title: Identification of PEX7 as the second gene involved in Refsum disease.
abstract: Patients affected with Refsum disease (RD) have elevated levels of phytanic acid due to a deficiency of the peroxisomal enzyme phytanoyl-CoA hydroxylase (PhyH). In most patients with RD, disease-causing mutations in the PHYH gene have been identified, but, in a subset, no mutations could be found, indicating that the condition is genetically heterogeneous. Linkage analysis of a few patients diagnosed with RD, but without mutations in PHYH, suggested a second locus on chromosome 6q22-24. This region includes the PEX7 gene, which codes for the peroxin 7 receptor protein required for peroxisomal import of proteins containing a peroxisomal targeting signal type 2. Mutations in PEX7 normally cause rhizomelic chondrodysplasia punctata type 1, a severe peroxisomal disorder. Biochemical analyses of the patients with RD revealed defects not only in phytanic acid alpha-oxidation but also in plasmalogen synthesis and peroxisomal thiolase. Furthermore, we identified mutations in the PEX7 gene. Our data show that mutations in the PEX7 gene may result in a broad clinical spectrum ranging from severe rhizomelic chondrodysplasia punctata to relatively mild RD and that clinical diagnosis of conditions involving retinitis pigmentosa, ataxia, and polyneuropathy may require a full screen of peroxisomal functions.
authors.affiliation: Department of Clinical Chemistry, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Daan M
authors.initials: DM
authors.lastname: van den Brink
authors.forename: Pedro
authors.initials: P
authors.lastname: Brites
authors.forename: Janet
authors.initials: J
authors.lastname: Haasjes
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Wierzbicki
authors.forename: John
authors.initials: J
authors.lastname: Mitchell
authors.forename: Michelle
authors.initials: M
authors.lastname: Lambert-Hamill
authors.forename: Jacqueline
authors.initials: J
authors.lastname: de Belleroche
authors.forename: Gerbert A
authors.initials: GA
authors.lastname: Jansen
authors.forename: Hans R
authors.initials: HR
authors.lastname: Waterham
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
mesh_terms: D000101:Acetyl-CoA C-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000483:Alleles; D002478:Cells, Cultured; D002896:Chromosomes, Human, Pair 6; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D000074437:Peroxisomal Targeting Signal 2 Receptor; D010831:Phytanic Acid / Q000097:blood; D010955:Plasmalogens / Q000096:biosynthesis / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D012035:Refsum Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D035781:Siblings; D012867:Skin / Q000166:cytology
chemical_list: C000614269:PEX7 protein, human; D000074437:Peroxisomal Targeting Signal 2 Receptor; D010955:Plasmalogens; D018160:Receptors, Cytoplasmic and Nuclear; D010831:Phytanic Acid; D006899:Mixed Function Oxygenases; C102623:PHYH protein, human; D000101:Acetyl-CoA C-Acetyltransferase