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Biomedical subjects

D Waggoner

Publications and source records attributed to D Waggoner.

9 recordsLinked to original sources
PubMed2005

Calibration of 6q subtelomere deletions to define genotype/phenotype correlations.

Testing for subtelomere abnormalities in patients with idiopathic mental retardation has become a useful diagnostic tool. However, limited data exist regarding genotype/phenotype correlations for specific subtelomere imbalances. We have ascertained five patients with 6q subtelomere deletions either as a result of an isolated deletion or as a result of an unbalanced translocation, and developed a molecular ruler assay utilizing BAC or PAC clones and determined the size of the deleted regions to range from <0.5 to 8 Mb. To establish genotype/phenotype correlations for distal 6q, we compared the clinical features of these patients to previously reported cases of 6q subtelomere and cytogenetically visible deletions and found that they shared multiple abnormalities, suggesting that the causative genes may lie in the region of the smallest 6q subtelomeric deletion, approximately 400 kb from the telomere. However, multiple unique features were present only in patients with cytogenetically visible 6q deletions, indicative that genes involved in the development of these features may lie more proximally on 6q. These initial studies demonstrate the ability to develop genotype/phenotype correlations for subtelomere rearrangements, which will aid in the diagnosis and prognosis of these patients and may help narrow the search for relevant developmental genes.

Calibration↗
PubMed2005

Multiple mechanisms are implicated in the generation of 5q35 microdeletions in Sotos syndrome.

BACKGROUND: Sotos syndrome is characterised by learning difficulties, overgrowth, and a typical facial appearance. Microdeletions at 5q35.3, encompassing NSD1, are responsible for approximately 10% of non-Japanese cases of Sotos. In contrast, a recurrent approximately 2 Mb microdeletion has been reported as responsible for approximately 50% of Japanese cases of Sotos. METHODS: We screened 471 cases for NSD1 mutations and deletions and identified 23 with 5q35 microdeletions. We investigated the deletion size, parent of origin, and mechanism of generation in these and a further 10 cases identified from published reports. We used "in silico" analyses to investigate whether repetitive elements that could generate microdeletions flank NSD1. RESULTS: Three repetitive elements flanking NSD1, designated REPcen, REPmid, and REPtel, were identified. Up to 18 cases may have the same sized deletion, but at least eight unique deletion sizes were identified, ranging from 0.4 to 5 Mb. In most instances, the microdeletion arose through interchromosomal rearrangements of the paternally inherited chromosome. CONCLUSIONS: Frequency, size, and mechanism of generation of 5q35 microdeletions differ between Japanese and non-Japanese cases of Sotos. Our microdeletions were identified from a large case series with a broad range of phenotypes, suggesting that sample selection variability is unlikely as a sole explanation for these differences and that variation in genomic architecture might be a contributory factor. Non-allelic homologous recombination between REPcen and REPtel may have generated up to 18 microdeletion cases in our series. However, at least 15 cannot be mediated by these repeats, including at least seven deletions of different sizes, implicating multiple mechanisms in the generation of 5q35 microdeletions.

Abnormalities, Multiple↗
PubMed2000

Pharmacological inhibition of phosphatidylcholine biosynthesis is associated with induction of phosphatidylinositol accumulation and cytolysis of neoplastic cell lines.

De novo production of phosphatidic acid (PA) in tumor cells is required for phospholipid biosynthesis and growth of tumor cells. In addition, PA production by phospholipase D has been cited among the effects of certain oncogenes and growth factors. In this report, it has been demonstrated that enhanced phospholipid metabolism through PA in tumor cells can be exploited pharmacologically for development of anticancer agents, such as CT-2584, a cancer chemotherapeutic drug candidate currently in Phase II clinical trials. By inhibiting CTP:choline-phosphate cytidylyltransferase (CT), CT-2584 caused de novo phospholipid biosynthesis via PA to be shunted away from phosphatidylcholine (PC) and into phosphatidylinositol (PI), the latter of which was doubled in a variety of CT-2584-treated tumor cell lines. In contrast, cytotoxic concentrations of cisplatin did not induce accumulation of PI, indicating that PI elevation by CT-2584 was not a general consequence of chemotherapy-induced cell death. Consistent with this mechanism of action, propranolol, an inhibitor of PA phosphohydrolase and phosphatidylcholine biosynthesis, was also cytotoxic to tumor cell lines, induced PI accumulation, and potentiated the activity of CT-2584 in cytotoxicity assays. As expected from biophysical properties of anionic phospholipids on cellular membranes, CT-2584 cytotoxicity was associated with disruption and swelling of endoplasmic reticulum and mitochondria. We conclude that CT-2584 effects a novel mechanism of cytotoxicity to cancer cells, involving a specific modulation of phospholipid metabolism.

Adrenergic beta-Antagonists↗
PubMed2000

Copper chaperone for superoxide dismutase is essential to activate mammalian Cu/Zn superoxide dismutase.

Recent studies in Saccharomyces cerevisiae suggest that the delivery of copper to Cu/Zn superoxide dismutase (SOD1) is mediated by a cytosolic protein termed the copper chaperone for superoxide dismutase (CCS). To determine the role of CCS in mammalian copper homeostasis, we generated mice with targeted disruption of CCS alleles (CCS(-/-) mice). Although CCS(-/-) mice are viable and possess normal levels of SOD1 protein, they reveal marked reductions in SOD1 activity when compared with control littermates. Metabolic labeling with (64)Cu demonstrated that the reduction of SOD1 activity in CCS(-/-) mice is the direct result of impaired Cu incorporation into SOD1 and that this effect was specific because no abnormalities were observed in Cu uptake, distribution, or incorporation into other cuproenzymes. Consistent with this loss of SOD1 activity, CCS(-/-) mice showed increased sensitivity to paraquat and reduced female fertility, phenotypes that are characteristic of SOD1-deficient mice. These results demonstrate the essential role of any mammalian copper chaperone and have important implications for the development of novel therapeutic strategies in familial amyotrophic lateral sclerosis.

Alleles↗
PubMed1998

The copper chaperone CCS directly interacts with copper/zinc superoxide dismutase.

Dominantly inherited mutations in the gene encoding copper/zinc superoxide dismutase (SOD1) result in the fatal motor neuron disease familial amyotrophic lateral sclerosis (FALS). These mutations confer a gain-of-function to SOD1 with neuronal degeneration resulting from enhanced free radical generating activity of the copper present in the mutant enzyme. The delivery of copper to SOD1 is mediated through a soluble factor identified as the copper chaperone for SOD1 (CCS). Amino acid sequence alignment of SOD1 and CCS reveals a striking homology with conservation of the amino acids essential for mediating SOD1 homodimerization. Here we demonstrate that CCS and SOD1 directly interact in vitro and in vivo and that this interaction is mediated via the homologous domains in each protein. Importantly, CCS interacts not only with wild-type SOD1 but also with SOD1 containing the common missense mutations resulting in FALS. Our findings therefore reveal a common mechanism whereby different SOD1 FALS mutants may result in neuronal injury and suggest a novel therapeutic approach in patients affected by this fatal disease.

Amino Acid Sequence↗
PubMed1975

An immunofluorescent study of cornea development in the chick.

The developmental pattern of appearance of a structural corneal antigenic determinant was studied by immunofluorescent methods. It was first detected in the primary corneal stroma at stage 23, and thereafter spread throughout the primary and secondary stroma. This antigen was absent from Bowman's membrane at its initial stage of development, suggesting that this membrane is a new structure in corneal morphogenesis, and not simply a modification of the primary stroma. This study also suggests that the antigenic determinant is a carbohydrate and is secreted by the corneal epithelial cells.

Animals↗