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Biomedical subjects

L M Davis

Publications and source records attributed to L M Davis.

66 records · Page 4Linked to original sources
PubMed1987

Factor IXAlabama: a point mutation in a clotting protein results in hemophilia B.

Factor IXAlabama is a variant factor IX molecule responsible for a clinically moderate form of hemophilia B. Twenty-five kilobases (kb) of the variant gene, including seven exons coding for the structural protein, were cloned and characterized. The restriction map and the arrangement of coding regions are identical to those of the normal gene. DNA sequence analysis of the coding regions revealed a single base-pair difference between the gene for factor IXAlabama and the normal factor IX gene. An adenine to guanine transition in the first nucleotide of exon d causes the substitution of a glycine codon (GGT) for the normal aspartic acid codon (GAT). This point mutation results in a single amino acid substitution at residue 47 of the zymogen and represents the genetic defect in factor IXAlabama.

Amino Acid Sequence↗
PubMed1986

The chromosome 11 gene map: genes for growth and development, Wilms' tumor deletions, and cancer chromosome breakpoints.

Human chromosome 11 is clearly a model autosome encoding genes and characteristics associated with both normal and abnormal growth and development, and several significant disorders. A fine-structure molecular, genetic, and physical map of this chromosome would add considerably to our knowledge of the organization and control of human genes and to an understanding of normal and abnormal human biology.

Animals↗
PubMed1985

Evidence for a prevalent dimorphism in the activation peptide of human coagulation factor IX.

We have independently isolated and characterized cDNA and genomic clones for the human coagulation factor IX. Sequence analysis in both cases indicates that threonine is encoded by the triplet ACT as the third residue of the activation peptide. This is in agreement with some earlier reports but in disagreement with others that show the alanine triplet GCT at this position. The discrepancy can thus be accounted for by natural variation of a single nucleotide in the normal population. Amino acid sequence analyses of activated factor IX from plasma samples of four individuals yielded two cases of alanine and two cases of threonine at the third position of the activation peptide. In factor IX from pooled plasma and in factor IX from a heterozygous individual, however, both alanine and threonine were found. Taken together, the findings show that a prevalent nondeleterious dimorphism exists in the activation peptide of human coagulation factor IX.

Alleles↗
PubMed1985

Application of molecular genetics to prenatal diagnosis and carrier detection in the hemophilias: some limitations.

Prenatal diagnosis and carrier detection in the hemophilias have received much attention in recent years. The error rate in prenatal diagnosis by fetoscopy is less than 1%; fetoscopy is not possible, however, until the second trimester of pregnancy. Carrier detection based on bioassays of plasma has an irreducible error rate (approximately 5%?), because of the "lyonization" phenomenon in heterozygous women, and the final results are always probabilistic. New DNA methods promise to alleviate these difficulties. Prenatal diagnosis can be accomplished in the first trimester. "Lyonization" is bypassed in carrier detection, and the results may sometimes be essentially nonprobabilistic. But the DNA methods have certain limitations of their own which are not widely appreciated. Aside from cost and the necessity to adopt a new technology, there are inherent genetic problems: mothers must be heterozygous for both a disease gene and a marker gene, final results are probabilistic if the marker gene lies outside the disease gene, and multiple marker genes are often in linkage disequilibrium. We have concluded that a clinical unit planning to use the DNA methods must also maintain the conventional methods at a high level of performance.

Crossing Over, Genetic↗
PubMed1985

Structure and function of factor IX: defects in haemophilia B.

The genetics of haemophilia B and the structure-function relationships of factor IX interactions with cofactors and substrates have been reviewed. Emphasis has been placed on contributions to our understanding made by analysis of variants. Amino acid substitutions at or near the site of activation lead to inactive factor IX or to factor IX species with decreased clotting activity. Release of the activation peptide is necessary for optimal interaction of factor IX with its cofactors and substrates. Abnormalities in the calcium binding region, whether Gla independent or dependent, also decrease clotting activity. The defects in haemophilia Bm variants somehow affect factor VII-tissue factor interactions with factor X. Other mutations may affect the factor IX heavy chain, probably at or near the active site. Amino acid substitutions may cause conformational changes in factor IX that interfere with other interactions such as with antithrombin III and factor VIII. Recombinant DNA techniques have been employed to analyse normal and abnormal factor IX genes. DNA sequence analysis of factor IX cDNA clones revealed the primary structure of the mature protein and a predicted leader peptide. Knowledge of the primary sequence of factor IX allowed identification of the specific defect in the factor IX Chapel Hill variant. Analysis of normal factor IX genomic clones has determined that the 35 kb gene is composed of eight coding exons and seven intervening sequences. Sequence analysis of the CRM+ variants will identify mutations disrupting the normal interactions of factor IX. Southern analysis of CRM- variants has revealed gross factor IX gene deletions in some cases. Such deletions have been employed for carrier deletion in some families. Restriction fragment length polymorphisms in the factor IX gene have also proven useful for carrier identification. Manipulations of the cloned factor IX gene to make specific mutations in vitro and improvements in the technology for expression of deliberately modified genes will further elucidate the relationships between factor IX structure and function.

Amino Acid Sequence↗
PubMed1985

Maternal death secondary to a dissecting aneurysm of the pulmonary artery.

True aneurysms of the pulmonary artery are most frequently associated with congenital heart lesions that have lead to sustained high pulmonary artery flow rates and pulmonary hypertension. A maternal death secondary to a dissecting aneurysm of the pulmonary artery is presented. Death occurred 17 hours postpartum, and the acute dissection may have been precipitated by the high flow rates accompanying parturition or, alternatively, by the Valsalva maneuver. The authors suggest a baseline chest radiograph and electrocardiogram in all women with known or suspected congenital heart disease to evaluate for pulmonary hypertension and pulmonary artery aneurysms. The occurrence of symptoms such as dyspnea or chest pain warrants repeat evaluation with strong consideration being given to right heart catheterization and pulmonary angiography. If a dissecting aneurysm is diagnosed, then emergency surgical repair seems warranted in view of the rapidity with which this condition progresses to death.

Adult↗
PubMed1984

Biologic properties of factor-independent nonadherent hematopoietic and adherent preadipocyte cell lines derived from continuous bone marrow culture.

Cell lines dependent for growth upon an inducer T-cell synthesized glycoprotein factor interleukin-3 have been derived from continuous mouse bone marrow cultures. These factor-dependent (FD) lines have been shown to be multipotential (erythroid/basophil/neutrophil) or (eosinophil/basophil/neutrophil); or are unipotent basophil or neutrophil granulocyte cell lines. Both classes of cloned FD lines have maintained self-renewal in vitro for several years with absolute growth dependence on freshly added IL-3. In four instances, factor-independent (FI) variant cell lines were derived, one by subculture in medium containing hydrocortisone and 25% horse serum and three by evolution of variants from cloned FD lines. One class of (FI) lines demonstrated adherent fibroblast-like morphology with differentiation to differentiated adipocytes in medium containing 10(-5) hydrocortisone. A second class of cell lines evolved from cloned FD lines and each grew in suspension culture to a saturation density over 10-fold greater than that for the parent FD line (greater than 10(7)/ml) and each contained no detectable hematopoietic cellular differentiation markers by histochemistry or cell surface receptors. In contrast to IL-3 dependent cell lines, (FI) cell lines failed to differentiate to mature granulocyte morphology in diffusion chambers in vivo. The FI cell lines formed no detectable CFUs in vivo, did not reconstitute hematopoiesis in irradiated mice and did not form tumors in vivo. The failure of the (FI) lines to form tumors and lack of detectable hematopoietic differentiation capacity indicates that these lines may represent an intermediate state between normally regulated hematopoietic cellular self-renewal and malignant transformation.

Adipose Tissue↗
PubMed1976

Isoenzyme composition of human plasma monoamine oxidase in normal subjects and in fibrotic liver disease.

Hydroxyapatite column chromatography elution profile reveals characteristic differences between monoamine oxidase (MAO) isolated from normal human plasma and from patients with hemochromatosis having hepatic fibrosis. In normal plasma, the alpha form constitutes about 84% of the enzyme, with the remainder in the beta and gamma forms. By contrast, in hemochromatosis there is less alpha form (less than 40%), an additional alpha1 form (about 20%) which was eluted immediately after alpha form, increased beta form (more than 25%), and no significant difference in gamma form. When calculated on the basis of total amount per liter, hemochromatosis is characterized by elevation of beta form (3- to 10-fold) and the presence of alpha1. These results also appear to indicate that the multiple forms separated by hydroxyapatite column chromatography represent true multiplicity of human plasma MAO in vivo.

Chromatography, Ion Exchange↗