Classical Ehlers-Danlos syndrome (EDS) is a heritable connective tissue disorder, characterized by skin hyper extensibility, widened atrophic scars, and hypermobility of small and large joints. It exhibits genetic heterogeneity, with alterations in the COL5A1, COL5A2 (components of type V collagen), COL1A1, COL1A2 (components of type I collagen), and TNXB (tenascin X) genes resulting in the phenotype. In addition, there is allelic heterogeneity since multiple mutations have been identified in all of the above genes, except for COL1A1. The work outlined in this proposal will enhance the current understanding of the clinical and molecular bases of classical EDS by a) systematically determining the relative contribution of mutations in COL5A1, COL5A2, TNX, COL1A1, and COL1A2 to the classical EDS phenotype; b) identifying genotype phenotype correlations that result from genetic heterogeneity and allelic heterogeneity in individuals with the classical EDS phenotype; and c) identifying polymorphic variants in the COL5A1 and COL5A2 genes, and identifying individuals with them in cis- and trans- to the primary mutation to determine the phenotypic consequences of these vadants (genetic modifiers). Additional experiments will address how mutations in the type V collagen genes alter fibrillogenesis and affect the ability of type V collagen to cross-link to type I collagen in the fibrils of connective tissue. Lastly, the differential use of COL5A1 exons 64A and 64B will be examined both during development and in different tissues, and the influence of exon choice on chain selection for collagen trimer formation bill be evaluated. Knowledge of how alterations within the genes involved in classical EDS affect the resulting phenotype will allow clinicians to predict the complications for which an affected individual is at greatest risk. This will enable medical care to be tailored to the individual's needs, potentially avoiding unnecessary tests and evaluations. Genotype-phenotype correlations will be useful in identifying risk factors for such medical problems as aortic aneurysms and degenerative joint disease.
|Mitchell, Anna L; Judis, LuAnn M; Schwarze, Ulrike et al. (2012) Characterization of tissue-specific and developmentally regulated alternative splicing of exon 64 in the COL5A1 gene. Connect Tissue Res 53:267-76|
|Mitchell, Anna L; Schwarze, Ulrike; Jennings, Jessica F et al. (2009) Molecular mechanisms of classical Ehlers-Danlos syndrome (EDS). Hum Mutat 30:995-1002|