A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform

Abstract

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.

The important role of biochemical and functional studies in the diagnostics of peroxisomal disorders

“…Both the clinical and genetic spectrum of the peroxisomal disorders is still expanding. The peroxisome biogenesis disorders include not only the Zellweger spectrum disorders (ZSDs, with an estimated incidence of 1 in 50,000 newborns in the United States) and Rhizomelic chondrodysplasia punctata (RCDP) type 1 (OMIM 215100), but also the recently identified RCDP type 5 (Baroy et al 2015) and a novel subclass of peroxisomal fission disorders (i.e. PEX11β (OMIM 614920) (Ebberink et al 2012; Thoms and Gartner 2012), DLP/DRP1 (OMIM 614388) (Waterham et al 2007) and MFF (Shamseldin et al 2012) deficiency).…”

“…Fibroblasts studies can also differentiate between the different types of RCDP, which are clinically indistinguishable especially at the severe end of the spectrum and which all have a plasmalogen deficiency in common (Wanders and Waterham 2006a, b; Braverman and Moser 2012; Buchert et al 2014; Baroy et al 2015). In addition, it can classify patients with a Refsum-like phenotype and increased phytanic acid levels in the RCDP spectrum (van den Brink et al 2003) and show that the patient does not suffer from classical Refsum disease but an attenuated form of RCDP type 1 (see Table 3, patient 6).…”

ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism

“…The clinical, biochemical and genetic spectrum of peroxisomal disorders is broad and still expanding. For example, recently, Heimler syndrome was recognised as a mild presentation of the Zellweger spectrum,4 and two novel types of RCDP (4 and 5)5 6 were identified. In this paper, we report a novel peroxisomal single enzyme deficiency affecting the peroxisomal β-oxidation of very long-chain fatty acids (VLCFAs), due to a deficiency of acyl-CoA binding domain containing protein 5 (ACBD5).…”

Plasmalogen biosynthesis is spatiotemporally regulated by sensing plasmalogens in the inner leaflet of plasma membranes

“…The initial two steps of plasmalogen synthesis are catalyzed by peroxisomal matrix enzymes, dihydroxyacetonephosphate acyltransferase (Dhapat) and alkylglycerone phosphate synthase (Agps), in which 1-alkyl-dihydroxyacetonephosphate (DHAP) is generated by replacing the acyl chain of 1-acyl-DHAP with a long chain fatty alcohol that is synthesized by fatty acyl-CoA reductase 1 (Far1), a peroxisomal C-tail anchored protein345. Deficiency of plasmalogen synthesis evoked by dysfunction of peroxisomal enzymes essential for the plasmalogen synthesis causes rhizomelic chondrodysplasia punctata (RCDP), a fatal genetic disease678. Plasmalogen deficiency is also found in peroxisome biogenesis disorders (PBDs) where plasmalogens level is severely reduced in several organs such as brain, heart, and kidney from patients with PBDs9, implying that de novo synthesis of plasmalogens plays a pivotal role in the tissue plasmalogen homeostasis.…”