The Ehlers-Danlos syndrome (EDS) are a group of biochemically and genetically distinct connective tissue disorders characterized by abnormalities of the skin, easy bruisability, and joint hypermobility. Although an underdiagnosed disease, EDS is estimated to affect approximately one in 20,000 individuals in the United States. Patients suffer from a range of clinical problems including abnormal and/or pigmented scar formation frequent dislocations of joints, arthritis at an early age, and death. Of the ten clinically recognized types of the disorder, defects in the proteins or genes for type III procollagen, lysyl hydroxylase, type I procollagen, and fibronectin have been described for EDS IV, VI, VII, and X, respectively. However, fibronectin have been described for EDS IV, VI, VII, and X, respectively. However, one of the most common forms of EDS (i.e., EDS I) has not been linked to a defect in a connective tissue matrix protein despite biochemical studies on skin and cultured connective tissue matrix protein despite biochemical studies on skin and cultured fibroblasts from patients with this disorder. A frequent ultrastructural finding in EDS I is larger than normal dermal collagen fibrils and smaller than normal bundles. This finding, together with the fact that EDS I is inherited in an autosomal dominant manner, suggests a defect in a structural protein of the connective tissue matrix involved in collagen fibril formation. Work from other laboratories has resulted in cDNA and genomic cloning of several connective tissue elements implicated in fibrillogenesis (i.e., collagens Type III and V, fibronectin, and proteoglycan core protein). Restriction fragment length polymorphisms (RFLPs) have also been described for three of these four genes. The hypothesis to be tested here is that EDS I is due to mutations in a gene for a structural macromolecule involved in collagen fibril formation. To test this hypothesis, linkage analysis between RFLP markers in these four connective tissue matrix genes and the disease locus will be performed in large families with EDS I and biochemical and molecular biological analysis of the defective protein and gene (including SDS-PAGE and peptide mapping, Northern and Southern blotting, S1 nuclease or chemical cleavage mapping of cDNA:RNA mismatches, polymerase chain amplification and dideoxy sequencing of the affected area of the mRNA or gene) will be initiated. The overall goal of this project is to identify the gene responsible for EDS I, to characterize the mutations in the gene, and to establish the basis for a biochemical diagnosis of this disorder.
| Thakker-Varia, S; Anderson, D W; Kuivaniemi, H et al. (1995) Aberrant splicing of the type III procollagen mRNA leads to intracellular degradation of the protein in a patient with Ehlers-Danlos type IV. Hum Mutat 6:116-25 |
| Stolle, C A; McGowan, M H; Heim, R A et al. (1991) Nucleotide sequence of a cDNA encoding rat brain carbonic anhydrase II and its deduced amino acid sequence. Gene 109:265-7 |
