Genetics and molecular basis of human peroxisome biogenesis disorders

Human peroxisome biogenesis disorders (PBDs) are a heterogeneous group of autosomal recessive disorders comprised of two clinically distinct subtypes: the Zellweger syndrome spectrum (ZSS) disorders and rhizomelic chondrodysplasia punctata (RCDP) type 1. PBDs are caused by defects in any of at least 14 different PEX genes, which encode proteins involved in peroxisome assembly and proliferation. Thirteen of these genes are associated with ZSS disorders. The genetic heterogeneity among PBDs and the inability to predict from the biochemical and clinical phenotype of a patient with ZSS which of the currently known 13 PEX genes is defective, has fostered the development of different strategies to identify the causative gene defects. These include PEX cDNA transfection complementation assays followed by sequencing of the thus identified PEX genes, and a PEX gene screen in which the most frequently mutated exons of the different PEX genes are analyzed. The benefits of DNA testing for PBDs include carrier testing of relatives, early prenatal testing or preimplantation genetic diagnosis in families with a recurrence risk for ZSS disorders, and insight in genotype–phenotype correlations, which may eventually assist to improve patient management. In this review we describe the current status of genetic analysis and the molecular basis of PBDs. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of peroxisomes in Health and Disease.

► Peroxisome biogenesis disorders (PBDs) are clinically, biochemically and genetically heterogeneous.
► PBDs are autosomal recessive disorders which can be caused by any of at least 14 different PEX genes.
► PEX genes encode proteins involved in peroxisome assembly, including protein import and peroxisome division.
► Genetic testing for all PEX genes is available as diagnostic service.