Disease relevance of PEX7

• Decreased phytanic-acid oxidation is also observed in human cells lacking PEX7, the receptor for the type-2 peroxisomal targetting signal (PTS2; refs 3,4), suggesting that the enzyme defective in Refsum disease is targetted to peroxisomes by a PTS2 [1].
• 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 [2].
• Mutations in PEX7 normally cause rhizomelic chondrodysplasia punctata type 1, a severe peroxisomal disorder [2].
• Importantly, cultured fibroblasts from patients with the rhizomelic form of chondrodysplasia punctata (RCDP) which are deficient for the PTS2 receptor protein, Pex7p, are unable to import the PTS2 reporter in this assay [3].

High impact information on PEX7

• Peroxisomal targeting signals (PTSs) are recognized by predominantly cytosolic receptors, Pex5p and Pex7p [4].
• A mutation resulting in C-terminal truncation of PEX7 cosegregates with the disease and expression of PEX7 in RCDP fibroblasts from CG11 rescues the PTS2 protein import deficiency [5].
• Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata [6].
• In a collection of 36 RCDP probands, we found two inactivating PEX7 mutations: one, L292ter, was present in 26 of the probands, all with a severe phenotype; the second, A218V, was present in three probands, including two with a milder phenotype [6].
• We conclude that PEX7 is responsible for RCDP (PBD CG11) and suggest a founder effect may explain the high frequency of L292ter [6].

Biological context of PEX7

• To determine whether the high frequency of the L292ter allele is due to a founder effect, we identified five polymorphic markers (four diallelic markers and one CA repeat) spanning the PEX7 gene [7].
• PEX7 gene structure, alternative transcripts, and evidence for a founder haplotype for the frequent RCDP allele, L292ter [7].
• Here we report the characterization of the PEX7 structural gene, which spans 102 kb on chromosome 6q21-q22.2 and contains at least 10 exons [7].
• Mutation analysis of PEX7 in 60 probands with rhizomelic chondrodysplasia punctata and functional correlations of genotype with phenotype [8].
• Rhizomelic chondrodysplasia punctata is a peroxisomal protein targeting disease caused by a non-functional PTS2 receptor [5].

Anatomical context of PEX7

• In this work, we found that Pex5pL directly interacts with the PTS2 receptor Pex7p, carrying its cargo PTS2 protein in the cytosol [9].
• Pex5pL-(Pex7p-PTS2 protein) complexes were detectable in wild-type CHO-K1 cells and were apparently more stable in pex14 CHO cells deficient in the entry site of the matrix proteins, whereas only the Pex7p-PTS2 protein complex was discernible in a Pex5pL-defective pex5 CHO mutant [10].
• Retinal photoreceptor dystrophies (RD) are a highly heterogeneous group of genetic disorders of the retina, representing the most frequently inherited form of visual handicap, affecting approximately 1.5 million people world wide [11].
• Therefore, ZPEG227 is a pex7 mutant possessing a newly identified mutation in mammalian pex7 cell lines [12].

Associations of PEX7 with chemical compounds

• The interaction is reduced upon cysteine alkylation and is impaired upon truncation of the N-terminus of Pex7p [13].
• NH2-terminal regions of Pex13p are required for its interaction with the PTS2-receptor while the COOH-terminal SH3 domain alone is sufficient to mediate its interaction with the PTS1-receptor [14].
• Two of eight patients with ZS, two of four with RCDP, and all of three classical Refsum patients showed increased levels of phytanic acid [15].
• AR-RCDP fibroblasts also showed a two- to seven-fold increase in the rate of hexadecanol synthesis, which was associated with an increase in the activity of acyl-CoA reductase [16].

Physical interactions of PEX7

• Pex5pL transports PTS1 proteins and Pex7p-PTS2 cargo complexes to the initial Pex5p-docking site, Pex14p, on peroxisome membranes, while Pex5pS translocates only PTS1 cargoes [17].

Other interactions of PEX7

• Disruption of the interaction of the longer isoform of Pex5p, Pex5pL, with Pex7p abolishes peroxisome targeting signal type 2 protein import in mammals. Study with a novel Pex5-impaired Chinese hamster ovary cell mutant [18].
• Molecular basis of Refsum disease: sequence variations in phytanoyl-CoA hydroxylase (PHYH) and the PTS2 receptor (PEX7) [19].
• PEX7 mutations cause the peroxisome biogenesis disorder (PBD) rhizomelic chondrodysplasia punctata (RCDP) [7].
• The peroxisomal membrane protein PEX14 is a key component of the peroxisomal import machinery and may be the initial docking site for the two import receptors PEX5 and PEX7 [20].
• Here we report functional Pex5p domains responsible for interaction with peroxins Pex7p, Pex13p, and Pex14p [17].

Analytical, diagnostic and therapeutic context of PEX7

• To relate PEX7 genotype and phenotype, we evaluated the consequence of the disease mutation on PEX7 RNA by Northern analysis and RT/PCR [8].
• Pex7p was eluted as a monomer in gel filtration chromatography [10].
• Normal human PEX7 expression rescues the cellular defects in cultured RCDP cells, and cDNA sequence analysis has identified a variety of PEX7 mutations in RCDP patients, including a deletion of 100 nucleotides, probably due to a splice site mutation, and a prevalent nonsense mutation which results in loss of the carboxyterminal 32 amino acids [21].

References