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Zellweger Syndrome) (Peroxisome Disease/Organelie Biogenesis/Sodium Carbonate Membrane Isolation/Immunoblots/Kidney) PAUL B

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Zellweger Syndrome) (Peroxisome Disease/Organelie Biogenesis/Sodium Carbonate Membrane Isolation/Immunoblots/Kidney) PAUL B Proc. Nati. Acad. Sci. USA Vol. 83, pp. 9193-9196, December 1986 Medical Sciences Presence of the peroxisomal 22-kDa integral membrane protein in the liver of a person lacking recognizable peroxisomes (Zellweger syndrome) (peroxisome disease/organelie biogenesis/sodium carbonate membrane isolation/immunoblots/kidney) PAUL B. LAZAROW*t, YUKIO FuJIKI*t, GILLIAN M. SMALL*, PAUL WATKINS§, AND HUGO MOSER§ *The Rockefeller University, New York, NY 10021; and §The John F. Kennedy Institute and Department of Neurology, The Johns Hopkins University, Baltimore, MD 21205 Communicated by DeWitt Stetten, Jr., August 11, 1986 ABSTRACT Peroxisomes have not been detected in liver consequences. Two possible defects are in the assembly of and kidney of patients with Zellweger syndrome. Some peroxi- the peroxisome membrane or in the import of matrix pro- some proteins are missing; others are present in normal teins. This paper communicates our first step in investigating amounts but are located in the cytosol. We have prepared an peroxisome membrane proteins in Zellweger syndrome. We antiserum against the 22-kDa integral membrane protein show that normal human liver contains an integral membrane characteristic of rat liver peroxisomes. The antiserum cross- protein that is the same size as, and cross-reacts immuno- reacts with the human liver counterpart, which likewise has a logically with, the 22-kDa integral membrane protein (22IMP) mass of 22 kDa. By immunoblot analysis, we demonstrate that that we previously demonstrated to be located exclusively in the 22-kDa protein is present in normal amount in Zellweger peroxisomes in rat liver (17). Rat 22IMP is synthesized on liver and is integral to a membrane. The result suggests that free polysomes at its final size (18). We report immunoblot peroxisome membranes are assembled in Zellweger syndrome analyses of this and other peroxisomal proteins in Zellweger but may be defective for the import of matrix proteins. As a liver and kidney. result, newly synthesized proteins are left in the cytosol, where some persist and others are degraded. Lacking their usual CASE HISTORY content, such aberrant peroxisomal membranes would be Patient RA presented as a classic example of Zellweger unrecognizable morphologically. Immunoblot analyses also syndrome. This girl was the first child of unrelated healthy showed that the peroxisomal hydratase-dehydrogenase is de- parents. Pregnancy was uneventful and birth weight was 3.0 ficient in Zellweger kidney as well as liver, but catalase is kg. The diagnosis of Zellweger syndrome was suggested by present in both organs. severe hypotonia and characteristic dysmorphic features including high forehead, wide-open fontanels, posteriorly Zellweger syndrome (1-4) is a fatal disease in which peroxi- rotated ears, high arched palate, simian creases, and equinus some assembly appears to be defective. Peroxisomes are deformity of feet. Chondrodysplasia calcificans was present abundant in normal human liver and kidney but have not been in the patellae and hips. Seizures were first noted at 1.5 weeks detected in these organs in Zellweger patients despite careful and were treated with phenobarbital. She required feeding by searches by electron microscopy and by electron microscop- nasogastric tube and intermittent oxygen therapy. She re- ic cytochemistry that reveals catalase (a characteristic mained unresponsive and severely hypotonic. She had sev- peroxisomal enzyme) (5-7). Peroxisomal proteins are syn- eral episodes of massive gastrointestinal bleeding. Pneumo- thesized at normal rates in patients with Zellweger syndrome nia caused her death at 4 months. Postmortem examination (8), but some fail to accumulate. These include the - showed patchy periportal and sinusoidal hepatic fibrosis. The oxidation enzymes (7, 9) and the first enzyme in the synthesis kidneys were studded with multiple cortical cysts. Adrenal of plasmalogens, dihydroxyacetone phosphate acyltransfer- cortical cells showed cytoplasmic inclusions characteristic of ase (10, 11). Very long chain fatty acids (C24, C26) accumulate Zellweger syndrome or adrenoleukodystrophy. (12, 13) and plasmalogens are deficient (14); death usually Control patients were a 2.5-year-old boy who died with no occurs within the first year after birth, often within weeks or history of liver disease (C in ref. 7), a 5.5-year-old female months. Farber disease patient (acid ceramidase deficiency), a 6-year- Other peroxisomal enzymes-e.g., catalase-accumulate old male X-linked adrenoleukodystrophy patient, and a to normal levels. However, the catalase is neither latent (15) woman who died of cancer at age 75. Postmortem liver and nor sedimentable (7), indicating that the enzyme is located in kidney biopsy samples were kept frozen at -80°C. the cytosol ofthe cell. These observations are consistent with our current understanding of peroxisome biogenesis (16): METHODS peroxisomal proteins are synthesized on free polyribosomes Biochemical Methods. Pieces of frozen tissue were sepa- and are imported posttranslationally into preexisting rated with a serrated knife, thawed, and homogenized in 4 vol peroxisomes, generally without proteolytic processing. Old of 0.25 M sucrose/5 mM imidazole buffer, pH 7.0/0.1% peroxisomes divide to form new ones. In the absence of ethanol with a Potter-Elvehjem homogenizer. Protein was peroxisomes, the newly synthesized proteins would be left in determined according to Lowry et al. (19) with bovine serum the cytosol, where some would be degraded, perhaps by the albumin as standard. Very long chain fatty acids (12), bile ubiquitin-mediated system, while others might survive. acids (20), and pipecolic acid (21) were measured as de- Zellweger syndrome is an autosomal recessive disease, scribed. which implies that a single genetic defect causes all the above Abbreviation: 22IMP, 22-kDa integral membrane protein of perox- isomes. The publication costs of this article were defrayed in part by page charge tTo whom reprint requests should be addressed. payment. This article must therefore be hereby marked "advertisement" *Present address: Meiji Institute of Health Science, 540 Naruda, in accordance with 18 U.S.C. §1734 solely to indicate this fact. Odawara, 250 Japan. 9193 Downloaded by guest on September 23, 2021 Proc. Natl. Acad. Sci. USA 83 (1986) Liver Kidney rated by NaDodSO4/PAGE in 7-15% polyacrylamide slab R C C Z C C Z CC gels (22) and immunoblotted by a modification (18) of Burnette's procedure (25). The antibody raised against peroxisomal 22IMP (rabbit no. 10-270) detected one major band (with a mass of22 kDa) in blots ofrat liver homogenates, and this antigen cosedimented with peroxisomes in cell fractionation experiments (not shown). The antiserum cross- reacted with a protein ofthe same size in control human liver 68 (Fig. 1). This human protein was an integral membrane protein by the criterion of not being solubilized by the carbonate procedure (22). Fibroblast Culture and Analyses. Skin fibroblasts were cultured as described (26). Fibroblasts from two 10-cm dishes were harvested by trypsinization, washed in 0.25 M sucrose/20 mM 4-morpholinepropanesulfonic acid (Mops), pH 7, and lysed with digitonin at 100 gg/ml in 800 /.l of the above medium. Half of the cell lysate was centrifuged for 10 min in a Fisher microcentrifuge. Catalase was assayed (27) (in 26-k the presence of0.1% Triton X-100) in the pellet, supernatant, and starting material. One unit ofcatalase decreases the H202 concentration to 1/10th in 1 min in a volume of 50 ml (28). Materials. 1251-labeled staphylococcal protein A was from New England Nuclear. Molecular mass standards were from .e-'i8^3'% 22LMIP Bethesda Research Laboratories: rabbit muscle phosphoryl- ase b (97.4 kDa), bovine serum albumin (68 kDa), ovalbumin 18-. U~ (45 kDa), a-chymotrypsinogen (25.7 kDa), bovine milk f- lactoglobulin (18.4 kDa), and egg white lysozyme (14.3 kDa). All other reagents were of analytical grade. RESULTS Patient RA had greatly increased concentrations of very long 1 2 3 4 5 6 7 8 9 chain fatty acids (C26 and C24) in plasma and in cultured skin FIG. 1. Immunoblot analysis of the peroxisomal 22IMP. Mem- fibroblasts (Table 1). An intermediate in the conversion of branes were isolated (22) from 200 ,g of homogenate (human liver cholesterol to bile acids, trihydroxycholestanoic acid, had and kidney) or 100 ug of rat liver. Z, Zellweger patient; C, human accumulated to very high levels in serum (Table 1). The blood controls; R, rat. The molecular mass markers are indicated in kDa to pipecolic acid concentration was slightly elevated. These the left. biochemical abnormalities are characteristic of Zellweger syndrome (12, 13, 21, 29). Total membranes were purified from the homogenates by Cultured skin fibroblasts from RA contained normal the carbonate procedure described previously (22). Treat- amounts of catalase activity, but the enzyme was not ment with 0.1 M Na2CO3 at 0°C for 30 min causes organelle sedimentable (Table 2), indicating that it was located in the membranes to rupture, releases matrix proteins, and strips cell cytosol, not in peroxisomes. off peripheral membrane proteins. The membranes, recov- By immunoblotting analysis, RA's liver lacked the ered by high-speed centrifugation, retain their phospholipids, peroxisomal bifunctional hydratase-dehydrogenase (Fig. 2 integral proteins, and characteristic trilamellar appearance. Left, lane 4) but contained normal amounts of catalase (Fig. Antiserum Preparation and Immunoblots. Rabbit antiserum 2 Right,
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