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CLASSIFICATION OF CONNECTIVE TISSUE DISORDERS

Some of the most common conditions that are transmitted genetically in families are disorders that produce clinically obvious changes in the bone, cartilage, skin, or relatively acellular tissues such as tendons that have been loosely defined as connective tissues. Because of their heritability, some of the disorders were recognized as potentially traceable to mutated genes soon after the principles of genetics were introduced into medicine by Garrod and others. About half a century later, McKusick emphasized the specificity of many of the diseases for selective connective tissues and suggested that they were probably caused by mutations in genes coding for the major proteins found in those tissues. In the past several decades, mutations in several hundred different genes expressed in connective tissues have been identified as the cause of many connective tissue disorders. However, classifying the disorders on the basis of either their clinical presentations or the mutations causing them continues to present a challenge for both the clinician and the molecular biologist.

Information on the disorders has continued to develop on two levels. The initial clinical classifications suggested by McKusick and many others had to be refined as more patients were examined. For example, some patients had skin changes similar to those commonly seen in Ehlers-Danlos syndrome (EDS), but this feature was overshadowed by other features such as extreme hypotonia or sudden rupture of large blood vessels. To account for the full spectrum of presentations in patients and families, many of the disorders have been reclassified several times, dividing each into a series of subtypes.

The identification of mutations causing the diseases has developed on a parallel track. The first genes cloned for connective tissues were the two genes coding for type I collagen (COL1A1 and COL1A2), the most abundant protein in bones, skin, tendons, and several other tissues. This facilitated early studies in patients with osteogenesis imperfecta (OI) that revealed mutations in type I collagen genes. Biochemical data, developed primarily with cultures of skin fibroblasts from affected individuals, demonstrated that the mutations dramatically altered the synthesis of collagen α-chains or the structure of collagen fibers. The results stimulated efforts to identify additional mutations in genes coding for structural proteins. Genes for collagens provided an attractive paradigm to search for mutations, since a series of different types of collagens were found in different connective tissues and the collagen genes were readily isolated by their unique signature sequences. Also, the collagen genes were vulnerable to a large number of different mutations because of unusual structural requirements of the protein. The search for mutations in collagen genes proved fruitful in that mutations were found in most patients with OI, in many patients with hyperextensible skin and hypermobile joints, in some patients with dwarfism, and in patients with other disorders, including some such as Alport syndrome (AS) that were not initially classified as disorders of connective tissue. Also, mutations in collagen ...

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