Genotypephenotype Correlation

Although more than 250 different mutations have been characterized in OI, a mechanism by which individual mutations cause various degrees of skeletal abnormalities is not well understood. Many investigators have attempted to correlate the type of mutation, the gene in which the mutation occurred, and the location of the mutation with phenotypical consequences. Mutations in the COL1A1 gene resulting in one null allele and in the synthesis of half the normal amount of functional proal(I) chains have mild clinical consequences in individuals with type I OI. The phenotypical effects of mutations that result in the generation of abnormal type I procollagen molecules are more deleterious than those of null mutations. The structural mutations affect connective tissues through a dominant negative mechanism, in which the presence of the mutant chain in the extracellular matrix directly disorganizes and weakens the matrix. Therefore the extent of mutant chain incorporation into extracellular fibrils can play a role in the clinical outcome. In general, bulky residues are more deleterious than small residues, but the existence of lethal substitutions by serine and alanine indicates that the region in which the substitution occurred is also important. Mutations in COL1A2 can alter up to 50% of the procollagen molecules, whereas similar mutations in COL1A1 can alter up to 75% of the newly synthesized molecules. It has also been proposed that the position of a mutation along the al(I) chains may be a crucial factor, with mutations closer to the carboxyl end resulting in a more severe phenotype than mutations near the amino terminal end of the chain.[6] However, there are many exceptions to these rules. Because the collagen triple helix is not a uniform structure and exhibits regional differences in its stability and ability to accommodate mutations, a regional model has been postulated for the relationship of genotype to phenotype.[7] Examination of the lethal clusters regularly occurring along the a2 chain revealed a striking alignment with the binding regions of proteoglycans. The genetic background and modifier genes as well as environmental or epigenetic factors may affect the expression of phenotype.

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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