elastin and Ehlers-Danlos-Syndrome

1. Arterial stiffness, which has independent predictive value for cardiovascular events, seems to have a genetic component, largely independent of the influence of blood pressure and other cardiovascular risk factors. 2. In animal models of essential hypertension (stroke-prone spontaneously hypertensive rats and spontaneously hypertensive rats), structural modifications of the arterial wall include an increase in the number of elastin-smooth muscle cell connections and smaller fenestrations of the internal elastic lamina, possibility leading to redistribution of the mechanical load towards elastic materials. These modifications may give rise to mechanisms explaining why changes in arterial wall material accompanying wall hypertrophy in these animals are not associated with an increase in arterial stiffness. 3. In monogenic connective tissue diseases (Marfan, Williams and Ehlers-Danlos syndromes) and the corresponding animal models, precise characterization of the arterial phenotype makes it possible to determine the influence of abnormal, genetically determined, wall components on arterial stiffness. 4. Such studies have highlighted the role of extracellular matrix signalling in the vascular wall and have shown that elastin and collagen not only display elasticity or rigidity, but are also involved in the control of smooth muscle cell function. 5. These data provide strong evidence that arterial stiffness is affected by the amount and density of stiff wall material and the spatial organization of that material.

Topics: Animals; Arteries; Cardiovascular Diseases; Collagen; Compliance; Disease Models, Animal; Ehlers-Danlos Syndrome; Elastin; Extracellular Matrix; Gene Expression Profiling; Genetic Predisposition to Disease; Humans; Hypertension; Marfan Syndrome; Oligonucleotide Array Sequence Analysis; Polymorphism, Genetic; Risk Factors; Tunica Intima; Tunica Media; Williams Syndrome

Tenascin-X is an extracellular matrix protein initially identified because the gene encoding it overlaps with the human CYP21B gene. Because studies of gene and protein function of other tenascins had been poorly predictive of essential functions in vivo, we used a genetic approach that critically relied on an understanding of the genomic locus to uncover an association between inactivating tenascin-X mutations and novel recessive and dominant forms of Ehlers-Danlos syndrome (EDS). Tenascin-X provides the first example of a gene outside of the fibrillar collagens and their processing enzymes that causes EDS. Tenascin-X null mice recapitulate the skin findings of the human disease, confirming a causative role for this gene in EDS. Further evaluation of these mice showed that tenascin-X is an important regulator of collagen deposition in vivo, suggesting a novel mechanism of disease in this form of EDS. Further studies suggest that tenascin-X may do this through both direct and indirect interactions with the collagen fibril. Recent studies show that TNX effects on matrix extend beyond the collagen to the elastogenic pathway and matrix remodeling enzymes. Tenascin-X serves as a compelling example of how human "experiments of nature" can guide us to an understanding of genes whose function may not be evident from their sequence or in vitro studies of their encoded proteins.

Topics: Adult; Animals; Collagen; Ehlers-Danlos Syndrome; Elastin; Female; Genes, Recessive; Humans; Joints; Male; Mice; Mice, Transgenic; Middle Aged; Mutation; Tenascin

Supravalvular aortic stenosis (SVAS), Marfan syndrome (MFS) and Ehlers-Danlos syndrome type IV (EDS IV) are three clinical entities characterized by vascular abnormalities that result from mutations of structural components of the extracellular matrix (ECM). Analyses of naturally occurring human mutations and of artificially generated deficiencies in the mouse have provided insights into the pathogenesis of these heritable disorders of the connective tissue. SVAS is associated with haploinsufficiency of elastin, one of the two major components of the elastic fibers. SVAS is characterized by narrowing of the arterial lumen due to the failure of regulation of cellular proliferation and matrix deposition. Mutations in fibrillin 1 are the cause of dissecting aneurysm leading to rupture of the ascending aorta. Fibrillin-1 is the building block of the microfibrils that span the entire thickness of the aortic wall and are a major component of the elastic fibers that reside in the medial layer. The vascular hallmark of EDS IV is rupture of large vessels. The phenotype is caused by mutations in type III collagen. The mutations ultimately affect the overall architecture of the collagenous network and the biomechanical properties of the adventitial layer of the vessel wall. Altogether, these genotype-phenotype correlations document the diversified contributions of distinct extracellular macroaggregates to the assembly and function of the vascular matrix.

Topics: Animals; Aortic Stenosis, Supravalvular; Blood Vessels; Collagen; Ehlers-Danlos Syndrome; Elastin; Extracellular Matrix; Extracellular Matrix Proteins; Fibrillin-1; Fibrillins; Humans; Marfan Syndrome; Mice; Microfibrils; Microfilament Proteins; Mutation; Vascular Diseases

The recent progress made in understanding the normal biology and biochemistry of the extracellular matrix of human skin has allowed us to identify several different levels at which errors could be introduced into the structure and metabolism of collagen or elastin, the two major fibrillar components of the dermis. Currently, several heritable cutaneous diseases are known to display distinct collagen or elastin abnormalities. This article reviews some of the heritable cutaneous diseases and highlights those entities in which definite information on molecular alterations in collagen or elastin is available.

Topics: Adult; Collagen; Collagen Diseases; Cutis Laxa; Ehlers-Danlos Syndrome; Elastin; Fibroma; Humans; Male; Osteopoikilosis; Osteosclerosis; Pedigree; Skin Diseases; Skin Neoplasms

Several inherited syndromes characterized by abnormal elastic fibers decreased in number and size could be collected under the heading of inherited elastolysis. This morphological concept does not prejudge the causal mechanisms of the elastolysis involving dermis and/or other organs. The elastic fibers anomalies result mainly from elastin crosslinking defects, developmental disturbances or excessive proteolysis.

Topics: alpha 1-Antitrypsin Deficiency; Ehlers-Danlos Syndrome; Elastin; Homocystinuria; Humans; Marfan Syndrome; Menkes Kinky Hair Syndrome; Skin; Skin Diseases

Topics: Animals; Cells, Cultured; Ceruloplasmin; Collagen; Copper; Cutis Laxa; Ehlers-Danlos Syndrome; Elastin; Hepatolenticular Degeneration; Humans; Liver; Menkes Kinky Hair Syndrome; Mice; Protein-Lysine 6-Oxidase

Topics: Collagen; Connective Tissue Diseases; Cutis Laxa; Ehlers-Danlos Syndrome; Elastin; Fibronectins; Humans; Marfan Syndrome; Metabolism, Inborn Errors; Osteogenesis Imperfecta; Prenatal Diagnosis; Proteoglycans; Skin

The elastic fibers present in various connective tissues of the body are responsible for physiologic elasticity of the organs. These fibers consist of 2 distinct components, elastin and the elastic fiber microfibrils. Controlled synthesis and balanced interaction of these 2 components are essential for normal fibrillogenesis. The intracellular biosynthesis of elastin by connective tissue cells, such as smooth muscle cells, involves assembly of the polypeptide chains on the membrane-bound ribosomes, hydroxylation of some prolyl residues to hydroxyproline, and secretion of the polypeptides packaged in Golgi vacuoles. In the extracellular space the elastin molecules assemble into fiber structures which are stabilized by the synthesis of complex covalent cross-links, desmosines. Recently, aberrations in the structure or metabolism of elastin have been detected in a variety of heritable and acquired diseases affecting skin and other connective tissues. These conditions include pseudoxanthoma elasticum, cutis laxa, and elastosis perforans serpiginosa, as well as arteriosclerosis and other degenerative changes of the vascular connective tissues.

Topics: Amino Acids; Arteriosclerosis; Chemical Phenomena; Chemistry; Collagen Diseases; Connective Tissue; Contractile Proteins; Cutis Laxa; Desmosine; Ehlers-Danlos Syndrome; Elastic Tissue; Elastin; Female; Glycoproteins; Humans; Hydroxyproline; Marfan Syndrome; Menkes Kinky Hair Syndrome; Muscle Proteins; Pancreatic Elastase; Peptide Biosynthesis; Protein Precursors; Pseudoxanthoma Elasticum; X Chromosome

It is apparent that significant progress has been made in our understanding of the biosynthesis, modifications, and maturation of collagen and elastin. We now recognize and partially understand special reactions involved in hydroxylations within the cell and complex cross-linking processes occurring outside the cell. Recent experiments (191) have shown that in human diploid fibroblast cultures of limited doubling potential (191) the hydroxylation of collagen prolyl residues appears to be "age" or passage-level dependent. With increasing passage level of these cultures, both the ascorbate requirements and the extent of collagen hydroxylation decrease. "Young" cell cultures have a strong requirement for complete hydroxylation and without ascorbate there is only about 50% of the normal level. "Middle-aged" cultures show higher hydroxylation without and full hydroxylation with ascorbate, whereas "old" (or cultures close to "senescence") are incapable of full hydroxylation with or without ascorbic acid. Although the overall system may show some deterioration with increasing passage levels, it appears that with increasing passage levels other components in the cell replace the ascorbate dependence of the hydroxylase system to a greater exten. In some ways, aging WI-38 cultures begin to resemble some transformed cells in their biochemical reactions, although they continue to remain diploid and eventually lose the ability to replicate. It is not yet known whether old animals can produce collagen, which may now be underhydroxylated, perhaps contributing to certain senescent changes. Careful examination of the hydroxylation index of collagen produced in organoid cultures of tissue biopsies as a function of donor age might be informative, particularly if one looks at the quality of collagen by employing collagenase and other proteolytic digests with collagen (191). One could comare the levels of frequent and characteristic peptide triplet sequences such as Gly-Pro-Hyp to Gly-Pro-Pro, Gly-Ala-Hyp to Gly-Ala-Pro, or Gly-Pro-Hyl to Gly-Pro-Lys and others for evaluation of hydroxylation throughout the entire molecule or at selected sequences.

Topics: Amino Acid Sequence; Animals; Antibody Specificity; Ascorbic Acid; Collagen; Connective Tissue; Copper; Ehlers-Danlos Syndrome; Elastin; Epitopes; Homocystinuria; Humans; Hydralazine; Lathyrism; Marfan Syndrome; Molecular Conformation; Platelet Aggregation; Procollagen-Proline Dioxygenase; Skin Diseases; Syndrome

Topics: Animals; Basement Membrane; Cattle; Collagen; Connective Tissue; Ehlers-Danlos Syndrome; Elastin; Epidermolysis Bullosa; Fibroblasts; Glycopeptides; Humans; Keloid; Lysine; Marfan Syndrome; Metabolism, Inborn Errors; Microbial Collagenase; Mixed Function Oxygenases; Progeria; Protein Biosynthesis; Pseudoxanthoma Elasticum; Wound Healing

Arterial tortuosity syndrome (ATS) is a rare autosomal recessive disease characterized by elongation and tortuosity of the large- and medium-sized arteries. ATS patients display features that are also found in Ehlers-Danlos syndrome (EDS) patients. ATS is caused by pathogenic mutations in the SLC2A10 gene, which encodes for the glucose transporter, GLUT10. This study aimed at examining the ultrastructure of skin for abnormalities that can explain the loose skin and arterial phenotypes of Arab patients with the p.S81R mutation in SLC2A10. Forty-eight patients with SLC2A10 mutation were recruited for this study. Skin biopsy specimens from three children with ATS and a healthy child were examined by electron microscopy to determine the ultrastructure of collagen and elastin. Histopathologic staining of sections from tissue biopsy specimens was also performed. Large spaces were observed among the collagen fibrils in the skin biopsy specimens obtained from ATS patients, suggesting disorganization of the collagen structures. Furthermore, elastin fiber contents and their thickness are reduced in the skin. In small muscular arteries in the skin from ATS patients, discontinuous internal elastic lamina, lack of myofilaments, and disorganized medial smooth muscle cells with vacuolated cytoplasm are present. The disorganization of collagen fibrils and reduced elastin contents in the skin may explain the loose skin phenotype of ATS patients similar to the EDS patients. The lack of elastin in small muscular arteries may have contributed to the development of arterial tortuosity in these patients.

Topics: Arabs; Arteries; Collagen; Ehlers-Danlos Syndrome; Elastin; Humans; Joint Instability; Skin Diseases, Genetic; Vascular Malformations

Ehlers-Danlos syndrome (EDS) is the name for a heterogenous group of rare genetic connective tissue disorders with an overall incidence of 1 in 5000. The histological characteristics of EDS have been previously described in detail in the late 1970s and early 1980s. Since that time, the classification of EDS has undergone significant changes, yet the description of the histological features of collagen morphology in different EDS subtypes has endured the test of time. Nonlinear microscopy techniques can be utilized for non-invasive in vivo label-free imaging of the skin. Among these techniques, two-photon absorption fluorescence (TPF) microscopy can visualize endogenous fluorophores, such as elastin, while the morphology of collagen fibers can be assessed by second-harmonic generation (SHG) microscopy. In our present work, we performed TPF and SHG microscopy imaging on ex vivo skin samples of one patient with classical EDS and two patients with vascular EDS and two healthy controls. We detected irregular, loosely dispersed collagen fibers in a non-parallel arrangement in the dermis of the EDS patients, while as expected, there was no noticeable impairment in the elastin content. Based on further studies on a larger number of patients, in vivo nonlinear microscopic imaging could be utilized for the assessment of the skin status of EDS patients in the future.

Topics: Collagen Type III; Collagen Type V; Connective Tissue; Ehlers-Danlos Syndrome; Elastin; Female; Humans; Middle Aged; Nonlinear Optical Microscopy; Pedigree; Protein Conformation; Skin

Tenascin-X (TNX) is a large 450 kDa extracellular matrix protein expressed in a variety of tissues including skin, joints and blood vessels. Deficiency of TNX causes a recessive form of Ehlers-Danlos syndrome characterized by joint hypermobility, skin fragility and hyperextensible skin. Skin of TNX deficient patients shows abnormal elastic fibers and reduced collagen deposition. The mechanism by which TNX deficiency leads to connective tissue alterations is unknown. Here we report that C-terminal domains of human TNX bind to major dermal fibrillar collagens and tropoelastin. We have mapped these interactions to the fibronectin type III repeat 29 (FNIII29) and the C-terminal fibrinogen domain (FbgX) of TNX. In addition we found that FNIII29 of TNX accelerates collagen fibrillogenesis in vitro. We hypothesize that TNX contributes to matrix stability and is possibly involved in collagen fibril formation.

Topics: Animals; Cattle; Ehlers-Danlos Syndrome; Elastin; Extracellular Matrix; Fibrillar Collagens; Humans; Recombinant Proteins; Tenascin

Two Turkish sibs with clinical features of Ehlers-Danlos syndrome type VI-B are presented. The hydroxylysine contents of dermis and gel electrophoresis of type I and type III collagen produced by fibroblasts were normal. Ultrastructural studies of skin collagen and elastic fibers showed discrete abnormalities. Other syndromes with similar clinical, biochemical and ultrastructural features are discussed.

Topics: Child, Preschool; Collagen; Diagnosis, Differential; Ehlers-Danlos Syndrome; Elastin; Eye Abnormalities; Female; Fibroblasts; Humans; Hydroxylysine; Infant; Joint Instability; Male; Pedigree; Sclera; Scoliosis; Skin

Occipital horn syndrome (OHS, Ehlers-Danlos syndrome type IX) belongs to the category of the copper metabolism disorders and is at present being investigated biochemically as is Menkes' disease. Unlike Menkes' disease, most patients with OHS have mild submentality. We report a case of OHS with severe central nervous system involvement and muscular atrophy in a 34-year-old male. He had psychomotor retardation and seizures since early childhood and now presented severe mental retardation and generalized muscular atrophy in addition to characteristic facial appearance, hyperelasticity of the skin and joint subluxation. Laboratory investigations revealed a low serum copper and ceruloplasmin level as well as intestinal non-absorption of copper. Radiographic imaging showed occipital exostoses, bladder diverticula, tortuosity of the peripheral vein and osteoporosis of the skeletal bones. The activity of lysyl oxidase, a copper-enzyme involved in cross-link formation in collagen, was found to be decreased in a skin-biopsy specimen. Electron-microscopic investigation of a muscle biopsy showed irregularity of the myofibrillar network and accumulation of concentric laminated bodies in the subsarcolemmal regions.

Topics: Adult; Atrophy; Calcium; Ceruloplasmin; Copper; Dopamine beta-Hydroxylase; Ehlers-Danlos Syndrome; Elastin; Electron Transport Complex IV; Humans; Lysine; Male; Monoamine Oxidase; Muscles; Occipital Lobe; Protein-Lysine 6-Oxidase; Radiography; Skin

Ehlers-Danlos Syndrome is a rare hereditary connective tissue disorder produced by collagen abnormalities. The Type IV variant causes vascular rupture in the second and third decades. Definitive diagnosis at present is based on demonstrating a deficiency of Type III collagen or procollagen chemically or in fibroblast cultures. Both require fresh tissue. We have shown in fixed autopsy tissue that the elastin in two EDS IV patients appears accordion-pleated with a high waviness index (WI) of 1.58 +/- 0.028 (n = 90) compared to 1.35 +/- 0.08 (n = 446) for 21 controls aged 9 to 71. The WI is the ratio of the length of elastin in the internal elastic lamina to the circumference. The group were significantly different statistically (p less than 0.01) with a randomized block design analysis. Vessel size and age did not alter the WI in either controls or patients. There was significant overlap of data points between the two groups so that no conclusions can be drawn on individual vessels. However, if the waviness index is greater than 1.8, the vessels are unlikely to be normal. We did not study patients with other connective tissue diseases. The WI may be a useful qualitative guide of abnormality in a retrospective study if the diagnosis of Ehlers-Danlos Type IV is entertained.

Topics: Adolescent; Adult; Aged; Aging; Arteries; Blood Vessels; Child; Ehlers-Danlos Syndrome; Elastin; Female; Humans; Middle Aged

The connective tissue of a lethal EDS IV case was investigated for the reasons of the manifested disturbances of the arterial wall. This functional disorder was attributed to the mechanical decoupling of elastin and collagen, with the premise of a composite material consisting of cellular, fibrillar, lamellar and other matrix components. A conceivable relation between the manifested deficiency of type III collagen and a disturbed anchoring of elastin is shown. These findings are supported by biochemical, morphological, x-ray and mechanical data.

Topics: Adult; Aorta; Biomechanical Phenomena; Collagen; Connective Tissue; Cyanogen Bromide; Ehlers-Danlos Syndrome; Elastin; Electrophoresis, Polyacrylamide Gel; Humans; Hydroxyproline; Macromolecular Substances; Male; Microscopy, Electron; Peptide Fragments; Tendons; X-Ray Diffraction

Topics: Connective Tissue Diseases; Ehlers-Danlos Syndrome; Elastic Tissue; Elastin; Humans; Pseudoxanthoma Elasticum

Topics: Amino Acid Oxidoreductases; Aminopropionitrile; Animals; Carbon Isotopes; Cartilage; Cells, Cultured; Chickens; Collagen; Culture Media; Ehlers-Danlos Syndrome; Elastin; Fibroblasts; Humans; Lysine; Marfan Syndrome; Procollagen-Proline Dioxygenase; Proline; Skin; Tritium

Topics: Adult; Collagen; Connective Tissue; Ehlers-Danlos Syndrome; Elastic Tissue; Elastin; Histocytochemistry; Humans; Lysine; Male; Microscopy, Electron; Renal Artery; Rupture, Spontaneous; Skin; Vascular Diseases

Topics: Adolescent; Adult; Amino Acids; Child; Ehlers-Danlos Syndrome; Elastin; Female; Humans; Skin

Topics: Animals; Arteriosclerosis; Cattle; Clinical Enzyme Tests; Dogs; Edetic Acid; Ehlers-Danlos Syndrome; Elastin; Electrophoresis; Enzyme Inhibitors; Geriatrics; Glycoproteins; Guinea Pigs; Haplorhini; Horses; Meat; Mice; Pancreatic Elastase; Peptide Hydrolases; Poultry; Rabbits; Rats; Research; Serum Globulins; Sheep; Sheep, Domestic; Swine