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EDS Type * Clinical Findings Inheritance Gene DefectsClassical (I/II) Skin and joint hypermobility, atrophic scars, easy bruising Autosomal dominant COL5A1, COL5A2 Hypermobility (III) Joint hypermobility, pain, dislocations Autosomal dominant Unknown Vascular (IV) Thin skin, arterial or uterine rupture, bruising, small joint hyperextensibility Autosomal dominant COL3A1 Kyphoscoliosis (VI) Hypotonia, joint laxity, congenital scoliosis, ocular fragility Autosomal recessive Lysyl-hydroxylase Arthrochalasia (VIIa,b) Severe joint hypermobility, skin changes mild, scoliosis, bruising Autosomal dominant COL1A1, COL1A2 Dermatosparaxsis (VIIc) Severe skin fragility, cutis laxa, bruising Autosomal recessive Procollagen N-peptidase *EDS were previously classified by Roman numerals. Parentheses show previous numerical equivalents. deficiency of lysyl hydroxylase results in the synthesis of collagen that lacks normal structural stability. The vascular type of EDS results from abnormalities of type III collagen. This form is genetically heterogeneous because at least three distinct types of mutations affecting the COL3A1 gene for collagen type III can give rise to this variant. Some affect the rate of synthesis of pro a1 (III) chains, others affect the secretion of type III procollagen, and still others lead to the synthesis of structurally abnormal type III collagen. Some mutant alleles behave as dominant negatives (see discussion under autosomal dominant disorders) and thus produce severe phenotypic effects. These molecular studies provide a rational basis for the pattern of transmission and clinical features that are characteristic of this variant. First, because vascular type EDS results from mutations involving a structural protein (rather than an enzyme protein), an autosomal dominant pattern of inheritance would be expected. Second, because blood vessels and intestines are known to be rich in collagen type III, an abnormality of this collagen is consistent with severe defects (e.g., spontaneous rupture) in these organs. In two forms of EDS—arthrochalasia type and dermatosparaxis type—the fundamental defect is in the conversion of type I procollagen to collagen. This step in collagen synthesis involves cleavage of noncollagen peptides at the N-terminal and C-terminal of the procollagen molecule. This is accomplished by N-terminal-specific and C-terminal-specific peptidases. The defect in the conversion of procollagen to collagen in the arthrocalasic type has been traced to mutations that affect one of the two type I collagen genes, COL1A1 and COL1A2. As a result, structurally abnormal pro a1 (I) or pro a2 (I) chains that resist cleavage of N-terminal peptides are formed. In patients with a single mutant allele, only 50% of the type I collagen chains are abnormal, but because these chains interfere with the formation of normal collagen helices, heterozygotes manifest the disease. By contrast, the related dermatosparaxis type is caused by mutations in the procollagen-N-peptidase genes, essential for the cleavage of collagens. In this case, the enzyme deficiency leads to an autosomal recessive form of inheritance. Finally, the classical type of EDS is worthy of brief mention, since molecular analysis of the variant suggests that genes other than collagen genes may be involved in the pathogenesis of EDS. In 30% to 50% of these cases, mutations in the genes for type V collagen (COL5A1 and COL5A1) have been detected. Surprisingly, despite a phenotype typical of EDS, no other collagen gene abnormalities have been found in these cases. This has led to the speculation that other proteins in the extracellular matrix, such as tenascin-X, may also be involved in regulating collagen synthesis. To summarize, the common thread in EDS is some abnormality of collagen. These disorders, however, are extremely heterogeneous. At the molecular level, a variety of defects, varying from mutations involving structural genes for collagen to those involving enzymes that are responsible for post-transcriptional modifications of mRNA, have been detected. Such molecular heterogeneity results in the expression of EDS as a clinically heterogeneous disorder with several patterns of inheritance. Date: 2016-04-22; view: 720
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