice died, exhibiting acute sequestration of erythrocytes in spleen, liver, and heart. These pathologies appear to result from a decreased oxygen affinity of the hybrid (human alpha/mouse beta) hemoglobins with a mild beta-thalassemia phenotype. Thus, these mouse models of sickle trait seem to manifest their renal pathology and sensitivity to hypoxia by mechanisms related to low tissue oxygen delivery and are different from the human syndrome. Analyses of parameters such as P(50), red cell indices, and genetic background are necessary in establishing potential relevance of any mouse model of the sickle cell syndromes.
Blood Cells Mol Dis
PMID:Pathophysiology of a sickle cell trait mouse model: human alpha(beta)(S) transgenes with one mouse beta-globin allele. 1183 63

The spectrum of disease causing mutations is immense. It just so happens that the overwhelming majority of genetic alterations in the APC gene with leads to adenomatous polyposis coli generate truncated gene products. This observation lead to the development of the in vitro synthesis protein assay (protein truncation test) which is a sensitive method to detect these truncated gene products from patient samples. This article describes the assay to detect truncated proteins for the APC gene, which can also be applied to other disease causing genetic alterations which commonly lead to truncations such in HNPCC, von Hippel-Lindau, osteogenesis imperfecta, retinoblastoma, BCRAI, beta-thalassemia, hemophilia B, Duchenene and Becker muscular dystrophy.
Mol Biotechnol 2002 Feb
PMID:Direct analysis for familial adenomatous polyposis mutations. 1187 75

The coexistence of beta- and gamma-globin gene mutations in the compound heterozygous state presents a rare in vivo model that provides important data on gene regulation of clinical interest. In this unique comparative study we present the hematological, biosynthetic, and molecular data from six adult compound heterozygotes for the Greek nondeletional hereditary persistence of fetal hemoglobin (nd-HPFH, Agamma-117 G-->A) and four frequent beta-thalassemia mutations (IVS I-110 G-->A, Cd 39 C-->T, IVS I-1 G-->A, and IVS I-6 T-->C) found in the Hellenic population. Fetal hemoglobin (HbF) levels were found to be considerably higher (25-50%) than in 19 Greek nd-HPFH heterozygotes (HbF=9.7+/-1.7%) and, interestingly, to depend on the type of the respective beta-thalassemia mutation, in trans to the nd-HPFH allele. All cases presented a typical beta-thalassemia heterozygote's phenotype despite the increased HbF and the normal HbA2 levels, as indicated by both the hematological indices and the biosynthetic ratios. These data were compared with those from two unique cases of Greek origin: a homozygous case of the Greek nd-HPFH and a compound heterozygote with HbS. Our data suggest that in these compound heterozygous cases the beta-thalassemic chromosome indirectly determines the final outcome of the gamma- and of the in cis beta-globin gene expression, most likely at the post-transcriptional level.
J Mol Med (Berl) 2002 Apr
PMID:A comparative study of Greek nondeletional hereditary persistence of fetal hemoglobin and beta-thalassemia compound heterozygotes. 1197 33


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