UvA-DARE (Digital Academic Repository) Molecular, biochemical end clinical aspects of peroxisomes biogenesis disorders Gootjes, J. Publication date 2004 Link to publication Citation for published version (APA): Gootjes, J. (2004). Molecular, biochemical end clinical aspects of peroxisomes biogenesis disorders. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:30 Sep 2021 Chapterr 8 Mutationall spectrum of peroxisome biogenesis disorders Jeannettee Gootjes, Josephine Vos, Geert T. Prins, Frank Schmohl, Janet Haasjes, Ronald J.A. Wanders,, Hans R. Waterham, parts of this chapter have been submitted for publication Chapterr 8 Mutationall spectrum of peroxisome biogenesis disorders Jeannettee Gootjes1, Josephine Vos1, Geert T. Prins1, Frank Schmohl1, Janet Haasjes1, Ronald J.A.. Wanders1-2, Hans R. Waterham2 Lab.Lab. Genetic Metabolic Diseases, Departments of Clinical Chemistry and "-Pediatrics (Emma Children'sChildren's Hospital), Academic Medical Centre - University of Amsterdam, Amsterdam, The Netherlands Netherlands Abstract t Peroxisomess are organelles that play an indispensable role in a large variety of metabolic processes,, including fatty acid a- and (3-oxidation and plasmalogen biosynthesis. The importancee of peroxisomes is underlined by the existence of several disorders caused by a dysfunctionn of peroxisomes. These disorders can be divided into single enzyme defects andd peroxisome biogenesis disorders (PBDs). The PBDs form a clinically and genetically heterogeneouss group of disorders due to defects in at least 13 distinct genes. The prototypee of this group of disorders is Zellweger syndrome with neonatal adrenoleukodystrophyy and infantile Refsum disease as milder variants. Common to PBDs aree liver disease, variable neurodevelopmental delay, retinopathy and perceptive deafness.. The PBDs are caused by mutations in the PEX genes, encoding proteins involved inn peroxisomal membrane biogenesis and peroxisomal matrix protein import. We here reportt the various mutations we identified so far in the different PEX genes. In addition, wee have listed all mutations reported in literature to date, to present a complete overview off the mutational spectrum of PBDs. Frequently occurring mutations are discussed as well ass the effects of the mutations on the encoded proteins and cellular and clinical phenotypes. Introduction n Peroxisomess are essential single-membrane bounded organelles found in virtually all eukaryoticc cells. They play an indispensable role in a large variety of metabolic pathways, includingg in man, among others, 1) fatty acid (3-oxidation of very-long chain fatty acids (VLCFAs),, notably C26:0, and of branched chain fatty acids, such as pristanic acid and the bilee acid intermediates di- and trihydroxycholestanoic acid, 2) etherphospholipid biosynthesis,, 3) phytanic acid a-oxidation and 4) L-pipecolic acid oxidation.1 The importancee of peroxisomes for human health and survival is underlined by the severe consequencess of defects in peroxisomal functions. These defects range from single enzyme deficienciess (e.g. X-linked adrenoleukodystrophy, Refsum disease) to defects resulting in a completee absence of functional peroxisomes, collectively known as the peroxisome biogenesiss disorders (PBDs). Thee PBDs include Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD) andd infantile Refsum disease (IRD). These disorders represent a spectrum of disease severityy with ZS being the most, and IRD the least severe disorder. Common to all three PBDss are liver disease, variable neurodevelopmental delay, retinopathy and perceptive deafness.11 Patients with ZS are severely hypotonic from birth and die before one year of 92 2 Mutationall spectrum of PBDs age.. Patients with NALD experience neonatal onset of hypotonia and seizures and suffer fromm progressive white matter disease, and usually die in late infancy.2 Patients with IRD mayy survive beyond infancy and some may even reach adulthood.3 Clinical differentiation betweenn these disease states is not very well-defined and patients can have overlapping symptoms.44 Due to the absence of functional peroxisomes in patients with a PBD, most peroxisomall metabolic functions are disturbed, resulting in accumulations of VLCFAs, pristanicc acid, bile acid intermediates, phytanic and L-pipecolic acid, and a deficiency of plasmalogens. Alll PBDs are autosomal recessively inherited and can be caused by mutations in at leastt 12 different PEX genes. These PEX genes encode proteins called peroxins, which are requiredd for the biogenesis of peroxisomes and either function in the assembly of the peroxisomall membrane or in the import of proteins (enzymes) into the peroxisome.5 The peroxinss PEX3, PEX 16 and PEX19 are involved in the assembly of the peroxisomal membranee as is also clear from the complete absence of peroxisomal remnants in cells of patientss with two severe mutations in any of the encoding genes. Cells of patients with twoo severe mutations in any of the other PEX genes still have peroxisomal remnants ("ghosts")) that contain some peroxisomal membrane proteins, but lack most of their matrixx proteins. These cell lines have a defect in the import of peroxisomal matrix enzymes,, implying that the encoding peroxins are involved in peroxisomal protein import. Afterr synthesis on free polyribosomes, peroxisomal matrix proteins carrying either a carboxy-terminall peroxisomal targeting sequence 1 (PTS1) or a cleavable amino-terminal PTS22 signal are recognized by the PTSl-receptor PEX5 and the PTS2-receptor PEX7 (see figuree 2, chapter 1). The resulting receptor-matrix protein complexes subsequently dock at thee peroxisomal membrane, a process in yeast facilitated by the peroxins PEX13, PEX14 andd PEX17. In humans, however, no PEX17 ortholog has been identified yet. The matrix proteinss are then translocated over the peroxisomal membrane, a process involving PEX2, PEX10,, and PEX12. The PTS-receptors likely are co-imported with their cargo and leave thee peroxisome after delivering their cargo.6 PEX1 and PEX6 have been proposed to be involvedd in the recycling of the receptors. The recently discovered PEX26 was shown to anchorr PEX6 and PEX1 to the peroxisomal membrane.7 Different isoforms of PEX11 have beenn postulated to play a regulatory role in peroxisome proliferation, after the finding that yeastt cells lacking PEX11 contain few giant peroxisomes and appear to be unable to segregatee the giant peroxisomes to daughter cells.8 Because of the different cellular phenotypee in yeast, as well as in the mouse PEX11 knock-out model9 a PEX11 deficiency is nott considered to be a PBD. Thee laboratory diagnosis of patients suspected to be affected with a PBD starts with the analysiss of various parameters in plasma (concentrations of VLCFAs, pristanic acid, phytanicc acid, bile acid intermediates, poly-unsaturated fatty acids and L-pipecolic acid) andd erythrocytes (plasmalogens).10 When the results point to a PBD, this is followed by the measurementt of various parameters in cultured skin fibroblasts (VLCFA concentration, C26:00 and pristanic acid (3-oxidation, phytanic acid a-oxidation, dihydroxyacetonephosphate-acyltransferasee activity and immunoblot analysis). The diagnosiss is completed by immunofluorescence microscopy with antibodies against the peroxisomall enzyme catalase, to confirm the absence of peroxisomes, and with antibodies againstt the peroxisomal membrane protein ALDP to reveal the presence or absence of peroxisomall ghosts in the fibroblasts. 93 3 Chapterr 8 Whenn the diagnosis of a PBD is established, cell fusion complementation analysis is performed,, to identify the defective PEX gene." In this technique, fibroblasts from a new patientt are fused with cells from a patient belonging to a known complementation group, therebyy combining the genetic information of both patients. When the cells do not complementt each other and there is no restoration of peroxisome formation, the defective geness in both patients are the same. If peroxisomes are formed, the defective gene in both patientss is different. Peroxisome formation is assayed by catalase immunofluorescence microscopy. Tablee 1 Results of complementation studies in 246 patients:: the Amsterdam experience Complementationn Group KKI* * Gifu" " Gene e Patients s %c c 1 1 E E PEX1 1 174 4 59 9 2 2 PEX5 5 5 5 2 2 3 3 PEX12 2 16 6 6 6 4 4 C C PEX6 6 31 1 12 2 7 7 B B PEXX 10 3 3 1 1 8 8 A A PEX26 6 4 4 2 2 9 9 D D PEX16 6 2 2 1 1 10 0 F F PEX2 2 7 7 3 3 11 1 R R PEX7 7 n.i. n.i. 12 2 G G PEX3 3 0 0 0 0 13 3 H H PEX13 3 2 2 1 1 14 4 J J PEX19 9 2 2 1 1 'Kennedyy Krieger institute, Baltimore, USA, bGifu univerisry,, Gifu, Japan,