title: PEX7 gene structure, alternative transcripts, and evidence for a founder haplotype for the frequent RCDP allele, L292ter.
abstract: We recently reported cloning a cDNA encoding Pex7p, the peroxisomal PTS2 receptor. PEX7 mutations cause the peroxisome biogenesis disorder (PBD) rhizomelic chondrodysplasia punctata (RCDP). In a survey of 44 RCDP probands, we found that one PEX7 allele, L292ter, accounted for 50% of mutant PEX7 genes. Here we report the characterization of the PEX7 structural gene, which spans 102 kb on chromosome 6q21-q22.2 and contains at least 10 exons. In addition to the predominant full-length transcript, we identified eight smaller PEX7 transcripts generated by alternative exon splicing in several tissues. However, none of these splice forms was able to restore PTS2 protein import into peroxisomes when expressed in RCDP fibroblasts nor did they inhibit PTS2 protein import when expressed in normal fibroblasts. To determine whether the high frequency of the L292ter allele is due to a founder effect, we identified five polymorphic markers (four diallelic markers and one CA repeat) spanning the PEX7 gene. We show that all 12 L292ter homozygotes in our patient sample have an identical haplotype at these five sites, consistent with the hypothesis that the L292ter mutation arose once on an ancestral chromosome in the Caucasian population.
authors.affiliation: Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: N
authors.initials: N
authors.lastname: Braverman
authors.forename: G
authors.initials: G
authors.lastname: Steel
authors.forename: P
authors.initials: P
authors.lastname: Lin
authors.forename: A
authors.initials: A
authors.lastname: Moser
authors.forename: H
authors.initials: H
authors.lastname: Moser
authors.forename: D
authors.initials: D
authors.lastname: Valle
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D016022:Case-Control Studies; D018902:Chondrodysplasia Punctata, Rhizomelic / Q000235:genetics*; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D005091:Exons; D018703:Founder Effect; D005796:Genes; D006239:Haplotypes; D006801:Humans; D007438:Introns; D051379:Mice; D008969:Molecular Sequence Data; D000074437:Peroxisomal Targeting Signal 2 Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid
chemical_list: D017931:DNA Primers; C000614269:PEX7 protein, human; D000074437:Peroxisomal Targeting Signal 2 Receptor; D018160:Receptors, Cytoplasmic and Nuclear