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Some of the most common conditions that are transmitted genetically in families are disorders that produce clinically obvious changes in the skeleton, skin, or other relatively acellular tissues 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 last several decades, many of the disorders have been linked to mutations in several hundred different genes expressed in connective tissues. However, classifying the disorders on the basis of either their clinical presentations or the mutations causing them is continuing to present a challenge for both the clinician and the molecular biologist.

The 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 over-shadowed 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 re-classified several times and each has been divided into a series of sub-types. The task was daunting. For example, a recent effort to classify all the heritable disorders that alter the skeleton defined 436 distinctive conditions that were divided into 42 major groups.

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, the most abundant protein in bones, skin, tendons and several other tissues. Some of the first assays in patients with osteogenesis imperfecta (OI) revealed mutations in Type I collagen genes. And biochemical data developed primarily with cultures of skin fibroblasts from the patients demonstrated that the mutations dramatically altered the synthesis or 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 hyper-extensible skin, in some patients with dwarfism, and in patients with other disorders, including some such ...

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