Metabolic defects, gene

Familial hypercholesterolaemia is characterized by a significant elevation in plasma LDL concentration. The basic metabolic defect appears to be abnormal LDL receptor function, arising from mutations in the LDL receptor gene. Several receptor mutations have been identified and hypercholesterolaemia severity as well as the age of onset of ischaemic heart disease has recently been demonstrated to vary according to the type of LDL receptor gene defect (Moorjani et al., 1993). 

Gene therapy for this metabolic defect may become available within the next few years. In vitro studies have demonstrated the feasibility of retroviral-mediated gene transfer of both the El-a and E2 subunits of the branched-chain decarboxylase complex [16,18],... 

Many diseases, such as hereditary metabolic defects and tumors, can still not be adequately treated. About 10 years ago, projects were therefore initiated that aimed to treat diseases of this type by transferring genes into the affected cells (gene therapy). The illustration combines conceivable and already implemented approaches to gene therapy for metabolic defects (left) and tumors (right). None of these procedures has yet become established in clinical practice. 

Van Gelder How do you reconcile the action spectrum data with the vitamin A-depletion data that we have presented As the perspective for this, in Neurospora, entrainment of the clock is resistant to vitamin A metabolic defects and in Drosophila it is resistant to vitamin A depletion. We found a similar result in the mammal with near-complete vitamin A depletion of the eye, and no attenuation in the response, as measured by immediate-early gene induction in the SCN. 

Another Arabidopsis mutant, murl, which lacks the ability to synthesize 1-fucose, possesses a defective gene encoding GDP-d-Man-4,6-dehydratase, a key enzyme in 1-fucose biosynthesis. Further analysis revealed that 1-Fuc is replaced by 1-Gal, a structurally similar monosaccharide, in the cell walls of this mutant with no adverse effects on plant physiology or metabolism (Rayon et al, 1999). Transgenic plants containing this mutation can also be used for foreign protein production. 

Mice with defective adiponectin genes are less sensitive to insulin than those with normal adiponectin, and they show poor glucose tolerance ingestion of dietary carbohydrate causes a long-lasting rise in their blood glucose. These metabolic defects resemble those of... 

Most metabolic disorders are inherited, meaning that they are passed by parents to their offspring in defective genes. Also, they have no cure. They are usually treated with medications and a special diet to provide the missing substances or remove the toxic ones that build up. 

Matzner, U., Habetha, M. and Gieselmann, V. (2000a). Retrovirally expressed human arylsulfatase A corrects the metabolic defect of arylsulfatase A-deficient mouse cells. Gene Ther. 7, 805-812. 

On the above view, NLSD is primarily a disease of defective phospholipid metabohsm and the TAG-derived route of phospholipid biosynthesis is essential for the normal functioning of skin, muscle, liver, and the central nervous system. Further studies on the fatty hver dystrophic mouse which bears a close resemblance to human NLSD [103] may identify fhe defective gene. Defective neutral phospholipid metabolism in this mouse model is reflected by a decreased phosphohpid content of peripheral nerve myelin [109]. The nature of the hpase(s) involved in normal TAG-to-phospholipid acyltransfer has not been characterized, but may be similar to a previously described microsomal neutral hpase [110] or to a carboxylesterase [111]. 

The authors used two deletion mutants in the glycolysis pathway to demonstrate this powerful technique. The two mutants without growth-rate phenotypes showed metabolic phenotypes when concentrations of six metabolites were measured (Raamsdonk et al., 2001). To analyze all the metabolites in the cell at the same time, they used NMR spectroscopy and found that changes in the concentrations of metabolites were similar in these two mutants. The authors concluded that mutant strains containing defective genes involved in similar pathways displayed metabolite profiles that could be clustered together using principal component analysis. 

Hyperthermia is a rare complication of anesthesia that is not completely understood. Most of the evidence points to the ryanodine receptor (chromosome 19ql3.1) as the defective gene product. This receptor is the Ca release channel of muscle sarcoplasmic reticulum. Stimulation of this channel leads to excessive Ca release from the cisternae of the sarcoplasmic reticulum, and that Ca prompts muscle contraction, an increase in body temperature, tachycardia, and subsequent metabolic acidosis. 

Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death. Development 121 (5), 1283-1299. 

A second metabolic defect in cholesterol synthesis leads to Smith-Lemli-Opitz syndrome (SLOS) (B.U. Fitzkey, 1999) [11]. SLOS is one of the most common autosomal D cessive disorders, with estimates of incidence ranging from 1 in 10,000 to 1 in 60,000 of live births [12]. Individuals with SLOS have markedly elevated levels of plasma 7-DHC and low plasma cholesterol levels. 7-DHC A7-reductase activity is deficient in SLOS patients samples, and cloning of the 7-DHC A7-reductase gene led to identification of over 100 missense and many null mutations in SLOS patients (RE. lira, 2003). 

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