Identification of PEX7 as the Second Gene Involved in Refsum Disease

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Identification of PEX7 as the Second Gene Involved in Refsum Disease Daan M. van den Brink, Pedro Brites, Janet Haasjes, Anthony S. Wierzbicki, John Mitchell, Michelle Lambert-Hamill, Jacqueline de Belleroche, Gerbert A. Jansen, Hans R. Waterham, J.A. Ronald Wanders The American Journal of Human Genetics Volume 72, Issue 2, Pages 471-477 (February 2003) DOI: 10.1086/346093 Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 1 Multipoint linkage analysis of markers on chromosome 6, with approximate locations of known loci. With approval from the ethics committee of each institution, 23 individuals, including 4 living patients with a clinical RD phenotype, from the two families were recruited through a specialized clinic, using diagnostic criteria specified elsewhere (Wierzbicki et al. 2000). A panel of 11 fluorescein-labeled dinucleotide repeat markers (Perkin Elmer) spanning 6q14-6qter (GenLink home page) was amplified from extracted patient lymphocyte DNA (Puregene), by PCR, and typed on an ABI 310 analyzer with GeneAmp software (Perkin Elmer). The data were analyzed using the GENEHUNTER linkage analysis program (Kruglyak et al. 1996), assuming complete penetrance for a recessive disorder and a mutation rate of 10−5. The allele frequency for the RD trait was assumed to be 0.001 on the basis of the prevalence of RD of 10−6 in the United Kingdom. Distances are in centimorgans from D6S242, which was taken arbitrarily as zero. Apolipoprotein (a) = APO(A); estrogen receptor = E2R; peroxin 7/RCDP type 1 = PEX7; fatty acid binding protein 7 = FABP7; oculodentodigital dysplasia = ODDD (MIM 164200). The American Journal of Human Genetics 2003 72, 471-477DOI: (10.1086/346093) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 2 Processing of PTS2 proteins into peroxisomes in control, classic RD, RCDP type 1, and probands 1 and 2. Lysates of fibroblasts were subjected to western blotting, using antibodies ADHAPS (a), peroxisomal 3-oxoacyl-CoA thiolase (b), and PhyH (c). Solid and open arrows indicate the position of the unprocessed and mature forms, respectively. Immunoblot analyses were performed, as described, for peroxisomal thiolase (Heikoop et al. 1990), ADHAPS (de Vet et al. 1997), and PhyH with affinity-purified antibodies (Jansen et al. 2000). The American Journal of Human Genetics 2003 72, 471-477DOI: (10.1086/346093) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 3 Functional complementation of PTS2-mediated peroxisomal protein import by PEX7 alleles. The three mutant PEX7 alleles identified in the two probands were coexpressed with PTS2-tagged GFP in cultured fibroblast of a patient with RCDP type 1, as described elsewhere (Motley et al. 1997, 2002), to test their ability to restore PTS2-mediated peroxisomal protein import. Expression of control PEX7 resulted in punctate peroxisomal fluorescence (A), whereas the Y40X allele resulted in cytosolic fluorescence (B). Expression of the 7-nt duplication (C) and the T14P allele (D) resulted in peroxisomal and cytosolic fluorescence, respectively. The American Journal of Human Genetics 2003 72, 471-477DOI: (10.1086/346093) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 4 Localization of peroxisomal thiolase in fibroblasts by immunofluorescence. Cultured fibroblasts derived from a control individual, a patient with RCDP type 1, and proband 1 were stained, as described elsewhere, for catalase and peroxisomal thiolase (Heikoop et al. 1991). No peroxisomal thiolase could be detected in the peroxisomes of proband 1, giving a cytosolic staining similar to that observed in the patient with RCDP type 1. The American Journal of Human Genetics 2003 72, 471-477DOI: (10.1086/346093) Copyright © 2003 The American Society of Human Genetics Terms and Conditions