Elastin disorders

Coacervation occurs in tropoelastin solutions and is a precursor event in the assembly of elastin nanofibrils [42]. This phenomenon is thought to be mainly due to the interaction between hydro-phobic domains of tropoelastin. In scanning electron microscopy (SEM) picmres, nanofibril stmc-tures are visible in coacervate solutions of elastin-based peptides [37,43]. Indeed, Wright et al. [44] describe the self-association characteristics of multidomain proteins containing near-identical peptide repeat motifs. They suggest that this form of self-assembly occurs via specific intermolecular association, based on the repetition of identical or near-identical amino acid sequences. This specificity is consistent with the principle that ordered molecular assembhes are usually more stable than disordered ones, and with the idea that native-like interactions may be generally more favorable than nonnative ones in protein aggregates. 

Pometun, M.S., Chekmenev, E.Y., and Wittebort, R.J., Quantitative observation of backbone disorder in native elastin, J. Biol. Chem., 279, 7982-7987, 2004. 

Deletions in the elastin gene (located at 7qll.23) have been found in approximately 90% of subjects with Williams syndrome, a developmental disorder affecting connective tissue and the central nervous system. The mutations, by affecting synthesis of elastin, probably play a causative role in the supravalvular aortic stenosis often found in this condition. A number of skin diseases (eg, scleroderma) are associated with accumulation of elastin. Fragmentation or, alternatively, a decrease of elastin is found in conditions such as pulmonary emphysema, cutis laxa, and aging of the skin. 

Correct answer = B. o1-Antitrypsin deficiency is a genetic disorder that can cause pulmonary emphysema even in the absence of cigarette use. An deficiency of a1-antitrypsin permits increased elastase activity to destroy elastin in the alveolar walls, even in nonsmokers. a1-antitrypsin deficiency should be suspected when chronic obstructive pulmonary disease develops in a patient younger than 45 years who does not have a history of chronic bronchitis or tobacco use, or when multiple family members develop obstructive lung disease at an early age. 

Cardiovascular Disorders and Copper. Sudden cardiac failure has been associated with copper deficiency (91J. There are two attractive mechanisms. First, the coronary arteries and aorta may become weakened from an inability to synthesize elastin due to a decrease in lysyl oxidase activity. Rupture of these major blood vessels has been shown to cause sudden death in animals suffering from copper deficiency. Second, a decrease in cytochrome oxidase activity during copper deficiency Impairs aerobic metabolism of the heart and increases the risk of hypertrophy. Hypertrophy, which may lead to high output congestive heart failure, is exacerbated by hypochromic anemia also caused by copper deficiency. 

In particular, excessive proteolysis of elastin by HLE has been implicated in pulmonary emphysema [19]. In this case, the imbalance appears to result from reduced levels of active extracellular alpha,-proteinase inhibitor (a,-PI), the primary plasma inhibitor of HLE. This decrease is caused either by a genetic disorder (PiZZ phenotype individuals) or by reduction in the elastase inhibitory capacity (EIC) of ai-PI due to its oxidative inactivation by tobacco smoke [20]. The detailed evidence supporting the potential role of elastase in the development of emphysema has been extensively reviewed [21] and will not be repeated here. The fact that HLE is also a potent secretagogue [22] may play a role in several disease states, including cystic fibrosis [23], chronic bronchitis [24], and acute respiratory distress syndrome (ARDS) [25]. The mechanism of the secretagogue activity is not known, but, since the HLE-induced secretion can be blocked by specific HLE inhibitors, it appears to require catalytic activity by the enzyme [26]. 

Early effects are gastrointestinal upsets and, more characteristically, loss of taste. Although a fall in the number of platelets is common, serious thrombocytopenia is less frequent. After long-term use of high doses, skin collagen and elastin are impaired, resulting in increased friability and sometimes in disorders such as perforating elastoma or cutis laxa the latter has also been observed in neonates. 

When penicillamine is administered for a long time and in high doses (for example for Wilson s disease) it can cause a characteristic delayed skin eruption, with increased friability, hemorrhagic bullous lesions, and miliary papules (66,260-266). The lesions develop predominantly in those parts of the skin that are often exposed to trauma. This disorder is a manifestation of the effects of penicillamine on collagen and elastin. Occasionally, these eruptions imitate other rare... 

Since all copper-dependent enzymes and metabolism are affected, biosynthesis of elastin and collagen is defective. Menkes victims usually die before 3 years of age, frequently from neurodegenerative defects or connective tissue disorders (Danks 1989). Identification of the Menkes gene or the Wilson s gene will not provide a cure. However, as with other hereditary diseases, early diagnosis gives promise for a major reduction in the frequencies of these diseases. 

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