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ABSTRACT

  1. Peroxisomes are single-membrane bounded organelles present in virtually all eukaryotic cells. Their shape, size, and number vary depending on the cell type and metabolic state. The peroxisomal membrane has organelle-specific integral membrane proteins. The matrix contains more than 50 enzymes for a variety of anabolic and catabolic functions. Peroxisomes are of interest because of their importance for the biology of the cell and their vital functions in health and disease.

  2. Peroxisome biogenesis includes synthesis of the membrane and matrix proteins in the cytosol followed by receptor-mediated import into the organelle. It also requires the expansion of the peroxisomal membrane and fission of peroxisomes during peroxisome proliferation. Peroxisome biogenesis pathways seem to be species specific; the organelle may be generated by growth and subsequent division of existing organelles and/or by the formation of new peroxisomes from the endoplasmic reticulum. The proteins involved in and necessary for peroxisome biogenesis are referred to as PEX proteins or peroxins. The respective genes are the PEX genes. To date, 16 human peroxins are known, and 35 altogether in all species.

  3. Inherited peroxisomal diseases include isolated deficiency of specific peroxisomal matrix proteins or defects in peroxisome biogenesis. The latter peroxisome biogenesis disorders are characterized by deficiency of several peroxisomal functions and include two distinct phenotypic spectra, Zellweger syndrome spectrum (ZSS) and rhizomelic chondrodysplasia punctata type 1 (RCDP1). Affected individuals have characteristic clinical features including dysmorphism and neurological impairment of variable severity. Biochemical markers including plasma very long chain fatty acids and cell membrane plasmalogens are abnormal. The primary genetic defects are mutations in any of 13 different PEX genes for ZSS and mutations in PEX7 for RCDP1.

  4. The effectiveness of treatment in patients with PBD is limited by the occurrence of multiple malformations that originate in fetal life prior to recognition of the need for therapy. Current treatments are largely symptomatic. The effort to develop effective therapies for these patients is supported by functional studies on peroxins together with thorough clinical, metabolic, and cellular characterization of mutant phenotypes in cell and animal models, which provide insight into the normal biology of peroxisome assembly and function as well as into the pathophysiology of PBD.

INTRODUCTION

Peroxisomes are organelles present in nearly all eukaryotic cells. They were recognized as biochemical and morphological entities with distinct metabolic functions about 50 years ago by the pioneering work of Christian De Duve and Baudhuin.1 Interest in peroxisomes stems from their role in biochemistry and cell biology and from their vital functions in health and disease.

Peroxisomal disorders represent a genetically and clinically heterogeneous group of inborn errors of metabolism with impaired peroxisome function. They are divided into two major categories. The first category, the peroxisome biogenesis disorders (PBDs), comprises disorders resulting from failure in organelle formation and is associated with multiple metabolic abnormalities. The second category includes disorders resulting from the deficiency of a single peroxisomal enzyme or protein with ...

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