Peroxisome Biogenesis Disorders

Abstract

Peroxisome biogenesis disorders (PBDs) are autosomal recessive, progressive disorders characterised by loss of multiple peroxisomal metabolic functions and defects in peroxisome assembly, consisting of 13 complementation groups (CGs). Two mutually distinct but complementary approaches, forward genetic approach using more than a dozen CGs of peroxisome‐deficient Chinese hamster ovary (CHO) cell mutants and the homology search by screening the human expressed sequence tag (EST) database using yeast peroxin (PEX) genes, have been taken in order to isolate mammalian PEX genes. Search for pathogenic genes responsible for PBDs of all 13 CGs is now accomplished. Prenatal DNA diagnosis using PEX genes is now possible for PBDs of all 13 CGs. Moreover, molecular mechanisms underlying peroxisome biogenesis involving membrane assembly and matrix protein import are currently investigated by making use of PEX genes and pex cell mutants.

Key Concepts:

  • A single cell comprises more than a dozen different organelles that have unique protein compositions. Mechanisms underlying when and how these proteins are transported should be defined.

  • The ways how the diverse sequences of proteins are recognised for translocation by the transport systems/machineries need to be delineated.

  • The proteins and the lipid environment catalysing the protein transport must be addressed.

  • Furthermore, during the cell cycle, each organelle must double in size, divide, and be delivered to its proper location in the daughter cells. How such events are accomplished and regulated should be defined.

  • In tackling such issues, genetic phenotype complementation screening using mammalian somatic cell mutants and by taking advantage of highly sensitive and rapid detection may lead to cloning of genes essential for protein trafficking and organelle assembly.

  • Mutations in genes are permanent alterations that may lead to changes in phenotype. Cell mutants are a highly useful tool in genetic, biochemical, as well as cell biological research.

  • Several methods including the most recent lipofection have been developed for transfecting DNA into animal cells.

  • Peroxisome biogenesis disorders (PBDs) are autosomal recessive, progressive disorders characterised by loss of multiple peroxisomal metabolic functions and defects in peroxisome assembly, consisting of more than a dozen complementation groups.

  • Genetic phenotype‐complementation of peroxisome assembly‐defective mutants of mammalian somatic cells such as Chinese hamster ovary (CHO) cells and of several yeast species including Saccharomyces cerevisiae and Pichia pastoris would lead to identification and characterisation of numerous genes that are essential for peroxisome biogenesis.

Keywords: peroxisome biogenesis disorders; Zellweger syndrome; phenotype; CHO cell mutants; PEX genes; peroxin; pathogenic genes; forward genetics; genetic phenotype complementation assay

Figure 1.

Peroxisome biogenesis disorders. (a) Patient with Zellweger syndrome. Severe hypotonia, multiple dysmorphism and hepatomegaly are distinct in this patient. (b) Immunofluorescent staining of peroxisomes. Skin fibroblasts were stained with anti‐catalase antibody. Cells were from a normal control (1) and a PBD patient with Zellweger syndrome (2). Scale: 20 μm.

Figure 2.

A schematic view of peroxisome biogenesis in mammals. The intracellular location and molecular properties of peroxins are shown. Peroxins are divided into three groups: (1) peroxins that are required for matrix protein import; (2) those including Pex3p, Pex16p and Pex19p, responsible for peroxisome membrane assembly (see Figure ); (3) those such as three forms of Pex11p, Pex11pα, Pex11pβ, and Pex11pγ, apparently involved in peroxisome proliferation where DLP1 and Fis1 co‐ordinately function. PTS1 and PTS2 proteins are recognised by Pex5p and Pex7p, respectively, in the cytoplasm. Two isoforms, Pex5pS and Pex5pL, of Pex5p are identified in mammals. PTS1 proteins are transported by homo‐ and hetero‐oligomers of Pex5pS and Pex5pL to peroxisomes, where Pex14p functions as a convergent, initial docking site of the ‘protein import machinery’ translocon. Pex5pL directly interacts with the PTS2 receptor, Pex7p, carrying its cargo PTS2 protein in the cytosol and translocate the Pex7p–PTS2 protein complex to Pex14p. PTS1 and PTS2 proteins are then released at the inner surface and/or inside of peroxisomes, downstream Pex14p and upstream Pex13p. Pex5p and Pex7p subsequently translocate to other translocon components such as the RING peroxins, Pex2p, Pex10p and Pex12p. Both Pex5p and Pex7p finally shuttle back to the cytosol. In regard to peroxisome‐cytoplasmic shuttling of Pex5p, Pex5p initially targets to an 800‐kDa complex containing Pex14p and then translocates to a 500‐kDa complex comprising RING peroxins. At the terminal step of the protein import reaction, Pex1p and Pex6p of the AAA family catalyse the export of Pex5p, where ubiquitination of Pex5p is most likely prerequisite for the Pex5p exit.

Figure 3.

A model for early stages of peroxisomal membrane biogenesis involving mutually dependent targeting of Pex3p and Pex16p. The initial membranes harbouring Pex3p or Pex16p culminate in indistinguishable, matured peroxisomes. Pex19p forms complexes with newly synthesised PMPs including Pex16p in the cytosol and transports them to the membrane protein receptor Pex3p, whereby peroxisome membrane is assembled (Class I pathway). With respect to biogenesis of Pex3p, Pex19p likewise forms a complex with newly synthesised Pex3p and translocates it to the Pex3p receptor Pex16p (Class II pathway). Of note, peroxisomes are assembled no matter which pathway initially proceeds.

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Further Reading

Applegarth DA, Wanders RJA, Shutgens RBH et al. (1997) Peroxisomal disorders. In: Applegarth DA, Dimmick JE and Hall JG (eds) Organelle Diseases, 1st edn, pp. 143–232. London: Chapman & Hall Medical.

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Web Links

Zellweger syndrome (ZS); LocusID: 7788. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=7788

Zellweger syndrome (ZS); MIM number214100. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?214100

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Fujiki, Yukio(May 2011) Peroxisome Biogenesis Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006109.pub2]