One of the author's previously published articles is inserted. / Bibliography: leaves 174-191. / xi, 213 leaves, [15] leaves of plates : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / A clinical and molecular study of patients with unequivocal Marfan sydnrome, or with an undiagnosed connective tissue disorder with some features in common with Marfan syndrome. Presents the phenotype of six Marfan patients with an FBN1 mutation, patients with Shprintzen-Goldberg syndrome or furlong syndrome, and two children with congenital aneurysms. Details the molecular screening of 44% of the FBN1 gene coding sequence for putative mutations. / Thesis (M.D.)--University of Adelaide, Dept. of Paediatrics, 1995

Congenital Contractural Arachnodactyly (CCA), also known as Beal's syndrome, is an autosomal dominant disorder characterized by multiple congenital joint contractures, arachnodactyly, dolichostenomelia, and scoliosis with only rare ocular or cardiovascular involvement. CCA has been linked to the fibrillin-2 (FBN2) gene located on chromosome 5q23-31. The phenotype ofCCA is similar to Marfan syndrome (MFS) which is caused by defects in the fibrillin-1 (FBNl) gene located on chromosome 15. Fibrillin-1 and fibrillin-2 are components of extracellular matrix (ECM) elastic microfibrils. The linkage studies performed on families affected with CCA suggest that another gene in the area ofFBN2 could also be responsible for CCA. Microfibril associated protein-3 (MF AP-3), another microfibril protein gene, has been localized to chromosome 5q32-33.2, the region of FBN2. This study involves mutation analysis of five patients affected with CCA, three of whom are representative of families affected with CCA. Mutation analysis was performed by chemical mismatch cleavage (CMC) analysis and nonisotopic RNase cleavage assay (NIRCA) analysis on both FBN2 and MF AP-3 cDNA. Prior to this study only two mutations in FBN2 have been reported in two isolated patients with CCA and none have been reported for MFAP-3. The two mutations reported in FBN2 have not been confirmed in other affected family members. Mutation analysis by CMC completed in this study did not reveal any mutations in either FBN2 or MF AP-3. Reanalysis by NIRCA revealed two mutations in FBN2. One mutation which results in the skipping of exon 31 occurs in an intron and its location is presently unknown. The other mutation, a G to C transversion at nucleotide 3340, predicting a histidine substitution for an asparagine, is a mutation at the -1 position of the 5' splice site of an intron which results in partial exon skipping although it is unknown whether exon 25 or 26 is skipped. The missense mutation and partial exon skipping result in two different forms of mutant fibrillin-2 molecules. Both of the mutations are present in patients with additional affected family members. Characterization of these mutations will confirm the cosegregation of FBN2 mutations with the CCA phenotype.

Ultraviolet radiation causes an alteration in DNA by modifying neighboring thymine bases resulting in the formation of a dimer. These dimers block the processes of transcription and translation and ultimately no protein is synthesized and the cell dies. However, DNA repair mechanisms correct this damage by excising the dimer from the DNA strand and inserting replacement bases which are joined to the original strand by DNA ligase. This allows transcription to resume and ultimately protein synthesis to take place.This research focused on determining the DNA damage and subsequent repair levels in a connective tissue disorder, namely Marfan syndrome. This information is important in understanding the clinical expression and management of life threatening conditions in Marfan syndrome individuals.Preliminary results indicate that at 20-25J/m2 UV dose (254nm) Marfan syndrome skin cells show a mean reduced survival value of 12% compared to normal human skin cells. Gel electrophoresis indicates a reduced DNA repair level 24h post UV irradiation for Marfan syndrome skin cells compared to normal human skin cells. These results suggest Marfan syndrome skin cells have reduced survival and DNA repair levels compared to normal human skin cells. / Department of Biology