Transport defects

ROOMANS G M (2001) Pharmacological treatment of the ion transport defect in cystic fihro is,. Expert Opin Investig Drugs. 10 (1) 1-19. 

Pfeiffer, R., et al. Luminal hetero-dimeric amino acid transporter defective in cystinuria. Mol. Biol. Cell 1999, 10, 4135-4147. 

Ito, K., Suzuki, H., Hirohashi, T., Kume, K., Shimizu, T., Sugiyama, Y., Molecular cloning of canalicular multispecific organic anion transporter defective in EHBR, Am. J. Physiol. 1997, 272, G16-G22. 

The cause is defective transport of dibasic amino acids by the proximal tubule and intestine. The transport defect occurs at the basolateral rather than the luminal membrane. Hyperammonemia reflects a deficiency of intra-mitochondrial ornithine. An effective treatment is oral citrulline supplementation, which corrects the hyperammonemia by allowing replenishment of the mitochondrial pool of ornithine. 

The biochemical classification of mitochondrial DNA is based on the five major steps of mitochondrial metabolism. These steps are illustrated in Figure 42-3 and divide mitochondrial diseases into five groups defects of mitochondrial transport, defects of substrate utilization, defects of the Krebs cycle, defects of the respiratory chain and defects of oxidation-phosphorylation coupling. 

Sirotnak FM, Moccio DM, KelleherLE, Goutas LJ (1981) Relative frequency and kinetic properties of transport-defective phenotypes among methotrexate-resistant L1210 clonal cell lines derived in vivo. Cancer Res. 41 4447 4452. 

Answer Aerosol delivery of the CFTR gene. Both viruses and liposome-DNA complexes are capable of successful CFTR gene transfer to the nasal and airway epithelia of patients with CF. In fact, gene transfer to the airways is one of the few areas where liposome-DNA complexes match the expression obtained using viral vectors without the viruses inflammatory side effects. Current trials are aimed at optimizing gene delivery with reduced toxicity to produce sustained correction of the epithelial transport defect. 

Three different rare genetic metabolic defects in sialic acid metabolism are known, as indicated in Fig. 4.3.2 [3, 21] (1) free sialic acid storage disease (SASD Online Mendelian Inheritance in Man, OMIM 604369, 269920), a lysosomal membrane transporter defect (2) sialuria (OMIM 269921), a feedback inhibition defect in sialic acid biosynthesis (3) sialidosis (OMIM 256550), a breakdown defect of sialyloli-gosaccharides caused by a defect of lysosomal sialidase. In all these genetic defects, an increased amount of sialic acid can be found in tissues and or body fluids, either bound to OGSs as in (3), or in its free state as in (1) and (2). 

Mancini GM, Beerens CE, Aula PP, Verheijen FW (1991) Sialic acid storage diseases. A multiple lysosomal transport defect for acidic monosaccharides. J Clin Invest 87 1329-1335... 

Male patients affected with X-linked Cr transporter defect have elevated urinary Cr concentrations only if this is expressed per mol creatinine (also mentioned Cr creatinine ratio). In plasma, Cr concentrations are within the normal limits. Also, GA is within the reference range in both plasma and urine. Female carriers of the defect may have elevated urinary Cr excretion (expressed per mol creatinine). However this is not a consistent finding in all carriers. 

Stromberger C, Bodamer OA, Stockler-Ipsiroglu S (2003) Clinical characteristics and diagnostic clues in inborn errors of creatine metabolism. J Inherit Metab Dis 26 299-308 Salomons GS, van Dooren SJ, Verhoeven NM, Marsden D, Schwartz C, Cecil KM, DeGrauw TJ, Jakobs C (2003) X-linked creatine transporter defect an overview. J Inherit Metab Dis 26 309-318... 

Mancini GM, Catsman-Berrevoets CE, de Coo IF, Aarsen FK, Kamphoven JH, Huijmans JG, Duran M, van der Knaap MS, Jakobs C, Salomons GS (2004) Two novel mutations in SFC6A8 cause creatine transporter defect and distinctive X-linked mental retardation in two unrelated Dutch families. Am J Med Genet A 132 288-295... 

In malabsorption of glucose and galactose, the carrier-mediated transport is defective. In severely malnourished patients, there may be a secondary transport defect in which all carbohydrates are difficult to absorb (Dahlqvist 1983). 

Carbohydrate abnormalities, such as renal glycosuria (a transport defect), pentosuria (enzyme deficiency, xylitol dehydrogenase I. lactase deficiencies, fructose intolerance, galactosemia, galacloki-nase deficiency, oxalosis, and several glycogenoses (von Gierke s, Forbes . Andersen s, Hers s. and Tarui s diseases). 

Kadowaki, T., Chen, S., Hitomi, M., Jacobs, E., Kumagai, C., Liang, S. et al. (1994) Isolation and characterization of Saccharomyces cerevisae mRNA transport-defective (mtr) mutants. J. Cell Biol, 126, 649-659. 

Zabner, J., Couture, L. A., Gregory, R. J., Graham, S. M., Smith, A. E. and Welsh, M. J. (1993). Adenovirus-mediated gene transfer transiently corrects the chloride transport defect in nasal epithelia of patients with cystic fibrosis. Cell 75, 207-216. 

Carnitine supplementation is also critical in these patients. In acute severe metabolic crises, carnitine can be administered intravenously. Oral carnitine supplementation can be used for chronic maintenance therapy. Note that as the primary transport defect will still be present, carnitine supplementation cannot normalize the patient s carnitine homeostasis. 

A transport-defective mutant of E. coli is advocated for the convenient preparation of ferric enterobactin (100). In S. typhirrmrium, as well as in E. coli, several proteins of the outer membrane are regulated by the iron content of the medium (101). 

The complex tetrapyrrole ring structure of heme is built up in a stepwise fashion from the very simple precursors sue-cinyl-CoA and glycine (Figure 32-2). The pathway is present in all nucleated cells. From measurements of total bilirubin production, it has been estimated that daily synthesis of heme in humans is 5 to 8mmol/kg body weight. Of this, 70% to 80% occurs in the bone marrow and is used for hemoglobin synthesis. Approximately 15% is synthesized in the liver and is used to produce cytochrome P-450, mitochondrial cytochromes, and other hemoproteins. The pathway is compartmentalized, with some steps occurring in the mitochondrion and others in the cytoplasm. Little is known about the transport of intermediates across the mitochondrial membrane, and no transport defect has yet been reported in the porphyrias. 

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