Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The aim of this study was to assess DNA repair capacity in lymphocytes of children with protein calorie malnutrition using the single-cell gel electrophoresis (comet) assay. Repair capacity was assessed by estimating the relative decrease of DNA migration length 5, 15, 30, and 60 min after hydrogen peroxide treatment, in three groups of children: well-nourished (WN), well-nourished infected (WN-I), and malnourished infected (MN-I). In addition, the DNA migration length was evaluated in all groups before and after peroxide treatment. Comparison of mean migration lengths observed in WN and WN-I children showed significant differences at all times tested; between WN-I and MN-I differences were also observed, except after hydrogen peroxide exposure. This implies that lymphocytes of WN-I and MN-I children were equally sensitive to hydrogen peroxide. Nevertheless, the MN-I group clearly shows the greatest overall percentage of damaged cells at all times tested. In relation to repair capacity, at 5 min it was approximately 30% in both groups of well-nourished children, but only 20% in MN-I; 15 min after exposure, repair capacity increased to 51% in well-nourished children but only to 31% in MN-I; and at 60 min this capacity increased to 82% in well-nourished but only to 55% in MN-I. These data indicate that lymphocytes of malnourished children show a decreased capacity to repair hydrogen peroxide-induced DNA damage compared to that of well-nourished controls. This reflects that only malnutrition is associated with decreased DNA repair capacity. Additionally, the data confirm that severe infection and malnutrition are two factors clearly associated with increased DNA damage.
Environ Mol Mutagen 2002
PMID:Hydrogen peroxide-induced DNA damage and DNA repair in lymphocytes from malnourished children. 1181 94

One-day-old chicks were reared using diets differing in their vitamin E and/or selenium content. The purpose of this research was to detect any possible imbalance in the antioxidant defense system, which could be related to development of nutritional pancreatic atrophy. Mitochondrial membranes from animals deficient in both nutrients, or just vitamin E, submitted to peroxidizability 'in vitro' had the production of TBARS greatly enhanced. Measurements of the 2-GSH/GSSG ratio suggested that selenium and vitamin E, the latter in higher magnitude, were responsible for maintenance of the reducing capacity of the cell. Enzymatic defense systems against oxidative stress were also studied. The results indicated that the total antioxidant enzymatic activity of pancreatic cells was not sufficient to scavenge all the ROS generated in the nutritionally deficient animals. The present study suggests that nutritional deficiency of selenium and/or vitamin E generates one imbalance between pro-oxidant and antioxidant systems in chicken pancreas, leading to oxidative stress and pancreatic atrophy.
Comp Biochem Physiol B Biochem Mol Biol 2002 Apr
PMID:Role of antioxidant systems in induced nutritional pancreatic atrophy in chicken. 1192 94

Transcription factor gene AP-2 gamma belongs to a family of four closely related genes. AP-2 gamma had been implicated in multiple functions during proliferation and differentiation based on its expression pattern in trophoblast, neural crest, and ectoderm cells in murine embryos. In order to address the question of the role of AP-2 gamma during mammalian development, we generated mice harboring a disrupted AP-2 gamma allele. AP-2 gamma heterozygous mice are viable and display reduced body sizes at birth but are fertile. Mice deficient for AP-2 gamma, however, are growth retarded and die at days 7 to 9 of embryonic development. Immunohistochemical analysis revealed that the trophectodermal cells that are found to express AP-2 gamma fail to proliferate, leading to failure of labyrinth layer formation. As a consequence, the developing embryo suffers from malnutrition and dies. Analysis of embryo cultures suggests that AP-2 gamma is also implicated in the regulation of the adenosine deaminase (ADA) gene, a gene involved in purine metabolism found expressed at the maternal-fetal interface. Therefore, AP-2 gamma seems to be required in early embryonic development because it regulates the genetic programs controlling proliferation and differentiation of extraembryonic trophectodermal cells.
Mol Cell Biol 2002 May
PMID:Transcription factor gene AP-2 gamma essential for early murine development. 1194 Jun 72

Maria Daria Haust, MD, has made many significant contributions to our understanding of atherogenesis in children, particularly in associating the earliest lesions (fatty spots and streaks) with the normal growth and remodeling of arteries. It is my privilege to link her early work to more recent findings which show that the early lesions seen in the arteries of children before puberty bear no relationship to the risk of atherosclerosis in later life. Furthermore, present evidence supports the view that intervening in childhood (2-15 years) with low-fat low-cholesterol diets or even worse, lipid-lowering drugs to prevent atheroslerotic plaques in adulthood is wasted effort. Overzealous parents may unwittingly induce malnutrition in their children and many children with restricted access to palatable foods, will yearn for them even more as they become older leading to over weightness. Pediatricians from various scientific bodies around the world vary in their advice to mothers regarding diets for children. The program adopted by Health Canada on the advice of pediatricians in that country, which is also supported by the European Society of Pediatrics, Gastroenterology and Nutrition, recommends that the fat content of diets for children should be tapered gradually from 40% of energy at 2 years of age to 30% of energy at the conclusion of linear growth (late adolescence).
Pediatr Pathol Mol Med
PMID:The role of dietary and plasma lipids in childhood atherogenesis. 1194 33

Glycogenosis type II (GSDII, Pompe disease) is an autosomal recessive lysosomal storage disease caused by a deficiency of acid alpha-glucosidase (acid maltase, GAA). The enzyme degrades alpha -1,4 and alpha -1,6 linkages in glycogen, maltose, and isomaltose. Deficiency of the enzyme results in accumulation of glycogen within lysosomes and in cytoplasm eventually leading to tissue destruction. The discovery of the acid a-glucosidase gene has led to rapid progress in understanding the molecular basis of glycogenosis type II and the biological properties of the GAA protein. The last decade has seen several developments: 1) extensive mutational analysis in patients with different forms of the disease, 2) characterization of the enzyme biosynthesis, processing, and lysosomal targeting, 3) generation of knockout mouse models, 4) development of viral vectors for gene replacement therapy, 5) the production of recombinant human enzyme, and 6) a shift in the enzyme replacement therapy approach from theory to practice. It is anticipated that the enzyme replacement therapy will be widely available for human use in the near future. Several recent reviews (including the most comprehensive one by R. Hirschhorn and A. Reuser [1]), address clinical, biochemical and genetic aspects of the disease, as well as development of new therapies for GSDII [2, 3, 4]. In this article we will review recent findings in the area including rapidly accumulating molecular genetic data (more than 20 mutations need to be added to the list), transcriptional control of gene expression, studies in mouse models, and new approaches to gene therapy. We will also highlight some emerging questions following the introduction of enzyme replacement therapy.
Curr Mol Med 2002 Mar
PMID:Acid alpha-glucosidase deficiency (glycogenosis type II, Pompe disease). 1194 32

Deficiency of the glycogen debranching enzyme (gene, AGL) causes glycogen storage disease type III (GSD-III), an autosomal recessive disease affecting glycogen metabolism. Most GSD-III patients have AGL deficiency in both the liver and muscle (type IIIa), but some have it in the liver but not muscle (type IIIb). Cloning of human AGL cDNAs and determination of the genomic structure and mRNA isoforms of AGL have allowed for the study of GSD-III at the molecular level. In turn, the resulting information has greatly facilitated our understanding of the molecular basis of this storage disease with remarkable clinical and enzymatic variability. In this review, we summarize all 31 GSD-III mutations in the literature and discuss their clinical and laboratory implications. Most of the mutations are nonsense mutations caused by a nucleotide substitution or small insertion or deletion; only one is caused by a missense amino acid change. Some important genotype-phenotype correlation have emerged, in particular, that exon 3 mutations (17delAG and Q6X) are specifically associated with GSD-IIIb. Three other mutations have appeared to have some phenotype correlation. Specifically, the splice mutation IVS32-12A>G was found in GSD-III patients having mild clinical symptoms, while the mutations 3965delT and 4529insA are associated with a severe phenotype and early onset of clinical manifestations. A molecular diagnostic scheme has been proposed to diagnose GSD-III noninvasively. The characterization of AGL mutations in GSD-III patients has also helped the structure-function analysis of this bifunctional enzyme important for glycogen metabolism.
Curr Mol Med 2002 Mar
PMID:Molecular characterization of glycogen storage disease type III. 1194 33

Protein-calorie malnutrition (PCM), as one of global health problems, arises during protein and/or energy deficit due to disease and nutritional inadequacy. Previously, we showed that PCM elicited oxidative stress with activation of the phase II detoxifying gene expression, which was reversed by cysteine supplementation. As part of the attempts to identify the cellular adaptive responses and the associated gene expression during PCM, the current study was initiated to analyze the genes differentially expressed in the rat during PCM. Among 1,916 bands amplified, 85 putative differentially amplified bands were enhanced by PCM in the liver, while the expression of 64 bands was suppressed. Northern and/or reverse transcription-polymerase chain reaction (RT-PCR) analyses revealed that PCM increased the expression of fibrinogen B beta chain, B cell translocation gene I (BTGI) and thyroid hormone responsive protein (THRP) mRNAs. The increase in the hepatic fibrinogen B beta chain mRNA was not prevented by cysteine supplementation, whereas cysteine decreased the enhancement in the rGSTA2 and microsomal epoxide hydrolase mRNA expression. Cysteine was also active in reversing the increase in BTG1 mRNA during PCM. This was supported by the increase in BTG1 mRNA in H4IIE cells exposed to sulfur amino acid-deprived medium. Northern blot analysis revealed that THRP, highly expressed in the brain in a tissue-specific manner, was induced by PCM and that cysteine supplementation abolished the THRP induction. Conversely, the level of hepatic albumin mRNA was markedly decreased by PCM, which was partially restored by cysteine supplementation. Differential display RT-PCR analysis allowed us to identify the genes that are responsive to oxidative stress during PCM and to characterize the differential role of cysteine on the expression of the fibrinogen B beta chain, BTG1 and THRP genes as a homeostatic adaptive response during protein deficiency.
Mol Cell Biochem 2002 Feb
PMID:Identification of genes enhanced by protein-calorie malnutrition by differential display polymerase chain reaction (expression of fibrinogen B beta chain, B cell translocation gene 1 and thyroid hormone responsive protein genes). 1195 59

HAP-1 is a huntingtin-associated protein that is enriched in the brain. To gain insight into the normal physiological role of HAP-1, mice were generated with homozygous disruption at the Hap1 locus. Loss of HAP-1 expression did not alter the gross brain expression levels of its interacting partners, huntingtin and p150glued. Newborn Hap1(-/-) animals are observed at the expected Mendelian frequency suggesting a non-essential role of HAP-1 during embryogenesis. Postnatally, Hap1(-/-) pups show decreased feeding behavior that ultimately leads to malnutrition, dehydration and premature death. Seventy percent of Hap1(-/-) pups fail to survive past the second postnatal day (P2) and 100% of Hap1(-/-) pups fail to survive past P9. From P2 until death, Hap1(-/-) pups show markedly decreased amounts of ingested milk. Hap1(-/-) pups that survive to P8 show signs of starvation including greatly decreased serum leptin levels, decreased brain weight and atrophy of the brain cortical mantel. HAP-1 is particularly enriched in the hypothalamus, which is well documented to regulate feeding behavior. Our results demonstrate that HAP-1 plays an essential role in regulating postnatal feeding.
Hum Mol Genet 2002 Apr 15
PMID:Targeted disruption of Huntingtin-associated protein-1 (Hap1) results in postnatal death due to depressed feeding behavior. 1197 76

Deficiency of liver arginase (AI) causes hyperargininemia (OMIM 207800), a disorder characterized by progressive mental impairment, growth retardation, and spasticity and punctuated by sometimes fatal episodes of hyperammonemia. We constructed a knockout mouse strain carrying a nonfunctional AI gene by homologous recombination. Arginase AI knockout mice completely lacked liver arginase (AI) activity, exhibited severe symptoms of hyperammonemia, and died between postnatal days 10 and 14. During hyperammonemic crisis, plasma ammonia levels of these mice increased >10-fold compared to those for normal animals. Livers of AI-deficient animals showed hepatocyte abnormalities, including cell swelling and inclusions. Plasma amino acid analysis showed the mean arginine level in knockouts to be approximately fourfold greater than that for the wild type and threefold greater than that for heterozygotes; the mean proline level was approximately one-third and the ornithine level was one-half of the proline and ornithine levels, respectively, for wild-type or heterozygote mice--understandable biochemical consequences of arginase deficiency. Glutamic acid, citrulline, and histidine levels were about 1.5-fold higher than those seen in the phenotypically normal animals. Concentrations of the branched-chain amino acids valine, isoleucine, and leucine were 0.4 to 0.5 times the concentrations seen in phenotypically normal animals. In summary, the AI-deficient mouse duplicates several pathobiological aspects of the human condition and should prove to be a useful model for further study of the disease mechanism(s) and to explore treatment options, such as pharmaceutical administration of sodium phenylbutyrate and/or ornithine and development of gene therapy protocols.
Mol Cell Biol 2002 Jul
PMID:Mouse model for human arginase deficiency. 1205 59

Multifocal myocardial necrosis (MMN) is an unusual cardiomyopathy of childhood, characterized by multiple patchy areas of myocardial fiber necrosis/fibrosis involving mainly the middle part of the left ventricle, but also, to a lesser extent, the right ventricle and the atria. These necrotic lesions are isolated and are not accompanied by an inflammatory reaction or vascular alterations. They are responsible for acute cardiac failure. MMN lesions are observed in various pathologic conditions including cystic fibrosis of the pancreas, pancreatic lipomatous hypoplasia/atrophy, malnutrition due to extensive intestinal resection with subsequent total parenteral feeding, and in Keshan disease. MMN is the main and the most characteristic feature of Keshan disease, an endemic and idiopathic condition affecting Chinese rural children. The causes and mechanisms of MMN presently are unknown. However, the presence of similar cardiac lesions in such different pathological conditions suggests the role of a selective deficiency of a hypothetical extrinsic factor (selenium, molybdenum iodide, other), probably crucial for the metabolism of the myocardial fiber.
Pediatr Pathol Mol Med
PMID:Multifocal myocardial necrosis: a distinctive cardiac lesion in cystic fibrosis, lipomatous pancreatic atrophy, and Keshan disease. 1255


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