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Biomedical subjects

J G Adams

Publications and source records attributed to J G Adams.

At least 73 records · Page 4Linked to original sources
PubMed1987

Hemoglobin Mississippi (beta 44ser----cys). Studies of the thalassemic phenotype in a mixed heterozygote with beta +-thalassemia.

Hemoglobin Mississippi (HbMS: beta 44ser----cys) has anomalous properties that include disulfide linkages with normal beta-, delta-, gamma-, and alpha-chains, and the formation of high molecular weight multimers. While heterozygotes for HbMS are clinically and hematologically normal and carriers of the beta +-thalassemia gene in our family had mild microcytic anemia, the proband with HbMS-beta +-thalassemia had a hemoglobin level of 7 g/dl, mean corpuscular volume (MCV) of 68 fl, reticulocytes of 2-6%, HbF of 18%, marked anisocytosis and poikilocytosis, and splenomegaly, all features of thalassemia intermedia. With oxidant stress, her erythrocytes developed multiple dispersed Heinz bodies, but HbMS was only mildly unstable. HbMS was susceptible to proteolytic degradation in the presence of ATP. The unexpectedly severe clinical findings in HbMS-beta +-thalassemia may result from the proteolytic digestion of HbMS, as well as the excessive alpha-chains characteristic of beta +-thalassemia, which combined provide the increment of cellular damage that results in the phenotype of thalassemia intermedia.

Child↗
PubMed1987

Molecular basis for nondeletion alpha-thalassemia in American blacks. Alpha 2(116GAG----UAG).

An American black woman was found to have the phenotype of moderately severe alpha-thalassemia normally associated with the loss of two to three alpha-globin genes despite an alpha-globin gene map that demonstrated the loss of only a single alpha-globin gene (-alpha/alpha alpha). Several individuals in her kindred with normal alpha-globin gene mapping studies (alpha alpha/alpha alpha) had mild alpha-thalassemia hematologic values consistent with the loss of one to two alpha-globin genes. These data suggested the presence of a nondeletion alpha-thalassemia defect in this family which segregates with the intact alpha alpha gene cluster. An abnormally migrating and highly unstable alpha-globin gene product was demonstrated by in vitro translation of the reticulocyte mRNA from the proposita and this mutant alpha-globin protein was mapped to the alpha 2-globin gene by hybrid-selected translation. The abnormal alpha 2-globin gene was cloned and sequenced. A single base mutation that results in a premature termination codon was identified at codon 116 (GAG----UAG). The defined alpha-globin genotype of the proposita (-alpha/alpha 116UAG alpha) and the positioning of this nonsense mutation at the alpha 2-globin gene locus are fully consistent with the observed alpha-thalassemia phenotype.

Aged↗
PubMed1987

Hb Mississippi [beta 44(CD3)Ser----Arg]: a new variant with anomalous properties.

Hb Mississippi was discovered in a 6-year-old Chinese girl with chronic anemia and thalassemia intermedia. Family studies revealed that she had inherited the Hb Mississippi from her father as well as inheriting a gene for beta+-thalassemia from her mother. Electrophoretic analyses of the hemolysate of the father of the father and the proband on polyacrylamide gels at pH 8.6 showed that the abnormal hemoglobin had three distinct mobilities. A similar pattern was also observed by isoelectricfocusing. In addition, multiple abnormal peaks were observed by high performance liquid chromatographic hemoglobin separations as well as high performance liquid chromatographic globin chain separation. Structural analysis of the abnormal hemoglobin demonstrated a single abnormality; the substitution of serine to cysteine at position 44 (CD3) of the beta-globin chain. Since CD3 is on the surface of the beta-globin chain, it was thought that polymerization of the abnormal hemoglobin by disulfide linkages might have been responsible for the anomalous behavior on electrophoresis and high performance liquid chromatography. Gel filtration chromatography on G-200 Sephadex confirmed this supposition and demonstrated that the abnormal globin chain polymerized with itself as well as with other globin chains.

Amino Acids↗
PubMed1986

Influence of HbS levels upon the hematological and clinical characteristics of sickle cell trait.

The variable concentration of HbS in individuals with sickle cell trait led us to study the relationship between HbS level and selected vascular events in 355 hospitalized black men with sickle cell trait. There were significant differences in hemoglobin concentration and mean corpuscular volume found in four groups divided by their HbS level, the lowest proportion of HbS (less than 30%) being associated with the lowest hemoglobin concentration (12.6 g/dl) and MCV (77 fl). The percent HbS did not influence the incidence of pulmonary embolism, thrombophlebitis, myocardial infarction, cerebrovascular accident, or idiopathic hematuria. Our results suggest that HbS level does not influence vascular disease, and while certain hematological alterations occur, they are very unlikely to have any clinical significance. Regardless of the proportion of HbS, sickle cell trait in black men is benign.

Anemia, Sickle Cell↗
PubMed1986

Effect of lead and ethanol upon gamma-globin synthesis in sickle reticulocytes.

There is evidence from both in vivo and in vitro studies that the synthesis of hemoglobin can be modified by posttranslational alterations in the assembly of the tetrameric molecule. Globin biosynthesis in reticulocytes of patients with sickle cell disease was studied to ascertain the effects of lead and ethanol on gamma-globin chain synthesis and hemoglobin assembly. In incubations containing lead (400 micrograms/dl) or ethanol (1.0 M) there were 86.7 +/- 139.7% and 542.7 +/- 397.0% increases in the relative synthesis of the gamma-globin chain. This was associated with a relative reduction in alpha-chain synthesis, as estimated by changes in the alpha/gamma + beta S synthesis ratio, as well as a marked reduction in total globin synthesis.

Anemia, Sickle Cell↗
PubMed1986

A new gene deletion in the alpha-like globin gene cluster as the molecular basis for the rare alpha-thalassemia-1(--/alpha alpha) in blacks: HbH disease in sickle cell trait.

A novel deletion of at least 26 kilobase of DNA, including both alpha-globin genes, the psi alpha- and psi zeta-globin genes, but sparing the functional zeta-gene was found in a 10-year-old black boy with HbH disease and sickle cell trait. This particular deletion has not previously been described in blacks. Its existence makes it likely that the absence of Hb Barts hydrops fetalis in blacks is due to the rarity of the chromosome lacking two alpha-globin genes rather than a result of early embryonic death due to the failure to synthesize embryonic hemoglobins because of deletion of functional zeta-globin genes.

Anemia, Sickle Cell↗
PubMed1984

Interaction between HBS-beta-o-thalassemia and alpha-thalassemia.

We have defined the clinical and laboratory characteristics of a group of patients with HbS-beta o-thalassemia plus alpha-thalassemia, by analysis of erythrocyte indices, hemoglobin A2 and F levels, globin biosynthesis studies and alpha-globin gene mapping. Patients with HbS-beta o + alpha-thalassemia closely resembled individuals with HbS-beta o-thalassemia except for balanced globin synthesis ratios and a lower HbF level. The frequency of painful crises, leg ulceration, aseptic necrosis of bone and acute chest syndrome was similar in HbS-beta o + alpha-thalassemia patients and controls with sickle cell anemia (HbSS), HbSS-alpha-thalassemia and HbS-beta o-thalassemia. These findings are consistent with previous work which failed to show a reduction in the vaso-occlusive severity of sickle cell disease by the coexistence of alpha-thalassemia.

Adolescent↗
PubMed1984

Effects of thalassemia and microcytosis on the hematologic and vasoocclusive severity of sickle cell anemia.

The characteristic clinical heterogeneity of sickle cell anemia (HbSS) may be, in part, a result of its interactions with alpha-thalassemia. Although alpha-thalassemia clearly affects some hematologic features of HbSS, its role in modulating the vasoocclusive severity of disease is not clear. To further explore this relationship, we examined the incidence of painful episodes, acute chest syndrome, aseptic bone necrosis, and leg ulcers in 3 patient groups with sickle cell disease: (1) 2,147 patients over age 2 yr, stratified according to mean corpuscular volume (MCV); (2) 183 patients selected on the basis of microcytosis and elevated HbA2, on whom globin biosynthesis studies were done; and (3) 125 patients who had alpha-globin genotype assigned by restriction endonuclease gene mapping. When patients were stratified by MCV, there was a reciprocal relationship between HbA2 levels and MCV, reflecting the presence of patients with beta o and alpha-thalassemia in the low MCV groups. The erythrocyte indices and HbA2 levels in patients classified as HbSS-alpha-thalassemia, by either globin synthesis studies or gene mapping, were very similar to those previously reported by others. Neither microcytosis, beta o, or alpha-thalassemia appeared to provide any clear protection from the vasoocclusive complication evaluated, and the prevalence of aseptic necrosis was increased in patients with microcytosis over age 20 yr and in groups with alpha-thalassemia. The effects of a reduced MCV and mean corpuscular hemoglobin concentration (MCHC), of possible benefit by themselves, when accompanied by a reduction in hemolysis and rise in hemoglobin concentration, as in HbSS-alpha-thalassemia, may cause sufficient rise in blood viscosity in critical vascular beds to impair blood flow and negate any amelioration of vasoocclusive complications in HbSS.

Adolescent↗
PubMed1983

The effects of alpha-thalassaemia in HbSC disease.

In HbSC disease, as in sickle cell anaemia, there is a spectrum of clinical severity. A reduced mean corpuscular volume and haemoglobin concentration, traits typical of thalassaemia, might retard sickling. We therefore ascertained the prevalence of alpha-thalassaemia in 53 adults with HbSC disease and related alpha-globin gene deletion to the haematologic and clinical findings. Alpha-globin genotype was identified by restriction endonuclease gene mapping. Indirect ophthalmoscopy and fluorescein angiography were used to document the presence of proliferative retinopathy. Bone necrosis and infarction were determined roentgenographically or by radionuclide scanning. Either heterozygous or homozygous alpha-thalassaemia-2 was present in 26% of patients. There was no relationship between alpha-globin genotype and haematocrit, pain crises, bone lesions, proliferation retinopathy or clinical severity score.

Adolescent↗
PubMed1983

Thalassemic hemoglobinopathies.

Hemoglobinopathies are due to changes in the normal amino acid sequence of globin. Thalassemias result from imbalance in the normal coordinated synthesis of the globin subunits that make up the hemoglobin tetramer. It is now apparent that a single globin gene can have coding region mutations which simultaneously produce a structural defect (hemoglobinopathy) and a biosynthetic defect (thalassemia). It is likely that two distinct mutations within the same gene can occur and produce a hemoglobinopathy with features of thalassemia. In this review the authors discuss such disorders and include the Hb Lepore and Constant Spring variants, hyper-unstable globins, mutations which create alternative sites for mRNA splicing, and amino acid substitutions likely to be associated with an additional thalassemia lesion within the same gene.

Globins↗
PubMed1983

Hemoglobin North Shore: a variant hemoglobin associated with the phenotype of beta-thalassemia.

Hemoglobin (Hb) North Shore (beta 134 val leads to glu) is a mutant hemoglobin that is associated with the phenotype of mild heterozygous beta-thalassemia. Heterozygotes are characterized low normal hemoglobin levels or mild anemia, microcytosis, increased HbA2, and 34%-38% Hb North Shore. The mechanism of the anemia and microcytosis associated with Hb North Shore was explored by studies of hemolysate thermal instability, peripheral blood globin biosynthesis, and whole blood oxygen affinity. Hb North Shore was mildly heat unstable in comparison to normal adult hemolysate. Pulse labeling of reticulocytes with 3H-leucine showed an alpha/beta ratio of 1.35 (normal 1.0). The beta North Shore/alpha ratio was 0.22-0.27, which was less than expected on the basis of gene dosage and less than that seen for most beta-chain variants. The beta A/alpha ratio was 0.50, as would be expected. The beta North Shore/alpha ratio was 0.26 after a 15-min pulse and did not decrease during 120 min of chase. These findings suggest that suboptimal synthesis rather than posttranslational degradation is responsible for the thalassemic phenotype associated with this variant hemoglobin. These observations parallel the findings in heterozygous HbE. It is not presently known whether the thalassemia phenotype is conferred by the structural mutation itself or by another mutation cis to the beta North Shore gene.

Amino Acids↗
PubMed1982

Hemoglobin Parchman: double crossover within a single human gene.

Structural analysis of a new variant hemoglobin revealed tryptic peptides with the amino acid composition of normal delta-globin, except for two internal peptides, which had the compositions of normal beta-globin. The most likely explanation for these findings is that a double, nonhomologous crossover between the delta-and beta-globin genes had occurred.

Amino Acid Sequence↗
PubMed1982

Thalassemia: recent insights into molecular mechanisms.

Recent advances in defining the molecular basis for the thalassemia syndromes are discussed. We now realize that the causes of the thalassemia phenotype are diverse and include gene deletions, nuclear RNA processing defects, nonsense mutations, fusion genes, termination codon mutants, and unstable globin chains.

Animals↗
PubMed1982

beta-thalassemia-? Selected pseudogenes.

The synthesis of delta-globin is directed by a gene whose inherent characteristics permit only limited expression, a gene resembling in some respects that of beta +-thalassemia. The existence of delta O-thalassemia and the presence of delta-globin genes in this condition recall the molecular findings in most types of beta O-thalassemia. The delta-globin and beta +-thalassemia genes may be evolving pseudogenes. Those for delta O and beta O-thalassemia are, in functional sense, already pseudogenes in that they closely resemble functional genes but lack a discernible protein product. In time they should accumulate sufficient changes in their nucleotide sequences which will make them more analagous to what we now recognize as pseudogenes. the selective pressure of Falciparum malaria infection may help maintain the beta-thalassemia "pseudogene" in many populations.

Adult↗
PubMed1982

Drug development.

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Clinical Trials as Topic↗