Rhizomelic chondrodysplasia punctata (RCDP) is a lethal autosomal recessive disease corresponding to complementation group 11 (CG11), the second most common of the thirteen CGs of peroxisomal biogenesis disorders (PBDs). RCDP is characterized by proximal limb shortening, severely disturbed endochondrial bone formation, and
mental retardation, but there is an absence of the neuronal migration defect found in the other PBDs.
Plasmalogen biosynthesis and
phytanic acid oxidation are deficient, but very long chain
fatty acid (VLCFA) oxidation is normal. At the cellular level, RCDP is unique in that the biogenesis of most peroxisomal
proteins is normal, but a specific subset of at least four, and maybe more, peroxisomal matrix
proteins fail to be imported from the cytosol. In this review, we discuss recent advances in understanding RCDP, most prominently the cloning of the affected gene, PEX7, and identification of PEX7 mutations in RCDP patients. Human PEX7 was identified by virtue of its sequence similarity to its Saccharomyces cerevisiae ortholog, which had previously been shown to encode
Pex7p, an import receptor for type 2 peroxisomal targeting sequences (PTS2). Normal human PEX7 expression rescues the cellular defects in cultured RCDP 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
nonsense mutation which results in loss of the carboxyterminal 32
amino acids. Identification of RCDP as a PTS2 import disorder explains the observation that several, but not all, peroxisomal matrix
proteins are mistargeted in this disease; three of the four
proteins deficient in RCDP have now been shown to be PTS2-targeted.