title: 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.
authors.affiliation: Department of Medical Genetics and.
authors.forename: Tuva
authors.initials: T
authors.lastname: Barøy
authors.affiliation: Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Janet
authors.initials: J
authors.lastname: Koster
authors.affiliation: Department of Clinical Neurosciences for Children, Women and Children's Division, Oslo University Hospital and University of Oslo, 0407 Oslo, Norway.
authors.forename: Petter
authors.initials: P
authors.lastname: Strømme
authors.affiliation: Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Merel S
authors.initials: MS
authors.lastname: Ebberink
authors.affiliation: Department of Medical Genetics and.
authors.forename: Doriana
authors.initials: D
authors.lastname: Misceo
authors.affiliation: Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Sacha
authors.initials: S
authors.lastname: Ferdinandusse
authors.affiliation: Department of Medical Genetics and.
authors.forename: Asbjørn
authors.initials: A
authors.lastname: Holmgren
authors.affiliation: Department of Medical Genetics and.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hughes
authors.affiliation: Department of Radiology and.
authors.forename: Else
authors.initials: E
authors.lastname: Merckoll
authors.affiliation: Department of Radiology and.
authors.forename: Jostein
authors.initials: J
authors.lastname: Westvik
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, 0424 Oslo, Norway.
authors.forename: Berit
authors.initials: B
authors.lastname: Woldseth
authors.affiliation: Willink Biochemical Genetics Unit, Manchester Academic Health Science Centre, Manchester M13 9WL, UK and.
authors.forename: John
authors.initials: J
authors.lastname: Walter
authors.affiliation: Child Development Centre, Bradford Teaching Hospitals NHS Foundation Trust St Luke's Hospital, Bradford BD5 0NA, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Wood
authors.affiliation: Department of Clinical Neurosciences for Children, Women and Children's Division, Oslo University Hospital and University of Oslo, 0407 Oslo, Norway.
authors.forename: Bjørn
authors.initials: B
authors.lastname: Tvedt
authors.affiliation: Department of Clinical Neurosciences for Children, Women and Children's Division, Oslo University Hospital and University of Oslo, 0407 Oslo, Norway.
authors.forename: Kristine
authors.initials: K
authors.lastname: Stadskleiv
authors.affiliation: Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.affiliation: Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Hans R
authors.initials: HR
authors.lastname: Waterham
authors.affiliation: Department of Medical Genetics and eirik.frengen@medisin.uio.no.
authors.forename: Eirik
authors.initials: E
authors.lastname: Frengen
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D018902:Chondrodysplasia Punctata, Rhizomelic / Q000235:genetics* / Q000378:metabolism; D059472:Exome; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D007223:Infant; D008297:Male; D010375:Pedigree; D000074435:Peroxisome-Targeting Signal 1 Receptor; D020675:Peroxisomes / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms; D021381:Protein Transport / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: C000614264:PEX5 protein, human; D000074435:Peroxisome-Targeting Signal 1 Receptor; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear