Disorders of peroxisome biogenesis due to mutations in PEX1: Phenotypes and PEX1 protein levels

Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantil e Refsum disease (IRD) are clinically overlapping syndromes, collectively c alled "peroxisome biogenesis disorders" (PBDs), with clinical features bein g most severe in ZS and least pronounced in IRD. Inheritance of these disor ders is autosomal recessive. The peroxisome biogenesis disorders are geneti cally heterogeneous, having at least 12 different complementation groups (C Gs). The gene affected in CG1 is PEX1. Approximately 65% of the patients wi th PBD harbor mutations in PEX1. In the present study, we used SSCP analysi s to evaluate a series of patients belonging to CG1 for mutations in PEX1 a nd studied phenotype-genotype correlations. A complete lack of PEX1 protein was found to be associated with severe ZS; however, residual amounts of PE X1 protein were found in patients with the milder phenotypes, NALD and IRD. The majority of these latter patients carried at least one copy of the com mon G843D allele. When patient fibroblasts harboring this allele were grown at 30 degreesC, a two- to threefold increase in PEX1 protein levels was ob served, associated with a recovery of peroxisomal function. This suggests t hat the G843D missense mutation results in a misfolded protein, which is mo re stable at lower temperatures. We conclude that the search for the factor s and/or mechanisms that determine the stability of mutant PEX1 protein by high-throughput procedures will be a first step in the development of thera peutic strategies for patients with mild PBDs.