Rare mutations

Several diseases involving dysregulation of MR function have been described although most of them are not causatively linked to the receptor itself. Pseudohypoaldosteronism for example is a syndrome of mineralocorticoid resistance characterized by urinary salt loss and dehydration. However, only very rarely mutations in the MR gene have been found in these patients so far. In most cases, this syndrome appears to be linked to defects in the subunits of the amiloride-sensitive sodium channel ENaC, a major target of mineralocorticoid action in the kidney. 

The following also points to a dysregulation of the ubiquitin-proteasome pathway as an important aspect of PD pathogenesis rare mutations in ubiquitin car-boxy-terminal hydrogenase LI (UCH-L1) associated with autosomal dominant PD in a German family [120], a UCH-L1 polymorphism associated with the develop-... 

Mann, W.A., Meyer, N., Weber, W., Meyer, S., Greten, H., and Beisiegel, U. (1995) Apolipoprotein E isoforms and rare mutations parallel reduction in binding to cells and to heparin reflects severity of associated type III hyperlipoproteinemia./. Lipid Res. 36, 517. 

Defects in MHC Class II molecules, while exposing affected subjects to a variety of infections, do not result in the severe immunodeficiency seen in patients with SCID. In contrast to mutations affecting MHC Class II molecules, defects in MHC Class I molecules are rare. Mutations affecting MHC Class I molecules are directed to genes on chromosome 6 at the MHC locus that code for peptide-transporter proteins (122). The function of these transporter proteins is to transport the peptide antigens so that a complex with the a chain of MHC Class I molecules and p 2-microglobulin is formed and transported to the surface of the cell. 

Familial dysbetalipoproteinemia (type III) is characterized by the accumulation of chylomicron and VLDL remnants, which are enriched in cholesterol compared to their precursors. The primary molecular cause of familial dysbetalipoproteinemia (type III) is the homozygous presence of the apolipoprotein E2 (apoE2) isoform, which is associated with recessive inheritance of the disorder [62]. However, only 1 in 50 homozygotes for apoE2 will develop type III hyperlipoproteinemia, which is clinically characterized by palmar and tuberous xanthomas, arcus lipoides, and premature atherosclerosis of coronary, peripheral, and cerebral arteries. Precipitating factors include diabetes mellitus, renal disease, hemochromatosis, but also familial hypercholesterolemia. In addition, some rare mutations in the apoE gene have been found to cause dominant and more penetrant forms of type III hyperlipoproteinemia. 

With this genetic approach only the common three apoE isoforms, E2, E3, and E4 are detected. Other rare mutations also leading to familial dysbetalipoproteinemia would be missed by this approach [88]. However, these rare variants are estimated to account for less than 1 % of the apoE isoforms and they show a dominant inheritance of familial dysbetalipoproteinemia. 

Further understanding of i gene function has come from study of rare mutations designated t. Mutants bearing... 

Altered target Modifications in the bacterial DNA gyrase, especially in amino acids at the N-terminus of the A subunit, have been associated with a decreased affinity for the fluoroquinolone. The B subunit of the gyrase is rarely mutated. 

The importance of PPARy in insulin sensitivity was confirmed with the finding, in Cambridge, of two families presenting with severe insuUn resistance in whom rare mutations of the PPARy gene caused loss of PPARy activity (Barroso 1, Gumell M, Crowley VE, et al 1989 Dominant negative mutations in human PPARy associated with severe insulin resistance, diabetes meUitus and hypertension. Nature 402 880-882.)... 

In the case of selective neutrality—this means that all variants have the same selective values—evolution can be modeled successfully by diffusion models. This approach is based on the analysis of partial differential equations that describe free diffusion in a continuous model of the sequence space. The results obtained thereby and their consequences for molecular evolution were recently reviewed by Kimura [2]. Differences in selective values were found to be prohibitive, at least until now, for an exact solution of the diffusion approach. Needless to say, no exact results are available for value landscapes as complicated as those discussed in Section IV.3. Approximations are available for special cases only. In particular, the assumption of rare mutations has to be made almost in every case, and this contradicts the strategy basic to the quasi-species model. 

Gangestad Most mutations have very small effects. Most deleterious mutations are also not fresh. We each carry on average up to 200 deleterious mutations that will eventually be taken out. These have occurred over generations, and each one has only a certain probability that it will be removed in any particular generation. Across individuals, the number of mutations should be close to normally distributed, with substantial variance. What is being talked about here is not just the rare mutation that creates mental retardation. 

Gangestad You don t need a lot of dominance variance to get inbreeding depression on a trait, if most of the trait s genetic variance is due to mutations. With rare mutations there are very few double recessive mutations, and therefore, almost all of the variance caused by each mutation is merely additive, even if the effect of double recessives is nonadditive. So rare mutations can produce low dominance variance yet substantial inbreeding depression. 

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