Biomedical subjects
Publications and source records attributed to D W Cox.
Apolipoprotein CII Toronto is a mutant non-functional apo CII resulting in apo CII deficiency. A portion of the mutant apo CII gene was cloned into lambda gt10 and subclones were sequenced. A deletion of one base was found in the codon for amino acid Thr68, resulting in alteration of six amino acids and premature termination of the protein at amino acid 74.
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Blood samples from 120 Tunisian Berbers of Gallala village were typed for Gm and Km immunoglobulin allotypes, alpha-1-antitrypsin variants and AB0 blood groups. The results were compared with those of other Berber groups. The combined data, considered in the light of sociological, historical and paleontological data, support the hypothesis that the Berbers are native to North Africa and their ancestors, the first modern man (Homo sapiens) of North Africa, were the founders of the European populations. The ancestors of the Berbers could have been an intermediate population between H. sapiens from Europe and from South Africa.
We have compared lung function in 3 subjects with no alpha 1-antitrypsin (alpha 1-protease inhibitor) (null homozygotes) with subjects having the typical deficiency, PIZZ. We identified a 31-yr-old woman, presenting with severe obstructive lung disease, who had no detectable plasma alpha 1-antitrypsin, indicating homozygosity for a "null" (or PI*QO) allele of alpha 1-antitrypsin. Two of her sisters have a similar deficiency, one with an onset of symptoms at 17 yr of age. Because of the likelihood that there are a number of different PI*QO alleles, the type in this family has been named null Mattawa (QOmattawa). All 3 homozygotes have shown a marked deterioration of lung function over a 7-yr period of follow-up. In contrast, lung function tests of 6 age-matched nonsmoking subjects with alpha 1-antitrypsin deficiency, PI type ZZ, showed no abnormalities of lung function. The 15 to 20% of the normal plasma concentration of alpha 1-antitrypsin associated with the PI*Z allele appears to provide some protection to the lung in comparison with a complete deficiency state.
Available evidence from in vitro studies suggests that the neurotoxic effects of bilirubin may be exacerbated by, or even require, additional factors such as hypoxia or asphyxia. The aim herein was to use 31P nuclear magnetic resonance spectroscopy to study the effects of bilirubin on brain energy metabolism in vitro under conditions of normoxia and hypoxia. 31P nuclear magnetic resonance spectra were acquired from guinea pig cerebral hemisphere slices during superfusion with solutions containing bilirubin and albumin in 5:1 molar ratio. The effects of bilirubin at concentrations between 400 nmol/liter and 120 mumol/liter were studied under normoxic conditions. Bilirubin caused no apparent disruption in brain energy metabolism during normoxia. The combined effects of bilirubin (40 mumol/liter) and hypoxia were studied. Hypoxia alone led to a steady state reduction in the phosphocreatine to inorganic phosphate peak-height ratio to 0.30 (0.27-0.32) [mean (range) n = 3]. Bilirubin (40 mumol/liter) in the presence of hypoxia caused a further reduction in the phosphocreatine to inorganic phosphate ratio to 0.18 (0.17-0.20) [mean (range) n = 3, p less than 0.01, analysis of variance] which was rapidly reversed on returning to normoxia. These results demonstrate that bilirubin at the concentration studied requires hypoxia, in addition, to cause a measurable disturbance of brain energy metabolism. The nature of this interaction is unknown, but it may reflect the effect of intracellular acidosis on bilirubin solubility or the oxygen dependence of brain mitochondrial bilirubin oxidase.
We have investigated the extent of genetic variation and the number of germ-line heavy-chain-variable (VH) genes to obtain information on the organization and repertoire of the VH genes. Our studies revealed extensive genetic variation in this region, indicated by restriction-endonuclease site polymorphisms. Analysis of the distribution of selected polymorphic loci revealed evidence of linkage disequilibrium, particularly between VH2 and VH3 subclass loci, indicating that the subclasses are interdispersed in the human germ-line chromosome. Absolute correlation was detected between alleles of a VH2 locus and the alleles of three VH3 loci, evidence for an extra set of VH genes, which are present in 48% of the Caucasian population. A preliminary estimate of the number of VH genes, approximately 50, indicates a smaller number of VH genes than suggested by the amount of protein variation. The extensive genetic variation we have observed may be associated with genetic differences in the immune response and potentially with variable susceptibility to autoimmune disorders.
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The cirrhosis and hepatocellular carcinoma associated with alpha 1-antitrypsin deficiency has been exclusively reported with the PI Z allele. We present a 63-yr-old white man with emphysema, cirrhosis, and hepatocellular carcinoma. The latter occurred on a background of diffusely distributed hepatocellular dysplasia. Serum protein electrophoresis suggested a deficiency of alpha 1-antitrypsin quantitated at 13% of normal. PI phenotyping showed that he had only the rare PI Mmalton allele, previously associated only with severe lung disease. Family studies demonstrated the distribution of this rare allele. The liver at autopsy displayed well-differentiated hepatocellular carcinoma in addition to alpha 1-antitrypsin deposits in normal, dysplastic, and malignant cells.
Alpha 1 antitrypsin deficiency is one of the most common metabolic disorders, frequently associated with obstructive lung disease and occasionally with childhood liver cirrhosis. Prenatal diagnosis of this deficiency has been accomplished using a DNA polymorphism detected by the restriction enzyme AvaII. A unique haplotype of DNA fragments is observed in deficient (PI type ZZ) subjects. Diagnosis is therefore possible directly from fetal tissue, unlike other prenatal diagnoses using linkage of a DNA polymorphism within a specific family. This approach must be modified for rare deficiency alleles of alpha 1 antitrypsin (PI* Mmalton, PI* Mdurate, and PI*QO or null). Knowledge of risk of severe disease in the fetus is important for the application of prenatal diagnosis. From the limited data available to date, the risk for a given PI ZZ fetus to develop severe liver disease has been estimated at 13% where a previous PI ZZ sib had no liver disease or liver disease which resolved during early childhood, and a risk of 40% where a previous PI ZZ sib had developed severe liver disease.
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Nuclei which are most appropriate for nuclear magnetic resonance (NMR) spectroscopy in biological systems include, in decreasing sensitivity, 1H, 19F, 23Na, 31P, 13C and 15N. Proton NMR has achieved remarkable prominence in imaging of the brain, and though clinical 1H spectroscopy is still in its infancy, current developments indicate that it will provide interesting information on brain metabolism. The naturally abundant form of phosphorus (31P) has proved particularly useful in studies on energy metabolism in metabolically perturbed states in the brain in vivo and in vitro. Dynamic studies on turnover rates of ATP and creatine phosphate can be performed using saturation transfer techniques. The use of 13C to follow intermediary metabolism shows great potential, even though it is a relatively insensitive nucleus and has only 1% natural abundance. 19F is a highly sensitive and naturally abundant nucleus. When covalently attached to various chelators, it provides a most sensitive method for accurate measurement of many cations of biological importance, by virtue of the chemical shift of the 19F on binding of the cation to the chelator.
Restriction-site variation in and around the alpha 1-antitrypsin gene has been studied using two genomic probes. With use of restriction enzymes SstI, MspI, and AvaII, three polymorphic sites have been described with a 4.6-kb probe in the 5' portion of the gene. With use of a 6.5-kb probe, polymorphisms in the coding and 3' regions of the gene have been detected with AvaII, MaeIII, and TaqI. All of these polymorphisms are of sufficiently high frequency to be useful in genetic mapping studies. The polymorphisms with AvaII and MaeIII (6.5-kb probe) are particularly useful for prenatal diagnosis. PI types and M subtypes tend to be associated with specific DNA haplotypes; there are two different types of DNA haplotypes associated with PI M1. The extent of linkage disequilibrium differs throughout the region of the alpha 1-antitrypsin gene.
Prenatal diagnosis of sixteen pregnancies at risk for alpha 1-antitrypsin (AAT) deficiency has been achieved by restriction fragment length polymorphism (RFLP) analysis and compared with diagnostic results using hybridisation of M and Z specific oligonucleotides. The results of both tests were in accord for all samples, although under routine laboratory conditions RFLP analysis was more reliable. Because RFLP analysis does not depend on the type of mutation it was possible, in the product of an MZ and SZ mating, to predict an MZ rather than an MS phenotype using the RFLP method. The strong linkage dysequilibrium between an AvaII RFLP and the Z allele increases its diagnostic usefulness. Even so it seems reasonable to use oligonucleotide analysis in families where no siblings are available for comparison. In all other situations RFLP analysis is as accurate and reliable as oligonucleotide analysis and is technically easier, making it the preferred means of diagnosis for informative kindreds.
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The abnormal type of alpha 1-antitrypsin, PI (protease inhibitor) type Z, is associated with inclusion bodies in the liver, which contain non-secreted alpha 1-antitrypsin. Our studies show that Z protein has an inherent tendency to aggregate, even in plasma. Depending upon conditions, from 15 to 70% of the Z protein in plasma was in a high-Mr form, compared with 1.5% of M type alpha 1-antitrypsin. The high-Mr complex in plasma cannot be disaggregated using Triton X detergent or reducing conditions. This increased tendency to aggregate can be explained by the mutation affecting, tertiary structure and salt bridge formation in Z protein. We have observed this same tendency to aggregate for Mmalton alpha 1-antitrypsin, a rarer variant also associated with a plasma deficiency.
DNA polymorphisms in the human immunoglobulin gamma (gamma) region have been studied in random Arabo-Berber Tunisians and in a large Tunisian Berber kindred. Haplotypes have then been designated, based on variation in the BamHI restriction fragments containing the C gamma 1, C gamma 2, C gamma 4, and C psi gamma genes. Two new haplotypes, in addition to the four previously described, have been observed. These new haplotypes, designated H5 and H6, were confirmed by family studies. The H5 haplotype was associated with black African Gm haplotypes (Gm1,17;..;5,6,11 and Gm1,17;..;5,11) (Gma,z;..;blc3bo and Gma,z;..;blbo) and probably represents a common haplotype in the black population. The haplotype H6 may be derived from H5. One of 39 random Tunisians was homozygous for a multigene deletion. DNA polymorphisms of the C gamma genes, in conjunction with Gm markers, provide highly variable genetic markers important for the characterization of human populations.