Zellweger syndrome (ZWS) is a disorder that is a member of a family of disorders that result from defects in the biogenesis and/or functioning of the peroxisomes and are referred to as peroxisome biogenesis disorders, PBDs. Although there are characteristic clinical features to Zellweger syndrome, this disorder is not due to defects in a single gene. In fact, at least 9 different loci have been associated with the development of Zellweger syndrome. These loci include:
the PEX1 gene on chromosome 7q21.2
the PEX2 gene on chromosome 8q21.1; the PEX2 gene is also known as the peroxisomal membrane protein 3, PXMP3
the PEX3 gene on chromosome 6q24.2; encodes a critical protein involved in targeting of proteins to the peroxisomal membrane
the PEX5 gene on chromosome 12p13.31; this gene encodes the receptor for proteins containing a PTS1 sequence for targeting to the peroxisomes, see below
the PEX6 gene on chromosome 6p21.1: functions with PEX5 encoded proteins in PTS1-containing protein targeting to peroxisomes
the PEX12 gene on chromosome 17q12
the PEX14 gene on chromosome 1p36.22; functions to interact with PEX5 encoded proteins that are bound to a PTS1-containing protein
the PEX26 gene on chromosome 22q11.21; encoded protein anchors PEX1p and PEX6p to the peroxisomal membrane
another undefined locus on chromosome 7q11.
Zellweger syndrome was first described in 1964 by Hans Zellweger and represents the prototypical PBD. Several related, but milder forms of PBDs, are now classified as the Zellweger spectrum disorders. These other diseases are neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD). Zellweger syndrome represents the extreme of the clinical manifestation of peroxisome biogenesis dysfunction with patients rarely surviving their first year of life. Zellweger syndrome is associated with either severe, moderate or mild defects in all peroxisome functions. An additional phenotypic spectrum in PBDs is represented by rhizomelic chondrodysplasia punctata, RCDP. RCDP is distinguished from the Zellweger spectrum PBDs by manifesting with more severe skeletal involvement as well as specific biochemical characteristics.
The peroxisomes are a single membrane organelle, similar to lysosomes, present in virtually all eukaryotic cells. The peroxisome is a specialized enzyme "factory" that contains in excess of 50 different enzymes involved in a variety of metabolic processes including β-oxidation of very long chain fatty acids, α-oxidation of fatty acids and synthesis of ether-lipids. Proteins that are involved in and necessary for correct peroxisome biogenesis are called peroxins (PEX). At least 15 PEX genes have been identified in humans. Enzymes that are targeted to the peroxisomes contain either of two amino acid consensus elements called peroxisome targeting sequences (PTS). The PTS1 is a C-terminal consensus sequence of –(S/A/C)(K/R/H)(L/M) referred to as the SKL motif. This sequence element is recognized by a cytosolic PTS1 receptor encoded by the PEX5 gene. There are two isoforms of PEX5 encoded proteins in humans identified as Pex5pS and Pex5pL (for short and long forms, respectively). The Pex5pL protein has an internal 37 amino acid insertion, hence the "long" designation. The PTS2 is an N-terminal consensus sequence of –(R/K)(L/V/I/Q)XX(L/V/I/H/Q)(L/S/G/A/K)X(H/Q)(L/A/F)–, (where X represents any amino acid). The PTS2 receptor is encoded by the PEX7 gene and the encoded protein is referred to as Pex7p. Proteins that are targeted to the membrane of the peroxisome (called peroxisome membrane proteins, PMPs) contain a consensus sequence identified as the PEX19 binding site (PEX19BS) and this site is recognized by the membrane protein receptor encoded by the PEX19 gene.
Pex5pS, Pex5L, and Pex7p interact with newly synthesized target proteins in the cytosol and direct them to the peroxisome. On the membrane of the peroxisome is a component of the protein import machinery encoded by the PEX14 gene called Pex14p. Following interaction of Pex5pS or Pex5pL, bound to a protein containing a PTS1 sequence, with Pex14p, the PTS1 containing protein is transferred into the peroxisome. The activity of Pex7p in peroxisome protein import actually requires Pex5pL as well. PTS2 containing proteins interact with Pex7p and then, in conjunction with Pex5pL, the complex interacts with Pex14p and the PTS2 containing protein is transferred into the peroxisome. Very few proteins contain a PTS2 sequence but one enzyme of note is phytanoyl-CoA hydroxylase (PHYH) which is defective in classic Refsum disease.
Zellweger syndrome is also known as cerebrohepatorenal syndrome. The most common clinical manifestations of ZWS include a series of characteristic craniofacial abnormalities. These defects include hypoplastic supraorbital ridges, epicanthal folds, a small nose with anteverted nares, a broad nasal bridge, full forehead, and large anterior fontanelle. Infants display severe hypotonia, weakness, and seizures. These latter symptoms, in association with the facial deformities, can lead to a diagnosis of Down syndrome. ZWS infants also have characteristic ocular defects including cataracts, glaucoma, corneal clouding, and optic nerve dysplasia.