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Molecular Basis for Peroxisome Biogenesis Disorders

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Molecular Machines Involved in Peroxisome Biogenesis and Maintenance

Abstract

The functional importance of peroxisomes in humans is highlighted by peroxisome-deficient peroxisome biogenesis disorders (PBDs) such as Zellweger syndrome (ZS), autosomal recessive, and progressive disorders characterized 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. Gene defects of peroxins required for both membrane assembly and matrix protein import are identified: ten mammalian pathogenic peroxins, Pex1p, Pex2p, Pex5p, Pex6p, Pex7p, Pex10p, Pex12p, Pex13p, Pex14p, and Pex26p, for 10 CGs of PBDs, are required for matrix protein import; three, Pex3p, Pex16p, and Pex19p, are essential for peroxisome membrane assembly and responsible for the most severe ZS in PBDs of three CGs, 12, 9, and 14, respectively; PEX11β mutation causes dysmorphogenesis of peroxisomes in ZS-like phenotype of CG16. Patients with severe ZS with defects of PEX3, PEX16, and PEX19 tend to carry severe mutation such as nonsense mutations, frameshifts, and deletions. Prenatal DNA diagnosis using PEX genes is now possible for PBDs of all 13 CGs.

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Abbreviations

CG:

Complementation group

CHO:

Chinese hamster ovary

ER:

Endoplasmic reticulum

PBD:

Peroxisome biogenesis disorder

PMP:

Peroxisomal membrane protein

PTS:

Peroxisomal targeting signal

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Acknowledgments

We thank K. Shimizu for figure illustrations. This work was supported in part by a CREST grant (to Y.F.) from the Science and Technology Agency of Japan, Grants-in-Aid for Scientific Research (19058011, 20370039, 24247038, 25112518, and 25116717 to Y.F.; 21770117 and 24770130 to K.O.; 21570116 and 24570134 to S.T.), Global Center of Excellence (GCOE) Program, Grants for Excellent Graduate Schools from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and grants (to Y.F.) from Takeda Science Foundation and Japan Foundation for Applied Enzymology.

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  1. Faculty of Sciences, Department of Biology, Kyushu University Graduate School, Fukuoka, 812-8581, Japan

    Y. Fujiki, K. Okumoto, S. Mukai & S. Tamura

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  1. Y. Fujiki
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  2. K. Okumoto
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  3. S. Mukai
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  4. S. Tamura
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Correspondence to Y. Fujiki .

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  1. Mauerbach, Austria

    Cecile Brocard

  2. Max F. Perutz Laboratories University of Vienna, Vienna, Austria

    Andreas Hartig

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Fujiki, Y., Okumoto, K., Mukai, S., Tamura, S. (2014). Molecular Basis for Peroxisome Biogenesis Disorders. In: Brocard, C., Hartig, A. (eds) Molecular Machines Involved in Peroxisome Biogenesis and Maintenance. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1788-0_5

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