Molecular genetics of Marfan syndrome and Ehlers-Danlos type IV

Two inherited disorders of connective tissue have major cardiovascular complications, Marfan syndrome and Ehlers-Danlos syndrome type IV. Major progress has been made toward understanding both the genetic defect and the molecular pathogenesis of these two disorders. Marfan syndrome results from mutations in the FBN1 gene, which encodes fibrillin-1, an extracellular matrix component found in structures called microfibrils. Histologic characterization of the effect of FBN1 mutations on fibrillin-1 cellular processing and microfibril formation has provided insights into fibrillin-1 function. Ehlers-Danlos syndrome type IV results from mutations in the COL3A1 gene, which encodes the polypeptides in type III collagen. Despite advances in the molecular genetics of these two disorders, there is not a molecular diagnostic test for these syndromes based on the identification of gene mutations. Marfan syndrome remains primarily a clinical diagnosis. Biochemical analysis of the amount of type III collagen produced by dermal fibroblasts has proven to be a powerful diagnostic test for Ehlers-Danlos syndrome type IV.