elastin and Genetic-Diseases--Inborn

Abdominal aortic aneurysms have usually been characterized as atheroslcerotic, but this view of their pathogenesis is a restricted one. As yet, no unified concept of pathogenesis has emerged, bat several factors appear to have an important role, including familial clustering, genetically determined and acquired biochemical alterations in the structural matrix of the aortic wall and bemodynamic mechanical factors. We review literature data concerning new pathogenic concepts of abdominal aortic aneurysms and particularly familial predisposition. Ultrasonographic screening is recommended in brothers (50 years) of patients with aneurysms of the abdominal aorta.

Topics: Aortic Aneurysm, Abdominal; Elastin; Genetic Diseases, Inborn; Humans

Elastic fibers form a network that contributes to the elasticity and resilience of tissues such as the skin. Histopathologic and ultrastructural abnormalities in the elastic fibers have been observed in several diseases of the skin and other tissues. Recent cloning of several genes involved in elastic fiber architecture has lead to the approach of the study of elastic fiber genodermatoses through molecular analysis. However, in genodermatoses, such as pseudoxanthoma elasticum, many of the genes encoding elastic fiber components have been excluded by genetic linkage analysis. In recent years, mutations in several of the genes encoding elastic fiber proteins have been demonstrated in other diseases. These include mutations in the fibrillin 1 gene in the Marfan syndrome, and genetic linkage of congenital contractural arachnodactyly to fibrillin 2, and, most recently, demonstration of abnormalities in the Menkes syndrome gene in X-linked cutis laxa. The first disorders to involve mutations in the elastin gene itself are, surprisingly, cardiovascular and neurobehavioral disorders, such as supravalvular aortic stenosis and Williams syndrome. These findings suggest that additional, as yet undiscovered, components of the elastic fiber network in the skin may hold the key to unraveling the molecular basis of the elastin-related genodermatoses.

Topics: DNA, Recombinant; Elastic Tissue; Elastin; Gene Expression Regulation; Genes; Genetic Diseases, Inborn; Genetic Linkage; Humans; Molecular Biology; Polymorphism, Genetic; Skin Diseases

The elastic properties of many tissues such as the lung, dermis, and large blood vessels are due to the presence of elastic fibers in the extracellular space. These fibers have been shown by biochemical and ultrastructural analysis to be comprised of two distinct components, a more abundant amorphous component and the microfibrillar component. The microfibrillar component is found in 10- to 12-nm fibrils which are located primarily around the periphery of the amorphous component but, to some extent, interspersed within it. The protein, elastin, makes up the highly insoluble amorphous component and is responsible for the elastic properties. Elastin is found throughout the vertebrate kingdom except for very primitive fish and possesses an unusual chemical composition consonant with its characteristic physical properties. Elastin is composed largely of glycine, proline, and other hydrophobic residues and contains multiple lysine-derived cross-links, such as the desmosines, which link the individual polypeptide chains into a rubber-like network. The intervening, hydrophobic regions of the polypeptide chains between the cross-links are highly mobile, and the elastic properties of the fibers can be described in terms of the theory of rubber elasticity. Recent application of recombinant DNA techniques has led to further understanding of the structure of elastin. Analyses of the bovine and human elastin genes have demonstrated that the hydrophobic and cross-linking domains are encoded in separate exons. These exons tend to be small, varying from 27 to 114 base pairs, and are separated by large intervening sequences. Furthermore, DNA sequence analysis has demonstrated that the elastin molecule contains two cysteine residues which were not previously identified near the carboxy terminus and which may be important in the interaction of elastin with other extracellular matrix proteins. Further DNA sequencing should determine the complete amino acid sequence of elastin. Biosynthetic studies and in vitro translation of elastin mRNA have demonstrated that a 72,000-dalton polypeptide, designated tropoelastin, is the initial translation product. Analysis of several developing systems has demonstrated that elastin synthesis is controlled by the level of elastin mRNA. After packaging into membrane-bound vesicles in the Golgi apparatus, tropoelastin is secreted by exocytosis into the extracellular space where it is cross-linked by a copper-requiring extracellular enzyme, lys

Topics: Amino Acid Sequence; Amino Acids; Animals; Aorta; Base Sequence; Biological Evolution; Bone Diseases; Chemical Phenomena; Chemistry; Cutis Laxa; DNA; Elastin; Genes; Genetic Diseases, Inborn; Humans; Lung Diseases, Obstructive; Macromolecular Substances; Marfan Syndrome; Microscopy, Electron; Protein-Lysine 6-Oxidase; Pseudoxanthoma Elasticum; RNA, Messenger; Species Specificity; Syndrome; Tropoelastin; Vascular Diseases