Molecular defects

NIDDM is a much more common disease than IDDM, accounting for about 85—90% of all cases of diabetes meUitus. Whereas NIDDM may be present at any age, the incidence increases dramatically with advanced age over 10% of the population reaching 70 years of age has NIDDM. Patients with NIDDM do not require insulin treatment to maintain life or prevent the spontaneous occurrence of diabetic ketoacidosis. Therefore, NIDDM is frequendy asymptomatic and unrecognized, and diagnosis requires screening for elevations in blood or urinary sugar. Most forms of NIDDM are associated with a family history of the disease, and NIDDM is commonly associated with and exacerbated by obesity. The causes of NIDDM are not well understood and there may be many molecular defects which lead to NIDDM. 

The Molecular Defect in Dnchenne Muscular Dystrophy Involves an Actin-Anchoring Protein... 

Shieh CC, Coghlan M, Sullivan JP et al (2000) Potassium channels molecular defects, diseases, and therapeutic opportunities. Pharmacol Rev 52 557-594... 

This group of conditions, in which myotonia (the failure of voluntary muscle to relax following contraction) may be a feature, can now be classified according to the primary molecular defect responsible for the relevant condition. The clinical features of the different conditions within this group can show some significant differences, even among the diseases now known to be due to mutations within the same genes (Table 1). 

The nature of the molecular defect Is unclear and presumably lies In the repression mechanism for the gene controlling formation of the enzyme protein. Exposure to any of the drugs listed In Table V results In further marked de-repressIon of enzyme synthesis and severe porphyria. 

Electrophoretic and kinetic studies of the patient s enzyme have been reported in several cases (F10). Most of them showed decreased substrate affinity and abnormal electrophoretic mobility. The main cause of P5N deficiency is considered to be an abnormality of P5N-I, probably arising from a structural gene mutation (H6). The precise molecular defect has not been clarified, because the normal gene for P5N-I has not been isolated. 

Low levels or absence of adenosine deaminase (ADA) is associated with one form of severe combined immunodeficiency disease (SCID) characterized by B-andT-lymphocyte dysfunction due to toxic effects of deoxyadenosine (HI9). Most patients present as infants with failure to thrive, repeated infections, severe lymphopenia, and defective cellular and humoral immunity. Disease severity is correlated with the degree of deoxyadenosine nucleotide pool expansion and inactivation of S-adenosylhomocysteine hydrolase in red blood cells. Up to now, more than 40 mutations have been identified (A4, H20, S5, S6). The majority of the basic molecular defects underlying ADA deficiency of all clinical phenotypes are missense mutations. Nonsense mutations, deletions ranging from very large to single nucleotides, and splicing mutations have also been reported. It is likely that severe... 

B9. Baronciani, L., Zanella, A., Bianchi, P Zappa, M Alfinito, E, Iolascon, A., Tannoia, N., Beutler, E., and Sirchia, G., Study of the molecular defects in glucose phosphate isomerase-deficient patients affected by chronic hemolytic anemia. Blood 88,2306-2310 (1996). 

M2. Maeda, M and Yoshida, A., Molecular defect of a phosphoglycerate kinase variant (PGK-Mat-sue) associated with hemolytic anemia Leu - Pro substitution caused by T/A - C/G transition in exon 3. Blood 77, 1348-1352(1991). 

T26. Turner, G., Fletcher, J., Elber, J., Yanagawa, Y Dav6, V., and Yoshida, A., Molecular defect of a phosphoglycerate kinase variant associated with haemolytic anaemia and neurological disorders in a large kindred. Br. J. Haematol. 91,60-65 (1995). 

Mutations in the antithrombin (AT) gene have been the basis of AT deficiency. In type I AT deficiency the level of circulating protein molecule and activity are reduced to nearly 50% of normal. Molecular defects in the AT gene resulting in gene deletions at specific DNA sequences may be the basis for type I AT deficiency predisposing such patients to thrombosis (82). 

Without going into the molecular defects in other coagulation factors, suffice it to say that our current understanding of mechanisms leading to the clinical expression of thrombosis and bleeding has been enhanced by the knowledge of such mutations. 

The lysosome is the subcellular organelle responsible for physiological turnover of cellular constituents. Their combined incidence is estimated to be 1 8,000 [2]. Knowledge about the molecular and cellular defects has advanced a great deal in recent years. Platt and Walkley [3] have proposed a new classification based on the nature of the molecular defects (Table 41-1). This system will be used here. 

TABLE 41-1 Lysosomal storage diseases classified on basis of molecular defects... 

Defects of complex II. These have not been fully characterized in the few reported patients, and the diagnosis has often been based solely on a decrease of succinate-cytochrome c reductase activity (Fig. 42-3). However, partial complex II deficiency was documented in muscle and cultured fibroblasts from two sisters with clinical and neuroradiological evidence of Leigh s syndrome, and molecular genetic analysis showed that both patients were homozygous for a point mutation in the flavoprotein subunit of the complex [17]. This was the first documentation of a molecular defect in the nuclear genome associated with a respiratory chain disorder. 

Coenzyme Q10 (CoQlO) deficiency. This mitochondrial encephalomyopathy has three main clinical presentations. A predominantly myopathic form is characterized by the triad of exercise intolerance, recurrent myoglobinuria, and CNS involvement. A more frequent ataxic form is dominated by ataxia and cerebellar atrophy, variously associated with weakness, developmental delay, seizures, pyramidal signs, and peripheral neuropathy, often simulating spinocerebellar atrophy. A third presentation with fatal infantile encephalomyopathy and renal involvement, has been described in two families. The biochemical defect (or defects) presumably involve different steps in the biosynthesis of CoQlO, but are still unknown, as are the molecular defects. Diagnosis, however, is important because all patients - and especially those with the myopathic and infantile forms - benefit from CoQlO supplementation [13,14]. 

Tein, I. Carnitine transport pathophysiology and metabolism of known molecular defects. /. Inker. Metab. Dis. 26 147-169, 2003... 

Thus, it has been shown that, in the majority of X-linked CGD patients, the abnormality is due to the failure to transcribe the mRNA encoding the large (/J) subunit of the b cytochrome. In these patients, both the heavy /)-chain and the light a-chain are absent, even though the molecular defect appears to be restricted to the heavy chain thus, expression of the heavy chain is somehow necessary for the expression/translation/stabilisation of the... 

Figure 5.1 Illustration of (a) molecular architecture of a SAM-forming molecule, (b) an idealized SAM and (c) a more realistic description with molecular defects (1), domain boundaries (2) and substrate topography such as steps (3).

The leptin story has been augmented by a second mouse genetic defect leading to obesity. These mice are known as db/db they are very similar to ob/ob mice. However, these mice have normal levels of leptin. Scientists at Millennium Pharmaceuticals identified the molecular defect in db/db mice. They lack the normal leptin receptor. Therefore, we have both sides of the coin ob/ob mice cannot make leptin, eat too much, and are therefore obese db/db mice make leptin, cannot respond to it for lack of the leptin receptor, eat too much, and are obese. Administration of leptin to ob/ob mice normalizes their body weight but administration of leptin to db/db mice has... 

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