Molecular Characterization of Peroxisome Biogenesis Disorders with Zellweger Syndrome Spectrum

Abstract

Peroxisome biogenesis disorders, Zellweger syndrome spectrum (PBD, ZSS) are constituted of three different phenotypically disorders: Zellweger syndrome (ZS), the most severe; neonatal adrenoleukodystrophy (NALD); and infantile refsum disease (IRD), the least severe, that have been originally described based on their biochemical and molecular bases of these disorders which had been fully determined. Individuals with PBD, ZSS usually come to clinical attention in the newborn period or later in childhood. The diagnosis of PBD, ZSS can be definitively determined by biochemical assays. Measurement of plasma very-long-chain fatty acid (VLCFA) levels is the most commonly used and most informative initial screen. Mutations in thirteen different PEX genes - those that encode peroxins, the proteins required for normal peroxisome assembly - have been identified in PBD, ZSS. Mutations in PEX1, the most common cause of PBD, ZSS, are observed in about 68% of affected individuals. Sequence analysis is available clinically for the following seven genes: PEX1, PXMP3 (PEX2), PRXR1 (PEX5), PEX6, PEX10, PEX12, and PEX26.

Full text

* Correspondence author;
Address: Genetics division, Biology Dept, Faculty of Sciences, University of Isfahan, Hezar-jerib Ave, Azadi Sq, Isfahan, IR Iran.
E-mail: kamranghaedi@yahoo.com
Molecular Characterization of Peroxisome Biogenesis
Disorders with Zellweger Syndrome Spectrum
Kamran Ghaedi1,2*, PhD; Issar Nassiri1, MSC
1. Genetics division, Biology Dept, Faculty of Sciences, University of Isfahan, IR Iran.
2. Stem cell Department, Royan Institute, Isfahan Research Campus, IR Iran
Received: 02/06/07; Revised: 04/08/07; Accepted: 13/08/07
Abstract
Peroxisome biogenesis disorders, Zellweger syndrome spectrum (PBD, ZSS) are constituted of three
different phenotypically disorders: Zellweger syndrome (ZS), the most severe; neonatal
adrenoleukodystrophy (NALD); and infantile refsum disease (IRD), the least severe, that have been
originally described based on their biochemical and molecular bases of these disorders which had
been fully determined. Individuals with PBD, ZSS usually come to clinical attention in the newborn
period or later in childhood. The diagnosis of PBD, ZSS can be definitively determined by
biochemical assays. Measurement of plasma very-long-chain fatty acid (VLCFA) levels is the most
commonly used and most informative initial screen. Mutations in thirteen different PEX genes - those
that encode peroxins, the proteins required for normal peroxisome assembly - have been identified in
PBD, ZSS. Mutations in PEX1, the most common cause of PBD, ZSS, are observed in about 68% of
affected individuals. Sequence analysis is available clinically for the following seven genes: PEX1,
PXMP3 (PEX2), PRXR1 (PEX5), PEX6, PEX10, PEX12, and PEX26.
Key Words: Zellweger syndrome; Neonatal adrenoleukodystrophy; Infantile refsum disease; PEX
Introduction
Peroxisome biogenesis disorders, Zellweger
syndrome spectrum (PBD, ZSS) are defined by a
continuum of three phenotypes described before
the biochemical and molecular bases of these
disorders had been fully determined: Zellweger
syndrome (ZS), neonatal adrenoleukodystrophy
(NALD) and infantile refsum disease (IRD)[1].
All of the peroxisome assembly disorders are
serious disorders, which frequently cause death
in the early stage of life. ZS is the most severe
and IRD the least severe of these phenotypes.
The generalizations that these labels represent are
still useful when facing undiagnosed individuals
and counseling their families, it should not
emphasize too much on assigning an affected
individual in placing to one of these categories.
However the affected persons are categorized in
broad range of phenotypic variations, as in
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276 Molecular characteristics of Zellweger syndrome. K Ghaedi, I Nassiri
individuals with PBD, ZSS Occasionally, the
subtlety of symptoms caused delaying in
diagnosis until adulthood. In the newborn period,
affected children are hypotonic, feed poorly, and
have distinctive facies, seizures, and liver cysts
with hepatic dysfunction. Infants with ZS are
significantly impaired and typically die during
the first year of life, usually having made no
developmental progress[1](Figure 1).
Older children have retinal dystrophy, sensori-
neural hearing loss, developmental delay with
hypotonia, and liver dysfunction[2]. The clinical
phenotypes of NALD and IRD are more variable
and may include developmental delays, hearing
loss, vision impairment, liver dysfunction,
episodes of hemorrhage, and intracranial
bleeding. While some affected children can be
very hypotonic, others learn to walk and talk.
Mutations in the twelve genes listed in Table 1
are known to cause PBD, ZSS in humans. These
genes encode proteins required for peroxisome
biogenesis called "peroxins"; the nomenclature
for naming these genes are "PEX" followed by a
number. A few of the peroxins appear to be
essential for peroxisome membrane formation [3].
However, the majority of known affected
individuals have mutations in PEX genes
encoding proteins essential for the import of
peroxisomal matrix proteins[4]. Mutations in the
two most commonly involved genes, PEX1 and
PEX6, are associated with the full continuous
clinical phenotypes. This clinical variability, in
general, is also found in individuals with
mutations in PEX10, PEX12, and PEX26.
PEX3, PEX16, and PEX19 mutations are
associated exclusively with the most severe
phenotype (ZS)[3]. Deficiencies in these three
genes cause a cellular phenotype without
peroxisome detected by immunocytochemical
analysis. Peroxisomal membrane formation is
completely absent in related patients fibroblast
cell lines from these individuals. No direct
association exists between the biochemical
phenotype and the deficient PEX gene. Thus, it is
not possible to identify the candidate gene based
solely on the biochemical phenotype. However, a
report suggests that two biochemical findings
(DHAP-AT and C26:0 β-oxidation activity) are
predictors of survival rate in individuals with
PBD, ZSS[5].
Metabolic Pathways
A variety of anabolic and catabolic pathways
occur in the peroxisome. β-oxidation and
plasmalogen synthesis are two fundamental
pathways localized there. The peroxisomal β-
oxidation enzymes are distinct from the
mitochondrial β-oxidation system. Straight-chain
VLCFA β-oxidation requires several enzymes
with very-long-chain acyl CoA synthetase, acyl
CoA oxidase, D-bifunctional protein (enoyl-CoA
Fig 1- Characteristic facial abnormalities in a neonatal affected by peroxisomal disorders. Peroxisomal
disorders are associated with characteristic facial abnormalities (high forehead, frontal bossing, small
face, low set ears, slanted eyes, etc.). Patients present as floppy children, due to their decreased muscle
tone (hypotonia). Developmental delay and mental retardation is common to all patients, and vision and
hearing are affected very soon. In general, these children are difficult to feed (personal communication
with professor Fujiki, Kyushu University, Japan).

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Iran J Pediatr, Vol 17 (No 3); Sep 2007
Table 1- Molecular Genetics of Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum[5,6,7]
Gene Symbol Chromosomal Locus Protein Name
PEX1 7q21-q22 Peroxisome biogenesis factor 1
PEX10 1p36.32 Peroxisome assembly protein 10
PEX12 17q12 Peroxisome assembly protein 12
PEX13 2p15 Peroxisomal membrane protein PEX13
PEX14 1p36.2 Peroxisomal membrane protein PEX14
PEX16 11p12-p11.2 Peroxisomal membrane protein PEX16
PEX19 1q22 Peroxisomal biogenesis factor 19
PEX26 22q11-21 Peroxisome assembly protein 26
PEX3 6q23-q24 Peroxisomal biogenesis factor 3
PEX5 12p13.3 Peroxisomal targeting signal 1 receptor
PEX6 6p21.1 Peroxisome assembly factor 2
PXMP3 8q21.1 Peroxisome assembly factor 1
hydratase and 3-hydroxyacyl-CoA dehydro-
genase), and peroxisomal β-ketothiolase. All of
these proteins have PTS1 signals (Peroxisomal
targeting signal type І) except for peroxisomal β-
ketothiolase, which is imported to the
peroxisome via a PTS2 signal[7]. These proteins
also play an important role in the side-chain
modification of bile acids. Thus, the defect in
peroxisomal fatty acid β-oxidation accounts for
the increase in very long chain fatty acids
(VLCFA) and branched-chain fatty acids such as
pristanic acid, and bile acid in the walls. A
unique branched-chain acyl CoA oxidase is used
for bile acids and pristanic acid, thus explaining
why these metabolites are normal in acyl-CoA
oxidase deficiency. The initial steps of plasma-
logen synthesis occur in the peroxisome and the
final stages of synthesis are completed in the
endoplasmic reticulum. Dihydroxyacetone
phosphate (DHAP)-acyl transferase and alkyl-
DHAP-synthase are PTS1 and PTS2 containing
proteins, respectively[8,9].
Peroxisome Biogenesis and Assembly
At least 29 peroxins are required for peroxisome
membrane biogenesis, fission, and protein import
to form competent organelles. Thus far,
mutations in 13 genes that encode peroxins are
associated with related human disorders. The
biogenesis of membranes is not well understood,
but mutations in three human PEX genes (PEX3,
PEX16, and PEX19) are associated with the
absence of peroxisome membrane structures [10,
11, 12]. The remaining proteins encoded by known
PEX genes contribute to the import machinery
required for matrix protein sorting, a complex
process that is being studied recently. In general,
peroxisomal matrix proteins are encoded by
nuclear genes and are translated on free
polyribosomes. PXR1 (PEX5) encodes a receptor
that recognizes proteins containing peroxisomal
targeting sequence 1 (PTS1), defined by the
carboxy terminal consensus sequences: serine-
lysine-leucine (SKL)[13]. PEX7 encodes the PTS2
receptor which recognizes proteins containing an
N-terminaly a peptide termed PTS2. Mutations in
PEX7 are associated with the clinically distinct
disorder RCDP[13]. Those two sub-complexes
have been proposed to be anchored by product of
in yeast which is associated with the more
lumenal aspect of the peroxisomal membrane and
its homologues has not been recognized in
mammals so far[14]. The two sub complexes
comprise the products of (a) PEX14, PEX17, and
PEX13, and (b) PEX10, PEX12, and PEX2 genes.
The first sub-complex plays a role in the docking
of the PTS1 and PTS2 receptors and their cargo
proteins. The second sub-complex appears to be
part of the translocation apparatus for matrix

278 Molecular characteristics of Zellweger syndrome. K Ghaedi, I Nassiri
proteins at peroxisomal membranes [15,16,17]. In
contrast, PEX1 and PEX6 products form a
complex that may play a role in the recycling of
the PTS1 and PTS2 receptors. Epistatic studies in
yeast indicate that PEX1, PEX6, PEX4 and
PEX22 products act at late step in the import
pathway, perhaps after the translocation
process[17]. However, the recent identification of
PEX26 gene has shown that the encoded protein
directly interacts with Pex1-Pex6 protein
complexes. Thus, all three proteins may play a
critical role in the presentation of PTS1 and PTS2
proteins to the peroxisomal membrane (Figure 2).
Diagnosis of Peroxisomal Biogenesis
Disorders
The diagnosis of PBD, ZSS can be determined by
biochemical and Sequence analyses assays.
Biochemical parameters could be detected in
blood and/or urine which should be confirmed
with data of cultured Patients fibroblasts.
Measurement of plasma very-long-chain fatty
acid (VLCFA) levels is the most commonly used
and most informative initial screen. Elevation of
C26:0 and C26:1 and the ratios C24/C22 and
C26/C22 are consistent with a defect in
peroxisomal fatty acid metabolism[9,19].
Fig 2- Peroxisome biogenesis and matrix protein import.
The various proteins are directed to their correct positions in the peroxisome - either incorporated into the
membrane or passing through it into the matrix by means of peroxisomal targeting signals (PTSs). A PTS
receptor is a mobile protein which repeatedly shuttles between the cytosol - recognizing and binding the PTS
protein - and the peroxisome, separating from it and leaving it for import. There are about fifteen other
proteins known to be necessary to the correct assembly of a peroxisome. The biogenesis of peroxisomes
starts with the peroxins Pex3p, Pex16p and Pex19p. The import of membrane proteins into extant
peroxisomes needs Pex19p for recognition, targeting and insertion via docking at Pex3p. Matrix proteins in
the cytosol are recognized by their targeting signals – PTS1 via Pex5p and PTS2 via Pex7p – and transported
to the docking complex Pex14p and Pex13p at the peroxisomal membrane. Pex5p integrated into the
peroxisomal membrane and the cargo is imported by Pex2p, Pex10p and Pex12p (personal communication
with professor Fujiki, Kyushu University, Japan).
PTS1 PTS2
14 13
5S 7
10 12 2
61
316
19
11α
cargo
cargo 5L
11βPTS2 cargo
PTS1
cargo
5S/L
5S/L
?
??
?
Peroxisome
Cytosol
11γ
26
Matrix protein
import
Primary membrane
biogenesis
Proliferation
& division
COOH-L-K-S-; terminal tripeptides-, C1-ignal typesargeting teroxisome PPTS1:
able presequenceterminal cleav-, N2
-ignal typesargeting teroxisome PPTS2:
Pex10p
Pex12p
Pex2p
RING
peroxins

279
Iran J Pediatr, Vol 17 (No 3); Sep 2007
Molecular genetic testing for carrier detection,
prenatal diagnosis and prognostication through
emerging genotype-phenotype correlations
should be done. These are including sequence
analysis of selected PEX1 gene exons at first step
and PEX gene screen algorithm at the second
step. the pregnancy rate of mutation in PEX1
exon 13 (where I700fs is localized) and exon 15
(where G843D is localized) in individual with a
PBD, ZSS identified to be slightly more than
50% of individuals[19]. To circumvent the need
for complementation studies, two slightly
different algorithms for analysis a subset of other
PEX genes and their exons have been developed:
recently sequence analysis of PEX1 exons 13, 15,
and 18, PEX2 exon 4, PEX6 exon 1, PEX10
exons 3-5, PEX12 exons 2 and 3, and PEX26
exons 2 and 3 has a sensitivity of 79%. Sequence
analysis of PEX1 exons 13 and 15, PEX2 exon 4,
PEX10 exons 4 and 5, PEX12 exons 2 and 3, and
PEX26 exons 2 and 3 has a sensitivity of
approximately 72% for the identification of at
least one mutation [20].
Differential diagnoses vary with the age of
presentation and most prominent feature of
presentation. PBD, ZSS in newborns is most
often confused with other conditions that result in
profound hypotonia including Down syndrome,
other chromosomal abnormalities, Prader-Willi
syndrome, spinal muscular atrophy, congenital
myotonic dystrophy type 1, and congenital
myopathies such as X-linked myotubular
myopathy and multiminicore myopathy. Older
children have been initially presumed to have
Usher syndrome type I or Usher syndrome type II
and other disorders of sensorineural hearing loss
and retinitis pigmentosa, Leber congenital
amaurosis, Cockayne syndrome, or congenital
infections [6,21].
An increase in plasma VLCFA concentration
consistent with a defect in peroxisomal fatty acid
metabolism could be associated with four main
disease types: a) PBD, ZSS; b) a single enzyme
deficiency (SED) of the peroxisomal β-oxidation
enzymes D-bifunctional protein (D-BP) or acyl-
CoA oxidase (AOx)[22]; c) X-linked adrenoleuko-
dystrophy (X-ALD) or adrenomyeloneuropathy
(AMN), caused by mutations in ABCD1; and d)
CADDS, a contiguous deletion syndrome with a
critical region spanning the genes ABCD1 and
BAP31[23] (table 2).
Prenatal Testing
Due to the severe nature and inability to treat
these disorders, many couples with an affected
child seek prenatal counseling for future
pregnancies. Prenatal diagnosis is possible by
biochemical or molecular analysis. Most
biochemical analyses that have been verified in
cultured fibroblasts from the index case which
can be used for prenatal testing with cultured
cells derived from chorionic villi or amniotic
fluid cells. To identify any molecular defect
DNA can be isolated from cells from chorionic
villus samples (CVS) or amniotic fluid for further
DNA analysis. Due to the risk of maternal cell
contamination (MCC), especially when using
CVS, it is essential to perform mother DNA
testing to rule out this possibility especially when
Table 3- Molecular Genetic Testing Used in Peroxisome Biogenesis Disorders, ZSS[20, 24, 25, 26]
Test Method Mutations Detected Mutation
Detection Rate
Sequence analysis of
select exons
PEX1 mutations in: exon 13 (I700fs); exon 15 (G843D) 50%
Sequence variations in PEX1, PXMP3 (PEX2), PEX10,
PEX12, PEX26
72%
Sequence analysis of
all coding exons
Sequence variations in PEX1, PXMP3 (PEX2), PEX6,
PEX10, PEX12, PEX5
95%
Direct DNA Mutations in PEX3, PEX13, PEX14, PEX16, PEX19 Unknown

280 Molecular characteristics of Zellweger syndrome. K Ghaedi, I Nassiri
cells from heterozygotic carriers for ZSS
disorders do not express partial defects, thus
there is no MCC causing for false positive result
[27]. Analysis of peroxisomal β-oxidation and
plasmalogen synthesis are the two pathways most
commonly assessed for prenatal testing [28,29].
Once the specific gene defect has been identified,
it is also possible to offer the couple an option of
preimplantation genetic diagnosis (PGD) [30].
Although CVS or amniocentesis is recommended
to confirm that only unaffected embryos were
implanted, PGD significantly improves the
chance of a normal pregnancy. Recently fetal
magnetic resonance imaging in the third trimester
was shown to be able to confirm defects
consistent with ZSS disorders, including ab-
normal cortical gyral patterns and renal cysts [31].
Therapy
The multiple biochemical abnormalities that
result from the failure of peroxisome assembly
and their importance in embryogenesis lead to
significant developmental abnormalities present
at birth and further progression postnatally.
Current treatment is supportive and focuses on
treating seizures and liver dysfunction, providing
hearing aids, ophthalmologic interventions, and
meeting other developmental needs. However,
the recognition of a larger number of PBD
patients with milder phenotypes who have longer
life has prompted renewed interest in
experimental therapies. Thus far therapeutic
interventions have targeted individual
biochemical defects and the effects have not been
studied in a systematic fashion. A diet low in
phytanic acid has been successful in the
treatment of ARD. Thus, its use in milder
individuals with PBD has been proposed but has
not been demonstrated to result in measurable
clinical improvement. Similarly, oral DHA
therapy can normalize blood DHA levels[32], but
its affect on clinical outcome has not yet been
proven[33]. Oral bile acid administration improved
hepatobiliary function in several infants with
ZS[34,35]. Liver transplantation has been reported
in one patient with IRD [36], but it is too early to
determine the benefit. Furthermore, potential
therapies have been proposed that would improve
peroxisome assembly based upon their effect in
cell culture models. For example, Wei et al. have
demonstrated that peroxisome proliferation in the
presence of 4-phenylbutyrate could improve β-
oxidation in cultured fibroblasts from ZSS
patients[37,38]. Mouse models have been
developed for PEX2, PEX5, PEX7 and PEX13
deficiency and are discussed in more details.
These models are useful for studying the
underlying pathophysiology, for investigating
existing therapies and for developing new
approaches to treatment.
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