Beals syndrome, also known as congenital contractural arachnodactyly (CCA), is an inherited disorder thought to be due to a defect in a connective tissue component. Affected individuals display a Marfanoid habitus, joint contractures, ear deformities and occasional cardiovascular defects. CCA has been presumed to be allelic to the Marfan syndrome (MfS) because of striking phenotypic similarities. However, recent linkage data indicates that a partially characterized gene on chromosome 5 is responsible for CCA rather than the fibrillin gene on chromosome 15 which is defective in MfS. The sequence of the putative CCA gene shows a high degree of identity with the fibrillin gene suggesting that the two proteins are related. However, the CCA gene product has not yet been isolated, nor is anything known about its tissue distribution or physiological function. Furthermore, no mutations have been identified in any CCA patient. The long-term objectives of this study are to determine the pathogenesis of CCA and to clarify its relationship to MfS. This involves defining and comparing the roles of the proteins involved and understanding the consequences of mutations in relationship to the disease phenotypes. The range and nature of mutations giving rise to CCA will be determined in a group of CCA patients using Chemical Mismatch Cleavage analysis. The consequences of those mutations to the structure and function of the defective protein will be determined by comparative analysis of the properties of normal and mutated domains. From a comparison of the deduced amino acid sequence of the CCA gene with fibrillin, dissimilar regions will be selected to make synthetic peptides specific for the CCA gene product. These will be used to prepare antisera and monoclonal antibodies for protein characterization. Immunofluorescent tissue staining and immunoelectron microscopy will reveal the tissue distribution of the epitope and tissue structures that contain the CCA gene product. The antibodies will also be used to isolate the protein from extracts or proteolytic digests of appropriate tissues or from cell culture medium. Limited protein sequence analysis will confirm that the isolated protein is indeed the CCA gene product. The homologous region between fibrillin and the CCA gene product consists largely of repeated epidermal growth factor precursor (pEGF)-like domains containing predicted calcium binding sites and domains that are homologous to a domain in TGF-beta-1 binding protein. Missense mutations in these domains have been identified in several Marfan patients. Phenotypic similarities between the MfS and CCA suggest that similar mutations may be found in CCA. In addition, fibrillin has a potential SH3 binding domain that is not present in the CCA protein. This strongly implicates this region as a site of protein- protein interaction making it an important distinguishing feature between the two proteins. An expression system in E. coli will be designed to synthesize selected structural domains so that the normal physiological function and the effect of CCA mutations can be studies. Elucidating the structural and functional differences between the CCA protein and fibrillin will help explain the comparative pathogenesis of these diseases and the role of the protein in the development of the human cardiovascular, skeletal and ocular systems.
|Babcock, D; Gasner, C; Francke, U et al. (1998) A single mutation that results in an Asp to His substitution and partial exon skipping in a family with congenital contractural arachnodactyly. Hum Genet 103:22-8|
|Kuo, H J; Maslen, C L; Keene, D R et al. (1997) Type VI collagen anchors endothelial basement membranes by interacting with type IV collagen. J Biol Chem 272:26522-9|
|Maslen, C; Babcock, D; Raghunath, M et al. (1997) A rare branch-point mutation is associated with missplicing of fibrillin-2 in a large family with congenital contractural arachnodactyly. Am J Hum Genet 60:1389-98|