RHIZOMELIC CHONDRODYSPLASIA PUNCTATA IS CAUSED BY DEFICIENCY OF HUMANPEX7, A HOMOLOG OF THE YEAST PTS2 RECEPTOR

The rhizomelic form of chondrodysplasia punctata (RCDP) is an autosoma l recessive disease of peroxisome biogenesis characterized by deficien cies in several peroxisomal proteins, including the peroxisomal enzyme s of plasmalogen biosynthesis and peroxisomal 3-ketoacyl thiolase(1). In cultured fibroblasts from patients with this disorder, both the per oxisomal targeting and proteolytic removal of the amino-terminal type 2 peroxisomal targeting sequence (PTS2) of thiolase are defective, whe reas the biogenesis of proteins targeted by carboxyterminal type 1 per oxisomal targeting sequences (PTS1) is unimpaired. We have previously isolated a Saccharomyces cerevisiae peroxisomal biogenesis mutant, pex 7 (formerly peb1/pas7)(2), which demonstrates a striking similarity to the cellular phenotype of RCDP fibroblasts in that PTS1 targeting is functional, but the peroxisomal packaging of PTS2 targeted thiolase is lacking. Complementation of this mutant has led to the identification of the protein ScPex7p(3,4), a PTSZ receptor(5,6). In this paper we r eport cloning of the human orthologue of ScPEX7, and demonstrate that this is the defective gene in RCDP. We show that expression of human P EX7 in RCDP cells rescues PTSZ targeting and restores some activity of dihydroxyacetone phosphate acyltransferase (DHAP-AT), a peroxisomal e nzyme of plasmalogen biosynthesis, and we identify the mutations respo nsible for loss of function of PEX7 in a compound heterozygote RCDP pa tient. These results imply that several peroxisomal proteins are targe ted by PTSZ signals and that the various biochemical and clinical defe cts in RCDP result from a defect in the receptor for this class of PTS .