PEX7 AND IT'S ROLE IN THE PATHOGENESIS OF RCDP

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DESCRIPTION (Adapted from investigator's abstract): Rhizomelic chondrodysplasio punctata (RCDP) is a peroxisome biogenesis disorder characterized by cataracts, skeletal abnormalities, profound growth failure and mental retardation. RCDP is inherited as an autosomal recessive trait and is caused by mutations in PEX7, which encodes Pex7p, the receptor for peroxisomal enzymes having a PTS2 sequence. The specific steps involved in the import of PTS2 proteins into peroxisomes are not known, but the P.I. favors a model in which Pex7p binds PTS2 proteins in the cytosol and transports them to the peroxisome. Pex7p contains six WD40 motifs that determine a beta propeller, a structure that provides multiple rigid surfaces for protein interactions. In RCDP, defective function of PTS2 enzymes is thought to produce unknown metabolic alterations that determine the RCDP phenotype. The overall goal of this proposal is to study the molecular and cellular biology of Pex7p and the pathogenesis of RCDP. The P.I. will achieve this by identification and functional analysis of disease related PEX7 mutations in 50+ RCDP probands, and functional analysis of wild type Pex7p. Dr. Braverman will evaluate Pex7p expression, subcellular location and ability to mediate PTS2 protein import. She will also determine the regions of Pex7p that bind PTS2 and interact with other peroxins. These studies will define the steps in PTS2 protein import and allow correlation of PEX7 defects with variations in RCDP phenotypes. The P.I. will generate a murine model of RCDP to investigate the biochemical alterations in PTS2 protein pathways and their relation to tissue pathology. The proposed strategy will utilize cre/lox technologies to engineer hypomorphic, null and conditional PEX7 alleles and produce mice with combinations of these alleles to develop useful models of RCDP. These mice will be characterized by clinical, radiological, histological and biochemical evaluations. This information will contribute to understanding the pathophysiology of RCDP as well as the normal biology of peroxisome assembly and function in bone, lens and CNS development.