Identification of PEX7 as the Second Gene Involved in Refsum Disease

• DOI: 10.1007/978-1-4419-9072-3_9
• Publication Date: 2011-09-17T22:35:26Z
• Authors: Daan M. Van Den B...; Pedro Brites; Janet Haasjes; Anthony S. Wierzb...; John Mitchell; Michelle Lambert-...; Jacqueline DeBell...; Gerbert A. Jansen; Hans R. Waterham; Ronald J.A. Wanders
• Keywords: Adult; Male; Genetic Linkage; Siblings; Plasmalogens; 610; Receptors, Cytoplasmic and Nuclear; Fibroblasts; Mixed Function Oxygenases; 3. Good health; Phytanic Acid; Phenotype; Mutation; Genetics; Humans; Genetics(clinical); Chromosomes, Human, Pair 6; Female; Refsum Disease; Acetyl-CoA C-Acetyltransferase; Alleles; Cells, Cultured; Peroxisomal Targeting Signal 2 Receptor; Skin

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.