Import of peroxisomal matrix
proteins, crucial for peroxisome biogenesis, is mediated by the cytosolic receptors PEX5 and PEX7 that recognize
proteins carrying
peroxisomal targeting signals 1 or 2 (PTS1 or PTS2), respectively. Mutations in PEX5 or 12 other PEX genes cause
peroxisome biogenesis disorders, collectively named the
Zellweger spectrum disorders (ZSDs), whereas mutations in PEX7 cause
rhizomelic chondrodysplasia punctata type 1 (
RCDP1). Three additional RCDP types, RCDP2-3-4, are caused, respectively, by mutations in GNPAT, AGPS and FAR1, encoding
enzymes involved in
plasmalogen biosynthesis. Here we report a fifth type of RCDP (RCDP5) caused by a novel mutation in PEX5. In four patients with RCDP from two independent families, we identified a homozygous frame shift mutation c.722dupA (p.Val242Glyfs(∗)33) in PEX5 (GenBank: NM_001131023.1). PEX5 encodes two
isoforms, PEX5L and PEX5S, and we show that the c.722dupA mutation, located in the PEX5L-specific exon 9, results in loss of PEX5L only. Both PEX5
isoforms recognize PTS1-tagged
proteins, but PEX5L is also a co-receptor for PTS2-tagged
proteins. Previous patients with PEX5 mutations had ZSD, mainly due to deficient import of PTS1-tagged
proteins. Similarly to mutations in PEX7, loss of PEX5L results in deficient import of PTS2-tagged
proteins only, thus causing RCDP instead of ZSD. We demonstrate that PEX5L expression restores the import of PTS2-tagged
proteins in patient fibroblasts. Due to the biochemical overlap between
RCDP1 and RCDP5, sequencing of PEX7 and exon 9 in PEX5 should be performed in patients with a selective defect in the import of PTS2-tagged
proteins.