A major part of our research effort on the peroxisomal disorders is directed towards understanding the relationship between a patient’s genotype and his/her biochemical and clinical phenotype; our particular focus being on patients with peroxisomal biogenesis or fatty acid oxidation defects. Since similar clinical phenotypes may result from defects in different genes, biochemical and complementation analyses are undertaken first to ascertain which gene is affected in a particular family. Once the defective gene is identified we can then look for the causative mutations. To date, we have been focusing on defects affecting the D-bifunctional protein, the peroxisomal targeting signal 2 receptor or the a-oxidation enzyme phytanoyl CoA hydroxylase. In addition, molecular analysis of the relevant defective PEX gene in patients falling into the Zellweger spectrum of peroxisomal biogenesis disorders (Zellweger syndrome, neonatal adrenoleukodystrophy and infantile Refsum’s disease) is being undertaken in collaboration with A/Prof Denis Crane’s group at Griffith University. Any novel mutations in the various genes are then investigated to see how they impact on peroxisomal biogenesis and/or function. In addition we look for correlations between the observed cell biology and metabolic changes and the clinical phenotype. A clearer understanding of the relationship between genotype and phenotype will provide better prognostic indicators for future patients, which is an important consideration when trying to optimise the clinical management of individual patients.
Other areas of interest include developing methods for the early detection of individuals with peroxisomal disorders, as well as looking for ways of boosting peroxisomal function in cells from patients with some residual peroxisomal function.
Maxwell MA, Nelson PV, Chin SJ, Paton BC, Carey WF, Crane DI (1999) A common PEX1 frameshift mutation in patients with disorders of peroxisome biogenesis correlates with the severe Zellweger syndrome phenotype. Human Genetics 105: 38-44
Poulos A, Stockham PC, Johnson DW, Paton BC, Beckman K and Singh H (1999) Metabolism of trideuterated iso-lignoceric acid in rats in vivo and in human skin fibroblasts in culture. Lipids 34: 943-949
Zhang Z, Suzuki Y, Shimozawa, N, Fukuda S, Imamura A, Tsukamoto T, Osumi T, Fujiki Y, Orii T, Wanders RJA, Barth PG, Moser HW, Paton B, Besley G and Kondo N (1999) Genomic structure and identification of 11 novel mutations of PEX6 (peroxisome assembly factor-2) gene in patients with peroxisome biogenesis disorders. Human Mutation 13: 487-496
Muntau AC, Mayerhofer PU, Paton BC, Kammerer S and Roscher AA (2000) Defective peroxisome membrane synthesis due to mutations in human PEX3 causes Zellweger syndrome, complementation group G. Am. J. Hum. Genet. 67: 967-975
Paton BC and Pollard AN (2000) Molecular changes in the D-bifunctional protein cDNA sequence in Australasian patients belonging to the bifunctional protein complementation group. Cell Biochem. Biophys. 32: 247-251
Harzer K, Hiraiwa M and Paton BC (2001) Saposins (sap) A and C activate the degradation of galactosylsphingosine. FEBS Lett: 508: 107-110
Hulková H, Cervenková M, Ledvinová J, Tochácková M, Hrebícek M, Poupetová H, Befekadu A, Berná L, Paton BC, Harzer K, Böör A, _míd F and Elleder M (2001) A novel mutation in the coding region of the prosaposin gene leads to a complete deficiency of prosaposin, and saposins, and is associated with a complex sphingolipidosis dominated by lactosylceramide accumulation. Hum. Molec. Genet. 10: 927-940
Muller VJ, Paton BC and Fietz MJ (2001) An Australasian diagnostic service for the neuronal ceroid lipofuscinoses. Eur. J. Paediat. Neurol. 5(Suppl. A): 185-189
Paton BC, Solly PB, Nelson PV, Pollard AN, Sharp PC and Fietz MJ (2002) Molecular analysis of genomic DNA allows rapid, and accurate, prenatal diagnosis of peroxisomal D-bifunctional protein deficiency. Prenatal Diagnosis 22: 38-41
