PEX7 gene structure, alternative transcripts, and evidence for a founder haplotype for the frequent RCDP allele, L292ter

We recently reported cloning a cDNA encoding Pex7p, the peroxisomal PTS2 re ceptor. PEX7 mutations cause the peroxisome biogenesis disorder (PBD) rhizo melic chondrodysplasia punctata (RCDP). In a survey of 44 RCDP probands, we found that one PEX7 allele, L292ter, accounted for 50% of mutant PEX7 gene s. Here we report the characterization of the PEX7 structural gene, which s pans 102 kb on chromosome 6q21-q22.2 and contains at least 10 exons. In add ition to the predominant full-length transcript, we identified eight smalle r PEX7 transcripts generated by alternative exon splicing in several tissue s. However, none of these splice forms was able to restore PTS2 protein imp ort into peroxisomes when expressed in RCDP fibroblasts nor did they inhibi t PTS2 protein import when expressed in normal fibroblasts. To determine wh ether the high frequency of the L292ter allele is due to a founder effect, we identified five polymorphic markers (four diallelic markers and one CA r epeat) spanning the PEX7 gene. We show that all 12 L292ter homozygotes in o ur patient sample have an identical haplotype at these five sites, consiste nt with the hypothesis that the L292ter mutation arose once on an ancestral chromosome in the Caucasian population. (C) 2000 Academic Press.