Rhizomelic Chondrodysplasia Punctata,a Peroxisomal Biogenesis Disorder Caused by Defects in Pex7p,a Peroxisomal Protein Import Receptor: A Minireview

Rhizomelic chondrodysplasia punctata (RCDP) is a lethal autosomal recessive disease correspondingto complementation group 11 (CG 11), the second most common of the thirteen CGs of peroxisomalbiogenesis disorders (PBDs). RCDP is characterized by proximal limb shortening, severely disturbedendochondrial bone formation, and mental retardation, but there is an absence of the neuronal migrationdefect found in the other PBDs. Plasmalogen biosynthesis and phytanic acid oxidation are deficient, butvery long chain fatty acid (VLCFA) oxidation is normal. At the cellular level, RCDP is unique in thatthe biogenesis of most peroxisomal proteins is normal, but a specific subset of at least four, and maybemore, peroxisomal matrix proteins fail to be imported from the cytosol. In this review, we discuss recentadvances in understanding RCDP, most prominently the cloning of the affected gene, PEX7,and identification of PEX7 mutations in RCDP patients. Human PEX7 wasidentified by virtue of its sequence similarity to its Saccharomyces cerevisiae ortholog, whichhad previously been shown to encode Pex7p, an import receptor for type 2 peroxisomal targetingsequences (PTS2). Normal human PEX7 expression rescues the cellular defects in culturedRCDP cells, and cDNA sequence analysis has identified a variety of PEX7 mutations in RCDP patients,including a deletion of 100 nucleotides, probably due to a splice site mutation, and a prevalent nonsensemutation which results in loss of the carboxyterminal 32 amino acids. Identification of RCDP as a PTS2import disorder explains the observation that several, but not all, peroxisomal matrix proteins aremistargeted in this disease; three of the four proteins deficient in RCDP have now been shown to bePTS2-targeted.