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Disorders of Peroxisome Biogenesis Due to Mutations in PEX1: Phenotypes and PEX1 Protein Levels Claudia Walter,1 Jeannette Gootjes,4 Petra A

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Disorders of Peroxisome Biogenesis Due to Mutations in PEX1: Phenotypes and PEX1 Protein Levels Claudia Walter,1 Jeannette Gootjes,4 Petra A View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Am. J. Hum. Genet. 69:35–48, 2001 Disorders of Peroxisome Biogenesis Due to Mutations in PEX1: Phenotypes and PEX1 Protein Levels Claudia Walter,1 Jeannette Gootjes,4 Petra A. Mooijer,4 Herma Portsteffen,1 Christina Klein,2 Hans R. Waterham,4 Peter G. Barth,5,6 Jo¨rg T. Epplen,3 Wolf-H. Kunau,1,2 Ronald J. A. Wanders,4,6 and Gabriele Dodt2 Institut fu¨r Physiologische Chemie, Abteilungen fu¨r 1Zellbiochemie und 2Systembiochemie, and 3Institut fu¨r Molekulare Humangenetik, Ruhr- Universita¨t Bochum, Bochum, Germany; Departments of 4Clinical Chemistry, 5Neurology, and 6Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD) are clinically overlapping syndromes, collectively called “peroxisome biogenesis disorders” (PBDs), with clinical features being most severe in ZS and least pronounced in IRD. Inheritance of these disorders is autosomal recessive. The peroxisome biogenesis disorders are genetically heterogeneous, having at least 12 different complementation groups (CGs). The gene affected in CG1 is PEX1. Approximately 65% of the patients with PBD harbor mutations in PEX1.Inthe present study, we used SSCP analysis to evaluate a series of patients belonging to CG1 for mutations in PEX1 and studied phenotype-genotype correlations. A complete lack of PEX1 protein was found to be associated with severe ZS; however, residual amounts of PEX1 protein were found in patients with the milder phenotypes, NALD and IRD. The majority of these latter patients carried at least one copy of the common G843D allele. When patient fibroblasts harboring this allele were grown at 30ЊC, a two- to threefold increase in PEX1 protein levels was observed, associated with a recovery of peroxisomal function. This suggests that the G843D missense mutation results in a misfolded protein, which is more stable at lower temperatures. We conclude that the search for the factors and/or mechanisms that determine the stability of mutant PEX1 protein by high-throughput procedures will be a first step in the development of therapeutic strategies for patients with mild PBDs. Introduction rological and hepatic abnormalities, renal cysts, and characteristic facial dysmorphic stigmata; these patients Peroxisomes are subcellular organelles, present in virtu- die at ages !1 year. Patients with IRD display the mildest ally every eukaryotic cell, that catalyze a variety of es- phenotype, with no significant cerebral abnormalities, sential functions. In humans, these functions include fat- and survive until or even beyond adolescence (Lazarow ty-acid b-oxidation, etherphospholipid biosynthesis, and Moser 1995). NALD is intermediate between ZS fatty-acid a-oxidation, isoprenoid biosynthesis, and other and IRD in severity, and patients usually die in early functions (van den Bosch et al. 1992; Wanders and Tager childhood. In recent years, an increasing number of pro- 1998). Disorders resulting from defects in peroxisom- teins, named “peroxins,” that are involved in the bio- al biogenesis include Zellweger syndrome (ZS [MIM genesis of peroxisomes have been identified (Sacksteder 214100]), neonatal adrenoleukodystrophy (NALD and Gould 2000). Complementation studies with mam- [MIM 202370]), infantile Refsum disease (IRD [MIM malian fibroblasts have so far shown the existence of 12 266510]), and rhizomelic chondrodysplasia punctata different groups; in 11 of these, the defective PEX gene type 1 (RCDP1 [MIM 215100]) (Lazarow and Moser is known (Moser 1999). Complementation group 1 1995; Wanders 1999). The first three diseases, listed in (CG1) is the largest, characterized by mutations in order of decreasing severity, represent a continuum of HsPEX1 (PEX1 [MIM 602136]), a gene coding for a clinical features, whereas RCDP displays a distinct phe- 143-kD AAA (ATPases associated with diverse cellular notype (Moser et al. 1995). Patients with ZS show neu- activities) protein (Portsteffen et al. 1997; Reuber et al. 1997; Tamura et al. 1998a). Approximately 65% of pa- Received March 7, 2001; accepted for publication April 17, 2001; tients affected with peroxisome biogenesis disorders electronically published June 1, 2001. (PBDs [MIM 601539]) belong to this group (Moser et Address for correspondence and reprints: Dr. Gabriele Dodt, Institut al. 1995; Maxwell et al. 1999; Wanders et al. 1999). fu¨ r Physiologische Chemie, Abteilung fu¨ r Systembiochemie, Ruhr- The clinical phenotypes of patients belonging to this Universita¨t Bochum, Universita¨tsstrasse 150, 44801 Bochum, Ger- group cover a spectrum of severity, ranging from ZS to many. E-mail: [email protected] ᭧ 2001 by The American Society of Human Genetics. All rights reserved. NALD and IRD. 0002-9297/2001/6901-0005$02.00 With respect to the molecular basis of these pheno- 35 36 Am. J. Hum. Genet. 69:35–48, 2001 Table 1 Intronic Primer Pairs Used to Amplify the HsPEX1 Exons for SSCP Analysis Sense (s) or Sequence Designation Antisense (as) 5-CTTTGCGGCGCTAGGGT-3 5inex1 s 5-GGCTGAAGATCAGGTGGCTC-3 3inex1 as 5-AAAATGTATACGAAAACCTTTTTTCC-3 5inex2 s 5-ATGTGATATTAGAAGAAAGTTATTGC-3 3inex2 as 5-GATTACATAGACTACATATACACCC-3 5inex3 s 5-CATTGATATTGTGAAGTAATTTAACC-3 3inex3 as 5-ATTTTTTTTAACTAGATATGGAGTGG-3 5inex4 s 5-GCACATTCATTTCTACTTTGGACTC-3 3inex4 as 5-AGAAATGAATGTGCACTAATGAGC-3 5inex5 s 5-TAAGAATTCGGAAATACATGAATGGCACAG-3 3exex5 as 5-CGCGTCAGCAACCTCTG-3 5exex5 s 5-TGTTTAAGCCACATAAAATTTCTCC-3 3inex5 as 5-TAGAAGCTAATATATCAATATTTATGC-3 5inex6 s 5-CAACTAGAAATCTTACAAAACGTG-3 3inex6 as 5-GTTAAAGTTAAGTTCAGATATGAGG-3 5inex7 s 5-TACAACTATTTAAATAGAAAAAAAAGTC-3 3inex7 as 5-CTCTGTTTCAGTACTAACTCTGC-3 5inex8 s 5-CAAGGTGTTACAAGGAACTTCATA-3 3inex8 as 5-AAGACATACTTTGAAATGTAAAACTG-3 5inex9 s 5-TTGACATTAACATCTACTTTAATATTTAC-3 3inex9 as 5-TCAGTCTTTTATCATGTAACTATGTAT-3 5inex10 s 5-TATTAAATGTTACAGAAAAATGAACAC-3 3inex10 as 5-CTGAATCTTGGTGGTTGCC-3 5inex11 s 5-GATATGTGTATTTATTAGATTGACAG-3 3inex11 as 5-GCACTGAAATGATACTGAAACCAT-3 5inex12 s 5-GACTGACAAAAGAACAAGACCTTA-3 3inex12 as 5-TACTTTTCCTAAGCTTTTGCACTA-3 5inex13 s 5-TATAAAAGGGACATAATTCAATAATC-3 3inex13 as 5-CTGATTTTCTCCAAATATACATTCAA-3 5ines14 s 5-TAGAAAGAAGATTCCAAGTTCAGG-3 3inex14 as 5-TATAGTGAATAATAACTAGTAAAAGAAG-3 5inex15 s 5-CATAAAGCCAAAGCCAATAATACAG-3 3inex15 as 5-TTAGTCATTTCTGTTTAGACTTGAG-3 5inex16 s 5-TTTACACTTTGAAATGGCTAACTG-3 3inex16 as 5-ATTTCCATGATTCATTTACACTTAG-3 5inex17 s 5-TGATTGATAAATAATAACAGAGTCAG-3 3inex17 as 5-ACTTTGCCAACTATGAAGCCTG-3 5inex18 s 5-ACCAAAATCTGATGACATGATGAC-3 3inex18 as 5-GTCATCATGTCATCAGATTTTGGT-3 5inex19 s 5-TAGCATTTGTTGGGTTTTGGAC-3 3inex19 as 5-ATTTATGAAGAAAATCATAAGATACAC-3 5inex20 s 5-TGACATTGTACTTCTTTTATCACTC-3 3inex20 as 5-TAAAATTGTTTACATCTTTAAACTGG-3 5inex21 s 5-AGAAATCACTGCAACTTTACACC-3 3inex21 as 5-GTTTTTTCTCTCCCCCTCTTCC-3 5inex22 s 5-TAAGAAGTTTTAACAATTATAATGAGG-3 3inex22 as 5-TTTTACATCCTTAATTTAACTCTTCG-3 5inex23 s 5-ACTTGTAATAGTAGCTGTACTTCC-3 3inex23 as 5-ATCCATTATCTTTTGTTTTGTAATGG-3 5inex24 s 5-CTGTTACAACATATGGAAAAGCC-3 3inex24 as NOTE.—Examples for designations: 5inexE is the sense primer attaching to the 5 end of exon E, and 3inexE is the antisense primer attaching to the 3 end of exon E. types, two relatively common alleles in the HsPEX1 gene 1999), and a second allele with a 1-bp insertion (c.2097- have been identified: one allele with a missense mutation 2098insT) resulting in a premature stop at amino acid (G843D) associated with milder PBDs (Portsteffen et al. 740, a mutation that is often present in patients with 1997; Reuber et al. 1997; Imamura et al. 1998a; Collins classical ZS (Collins and Gould 1999; Maxwell et al. and Gould 1999; Ga¨rtner et al. 1999; Maxwell et al. 1999). Fibroblasts harboring the G843D allele are char- Table 2 Relationships between Genotype, Clinical Phenotype, Biochemical Parameters, and the PEX1 Protein Level, in Fibroblasts from Patients of CG1 MUTATION (CDNA LEVEL,PROTEIN LEVEL) DISEASE CATEGORY AGE AT DEATH PEX1 PROTEIN LEVEL VLCFA DHAPAT ACTIVITYb AND PATIENT IIIOR AT PRESENT (% of control) C26:C22 RATIOa (nmol/2h # mg protein) Nonclassical ZS: 2 c.2528GrA, G843D c.2528GrA, G843D 2 years, 9 mo ∼3 .45 .5 22 c.2528GrA, G843D c.2528GrA, G843D 9 years !10 .30 2.1 26c c.2528GrA, G843D c.2528GrA, G843D 8 years, alive ∼15 .18 .2 27c c.2528GrA, G843D c.2528GrA, G843D 27 years, alive ∼10 .12 2.4 31c c.2528GrA, G843D c.2528GrA, G843D 45 years, alive ∼7 .49 1.4 10c c.2528GrA, G843D c.2097-2098insT, P740X 41 years, alive ∼5 .29 1.2 13c c.2528GrA, G843D c.2097-2098insT, P740X 5.5 years, alive !5 .39 .6 20 c.2528GrA, G843D c.2097-2098insT, P740X 9 years 5–10 .27 1.9 28 c.2528GrA, G843D c.2097-2098insT, P740X 2.5 years 5–10 .70 1.5 30c c.2528GrA, G843D c.2097-2098insT, P740X 21 years, alive !5 .18 1.4 7d c.2528GrA, G843D 3850TrC, X1284Q Unknown, 12 years ∼3 .28 nde 9c c.1777GrA, G593R c.2071ϩ1GrT 6 years, alive ∼7 .12 4.3 1.07ע1.59 16.עSD .31 ע Mean Classical ZS: 1 c.2528GrA, G843D c.2846GrA, R949Q 3 mo ∼50 .34 2.0 17 c.2097-2098insT, P740X c.2097-2098insT, P740X 2 mo 0 .52 .5 19 c.2097-2098insT, P740X c.2097-2098insT, P740X Unknown 0 .32 1.1 23 c.2097-2098insT, P740X c.2097-2098insT, P740X 1 year 0 .60 .5 6 c.788-789delCA, T268X c.2097-2098insT, P740X 3 mo 0 .73 .5 16 c.2926ϩ2TrC c.2097-2098insT, P740X Unknown 0 .33 .5 11 c.2730delA, V960X c.2730delA, V960X 3 mo 0 .31 .1 12 c.2730delA, V960X c.2730delA, V960X 3 mo 0 .48 .1 14 c.1670ϩ5GrT c.1670ϩ5G-T 18 mo 0 .61 .1 5 c.434-448delf c.2008CrA, L670M 1 day 0 .59 .4 55.ע58. 14.עSD .48 ע Mean a Control values: mean p .04; range p .03–.07. .nmol/2h # mg protein 2.0 ע b Control value: 8.5 c Patient’s phenotype is IRD. d Patient’s phenotype is NALD. e nd p not determined. f Patient has c.434-448del and insertion of GCAA. 38 Am. J. Hum. Genet. 69:35–48, 2001 Figure 1 Common mutations of CG1, and resulting PEX1 protein levels.
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