Novel PEX1 mutations and genotype-phenotype correlations in Australasian peroxisome biogenesis disorder patients.

The peroxisome biogenesis disorders (PBDs) are a group of neuronal migration/neurodegenerative disorders that arise from defects in PEX genes. A major subgroup of the PBDs includes Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD). These three disorders represent a clinical continuum with Zellweger syndrome the most severe. Mutations in the PEX1 gene, which encodes a protein of the AAA ATPase family involved in peroxisome matrix protein import, account for the genetic defect in more than half of the patients in this PBD subgroup. We report here on the results of PEX1 mutation detection in an Australasian cohort of PEX1-deficient PBD patients. This screen has identified five novel mutations, including nonsense mutations in exons 14 and 19 and single nucleotide deletions in exons 5 and 18. Significantly, the allele carrying the exon 18 frameshift mutation is present at moderately high frequency (approx. 10%) in this patient cohort. The fifth mutation is a missense mutation (R798G) that attenuates, but does not abolish PEX1 function. We have evaluated the cellular impact of these novel mutations, along with that of the two most common PEX1 mutations (c.2097-2098insT and G843D), in PBD patients by determining the levels of PEX1 mRNA, PEX1 protein, and peroxisome protein import. The findings are consistent with a close correlation between cellular phenotype, disease severity, and PEX1 genotype.

The effect of osteogenic protein-1 in an in vivo physeal injury model.

The physis has limited ability to undergo repair, and injury may result in growth arrest. Osteogenic protein-1 promotes bone formation in diaphyseal defects, chondrocyte proliferation, and matrix synthesis. The authors' goal was to determine if the presence of osteogenic protein-1 in a defect involving the physis would promote cartilage repair, and in doing so, to determine the effect of osteogenic protein-1 on physeal growth. An ovine model of growth plate damage was used, in which the proximal medial physis of the tibia was partially ablated. The defect was filled with a Type I collagen paste containing osteogenic protein-1 (350 microg) or collagen alone. Growth rate was measured at 4, 14, and 56 days, and the defects were analyzed histologically at 4, 14, and 56 days. Bone bridge formation occurred within the defect site. However, osteogenic protein-1 promoted outgrowth of the adjacent physeal cartilage. The physeal cartilage underwent expansion until the mineral forming within the defect site blocked its progress. The effect was localized because only that portion of the physis at the defect margin appeared to be affected.