Molecular basis for peroxisome biogenesis disorders

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.