**Part 3**

**Multifactorial or Polygenic Disorder** 

318 Advances in the Study of Genetic Disorders

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Vanakker, O.M., Voet, D., Petrovic, M., van Robaeys, F., Leroy, B.P., Coucke, P., & de Paepe,

Vanakker, O.M., Martin, L., Gheduzzi, D., Leroy, B.P., Loeys, B.L., Guerci, V.I., Matthys, D.,

Vanakker, O.M., Leroy, B.P., Coucke, P., Bercovitch, L.G., Uitto, J., Viljoen, D., Terry, S.F.,

Vanakker, O.M., Martin, L., Schurgers, L.J., Quaglino, D., Costrop, L., Vermeer, C., Pasquali-

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**16** 

*Chile* 

*Facultad de Medicina,* 

**Peroxisomal Biogenesis:** 

Manuel J. Santos1 and Alfonso González2

*Pontificia Universidad Católica de Chile* 

**Genetic Disorders Reveal the Mechanisms** 

*1Departamento de Biología Celular y Molecular and Departamento de Pediatría,* 

*de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas,* 

*2Departamento de Inmunología Clínica y Reumatología, Facultad de Medicina, y Centro* 

Peroxisomes are small and abundant membrane-bound organelles that contain enzymes for a variety of metabolic functions, including ß-oxidation of fatty acids, synthesis of plasmalogens and bile acids, and H2O2 production (1, 2). A group of human genetic diseases involves peroxisomal disorders (3) derived from two type of alterations: i) defects in a single peroxisomal enzyme, as found in X-Linked Adrenoleukodystrophy and Acatalasemia; and ii) Peroxisome Biogenesis Disorders (PBDs), which include the Zellweger's Syndrome (ZS). Intense research has been devoted for decades to understand the mechanisms of biogenesis and maintenance of peroxisomes. Despite the paramount progress, there are still enigmatic aspects, specially regarding the pathways followed by peroxisomal membrane proteins and the origin of peroxisomal membrane precursors (2). Here we give an overview of the evidence that involves the endoplasmic reticulum (ER) from the most important genetic tools in the field: fibroblast cultures derived from Zellweger patients and yeast mutants.

**2.1 Zellweger's Syndrome (ZS) as the prototypic Peroxisome Biogenesis Disorder** 

ZS is characterized by craniofacial dysmorphia, neurological impairment, severe metabolic disturbances and neonatal death, caused either by complete absence of peroxisomes or by defects in protein importation into peroxisomal membrane precursors (1, 4-8). From the clinical point of view, a severity spectrum of these disorders has been established (SZ spectrum), including Neonatal Adrenoleukodystrophy (NALD; MIM 202370), Infantile Refsum disease (IRD; MIM] 266510) and SZ (ZS; MIM 214100) as the most severe (8). Initial studies in liver biopsies of ZS patients failed to find evidence of peroxisomal components and thus led to the notion that ZS patients lack peroxisomes (9). Later studies in Zellweger fibroblasts detected membranes containing peroxisomal membrane proteins (PMPs) but that lack most of the matrix proteins and were called "peroxisomal membrane ghosts" (10-12). Since then, a defect in the peroxisomal importing machinery for matrix proteins became

**2. Peroxisome biogenesis: challenging the paradigm** 

**1. Introduction** 

**(PBD)** 
