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At least 649 records · Page 36Linked to original sources
PubMed1993

Evidence of post-transcriptional regulation in mammalian mitochondrial biogenesis.

We have previously shown that the nuclear-encoded gene's expression of mitochondrial beta-subunit of the F1-ATPase complex in rat liver is regulated at the translational level (Luis, A.M., Izquierdo, J.M., Ostronoff, L.K., Santarén, J., Salinas, M., and Cuezva, J.M. (1993) J. Biol. Chem. 268, 1868-1875). In this paper we report that the different steady-state levels of ATP synthase beta subunit mRNA detected in rat tissues are not paralleled by a proportional content of immunodetectable beta-F1-ATPase protein. The results suggest that tissue-specific transcriptional and post-transcriptional mechanisms contribute to differential mitochondrial biogenesis in mammalian cells. On the other hand, steady-state mRNA levels of the mitochondrial encoded ATP synthase subunits (ATP 6+8) indicate that nuclear and mitochondrial-encoded transcripts for this complex are in close relation, that is, the expression of both nuclear and mitochondrial genes is coordinated in all tissues examined.

Animals↗
PubMed1999

Caveolin-1 expression and caveolae biogenesis during cell transdifferentiation in lung alveolar epithelial primary cultures.

Caveolae are omega-shaped invaginations of the plasmalemma possessing a cytoplasmic membrane protein coat of caveolin. Caveolae are present in the in vivo alveolar epithelial type I (ATI) lung cell, but absent in its progenitor, the alveolar epithelial type II (ATII) cell. In primary culture ATII cells grown on a plastic substratum acquire with time an ATI-"like" phenotype. We demonstrate that freshly isolated rat ATII cells lack caveolae and expression of caveolin-1 (a critical caveolae structural protein). As the ATII cells acquire an ATI-like phenotype in primary culture caveolin-1 expression increases, with caveolin-1 signal at 192 h postseeding up to 50-fold greater than at 60 h; caveolae were morphologically evident only after 132 h. When maintaining the differentiated ATII phenotype with time, i.e., culture upon collagen with an apical interface of air, a temporal increase in caveolin-1 expression was not observed, with only very faint signals evident even at 192 h postseeding; at no time did these cultures display caveolae. In late primary ATII cultures caveolin-1 expression and caveolae biogenesis occur as a function of in vitro transformation from the ATII to the ATI-like phenotype. The results have broad implications for the in vitro study of the role of caveolae and caveolin in alveolar epithelial cell biology.

Animals↗
PubMed1993

Biogenesis of surface domains during spermiogenesis in the guinea pig.

During mammalian spermiogenesis a spherical spermatid is transformed into a highly asymmetric sperm cell. Concurrently, the plasma membrane of the cell develops into a mosaic of discrete membrane regions, with each region containing a unique set of proteins. Biogenesis of these surface domains was studied by following the surface expression and localization of nine different antigens during spermiogenesis. Each of these antigens exhibits one of four distinct patterns of localization on testicular sperm (whole cell, whole head, anterior tail, and posterior tail), indicating that there are at least three distinct surface domains on testicular sperm. Our results on the timing of antigen localization suggest that the generation of surface domains in mammalian sperm is a complex process. This process involves temporal and spatial regulation of surface expression of the antigens, as well as the specific removal of antigens from inappropriate domains after they have reached the cell surface.

Animals↗
PubMed1995

Biogenesis of the posterior-tail plasma membrane domain of the mammalian spermatozoon: targeting and lateral redistribution of the posterior-tail domain-specific transmembrane protein CE9 during spermiogenesis.

We used immunoperoxidase histochemistry and confocal immunofluorescence microscopy to examine the events involved in the compartmentalization of CE9 to the posterior-tail plasma membrane domain during spermatogenesis in the rat. We identified two major episodes of spermatogenesis during which CE9 appeared to accumulate in relatively large amounts intracellularly within elements of the secretory pathway. The first episode encompassed cells from preleptotene through early pachytene primary spermatocytes and was evident as intense intracellular labeling of the endoplasmic reticulum and the Golgi complex. The second episode encompassed spermatids in steps 8-12 of spermiogenesis and was evident as intense intracellular labeling of the Golgi complex and smaller vesicular structures observed within the cytoplasm of the spermatid. Between these two episodes, CE9 was detected in considerably reduced amounts. Although present within the Golgi complex and the acrosomic system throughout much of the first half of spermiogenesis, CE9 was not detected on the tail of the spermatid until steps 8-9 of spermiogenesis. Although detected initially in relatively small amounts along the entire length of the tail beginning at steps 8-9, there was no evidence for the presence of relatively large amounts of CE9 on the tail or anywhere else on the surface of the spermatid until after step 11 of spermiogenesis. Between step 11 and steps 13-14 of spermiogenesis, CE9 was observed to accumulate in relatively large amounts on the whole tail coincident with its apparent loss from the Golgi complex. CE9 was observed to then undergo further compartmentalization to the posterior-tail domain sometime between steps 13-14 of spermiogenesis and spermiation. Our results suggest that CE9 is synthesized and enters the secretory pathway throughout much of spermatogenesis, but that the site of accumulation of CE9 varies considerably as a function of development. With respect to the biogenesis of the posterior-tail plasma membrane domain, our results suggest that CE9 is targeted from the Golgi complex to the plasma membrane of the whole tail during mid to late spermiogenesis and then redistributes laterally into the posterior-tail domain coincident with the caudal migration of the annulus late in spermiogenesis. This proposed pathway has a number of important implications for the logistical capabilities of the mammalian spermatid.

Animals↗
PubMed1996

Synthesis of the mammalian synaptic vesicle protein synaptophysin in insect cells: a model for vesicle biogenesis.

The N-glycosylated integral membrane protein synaptophysin is one of the major polypeptide components of small presynaptic transmitter-containing vesicles in neurons and of similar vesicles in neuroendocrine cells of mammals. Functional properties, including a possible participation in channel formation, have been investigated by integration of purified synaptophysin into planar lipid bilayers. To overcome some of the inherent limitations of such an in vitro approach we have overexpressed the rat synaptophysin cDNA in nonneuronal, non-neuroendocrine insect cells with the help of recombinant baculovirus. The complete polypeptide was produced in infected ovarian Sf9 cells at levels exceeding those observed in rat brain. The partially N-glycosylated molecules could be extracted from membranes with non-ionic detergents, most effectively with n-octyl-beta-D-glucopyranoside, and could be enriched on chromatofocusing columns. By immunoelectron microscopy synaptophysin was shown to be integrated in the correct orientation into the endoplasmic reticulum, various pleomorphic vesicles and the plasma membrane. Using cell fractionation, including density gradient centrifugation and immunoisolation, we characterized distinct synaptophysin-rich vesicles. These vesicles may help to understand molecular principles of vesicle biogenesis in general and the function of synaptophysin in particular.

Animals↗
PubMed1999

The pink-eyed dilution locus controls the biogenesis of melanosomes and levels of melanosomal proteins in the eye.

The pink-eyed dilution (p) locus is known to control the quantity of melanin pigment made within melanocytes and retinal pigment epithelium (RPE) in the eye. We have examined the effects of several mutant allele combinations at the murine p locus on the number and morphology of melanosomes in choroidal melanocytes and RPE cells as well as on the levels of four proteins known to be present within melanosomes: tyrosinase, tyrosinase-related proteins 1 and 2 (TRP-1 and TRP-2) and lysosome-associated membrane protein-1 (LAMP-1). By electron microscopy, we observed a modest diminution in the size and number of choroidal melanosomes in pbs/pJ mice but a more dramatic decrease in the RPE in comparison with wild-type P/P mice. By contrast, a drastic reduction in melanosome size and number was present in the choroid and RPE of pun/pun and p6H/pcp mice, and in the RPE of p6H/pcp mice, melanosomes were essentially undetectable. In wild-type mice, levels of tyrosinase, TRP-1 and TRP-2 were high at birth and showed a second peak of expression at 10-14 days of age, declining to undetectable levels by 42 days. All three mutant allele combinations reduced the levels of these melanosomal proteins with the relative severity of effects being p6H/pcp>pun/pun>pbs/pJ. In the null p6H/pcp mice, levels of these proteins were extremely low at birth, no postnatal peak was observed, and levels declined to undetectable by 14 days. Levels of LAMP-1 in wild-type mice rose initially and then declined whereas in the mutant mice, levels decreased gradually from birth. Higher levels of LAMP-1 were observed in each of the mutants than in the wild-type mice at 21 days of age. Our results demonstrate that mutations at the p locus affect the size, number, shape and contents of melanosomes, implicating the p gene product in the normal biogenesis of this organelle.

Animals↗
PubMed1996

Thymidine kinase as a selectable marker for studying the biogenesis of glycosomes in Trypanosoma brucei.

The import of proteins into the glycosome of T. brucei has been studied as a potential target for antitrypanosomal chemotherapy. We have previously reported on the C-terminal tripeptides, such as SKL and its analogs, which function as targeting signals in the import of proteins into glycosomes. Recently, we tested the herpes simplex virus thymidine kinase gene (tk) as both a potential positive and a negative selectable marker in T. brucei for isolating glycosome-deficient T. brucei mutants in the procyclic form and complementation studies to identify genes involved in glycosomal biogenesis. The transforming vectors that we have constructed contained the hygromycin phosphotransferase gene (hyg) coupled either to the tk gene (ptk) or to the gene encoding the thymidine kinase fused with the glycosomal targeting signal (ptk-SKL) at the C-terminus. Individual constructs were introduced into the T. brucei 427 procyclic cells by electroporation, and the transformants were selected under hygromycin B (50 micrograms/ml) and cloned. The thymidine kinase activity in the crude extracts of transformants was determined. Differential digitonin treatment of the transformants indicated that the tk-SKL protein was apparently localized to the glycosomal fraction, as expected, whereas the tk protein was found in the soluble fraction. [methyl-3H]Thymidine was incorporated into the nucleic acids of the transformant 427/ptk to a level twice as high as that incorporated into 427/ptk-SKL and the wild type. In the presence of 100 microM ganciclovir, the growth of 427/ptk was totally inhibited, whereas growth of 427/ptk-SKL and the wild type was unaffected. When 150 microM trimethoprim was added to the culture medium, growth of 427/ptk-SKL and the wild type was completely arrested while that of 427/ptk remained normal. We have thus established the methodology for both positive and negative selection of potential glycosome-deficient mutants of T. brucei 427/ptk-SKL.

Amino Acid Sequence↗
PubMed1998

Genomic structure of PEX13, a candidate peroxisome biogenesis disorder gene.

The peroxisome biogenesis disorders (PBDs) are a set of lethal genetic diseases characterized by peroxisomal metabolic deficiencies, multisystem abnormalities, mental retardation, and premature death. These disorders are genetically heterogeneous and are caused by mutations in genes, termed PEX genes, required for import of proteins into the peroxisomal matrix. We have previously reported the identification of human PEX13, the gene encoding the docking factor for the PTS1 receptor, or PEX5 protein. As such, mutations in PEX13 would be expected to abrogate peroxisomal protein import and result in PBD phenotypes. We report here the structure of the human PEX13 gene. PEX13 spans approximately 11 kb on chromosome 2 and contains four exons, one more than previously thought. The corrected PEX13 cDNA is predicted to encode a protein product with a molecular mass of 44,312 Da. We examined the ability of PEX13 expression to rescue the peroxisomal protein import defects of fibroblast cells representing all known PBD complementation groups. No complementation was observed, suggesting that this gene is not mutated in any set of existing patients. However, given that complementation group assignments have been determined for only a subset of PBD patients, it is possible that PEX13-deficient patients may exist at a low frequency within our existing PBD patient population or within ethnic groups underrepresented in our patient pool.

Amino Acid Sequence↗
PubMed2002

Pex13, the mouse ortholog of the human peroxisome biogenesis disorder PEX13 gene: gene structure, tissue expression, and localization of the protein to peroxisomes.

Pex13 encodes an SH3-containing peroxisomal membrane protein required for the import of proteins into peroxisomes. In humans, mutations in PEX13 can disrupt peroxisome biogenesis and lead to peroxisomal metabolic dysfunction and neurodegenerative disease. We report here on the mouse gene Pex13 and its encoded protein. Mouse Pex13 spans 18 kb and consists of four exons. We detected Pex13 transcripts in all mouse tissues tested, with highest levels in liver and testis. The Pex13 open reading frame predicts a 44.5-kDa protein that displays 91% sequence identity to the human PEX13 protein. We have localized PEX13 protein to peroxisomes in mouse liver and show that this protein also sorts to peroxisomes in human skin fibroblasts. These data indicate that the structure and properties of the mouse and human PEX13 proteins are almost identical. We infer from these findings that targeted disruption of mouse Pex13 would provide an appropriate model for the study of PEX13 dysfunction in humans.

Amino Acid Sequence↗
PubMed1994

OXA1, a Saccharomyces cerevisiae nuclear gene whose sequence is conserved from prokaryotes to eukaryotes controls cytochrome oxidase biogenesis.

Yeast cells carrying a mutation in the OXA1 nuclear gene are respiratory deficient and lack cytochrome oxidase activity. We successively examined the different steps in the expression of the mitochondrial genes encoding the cytochrome oxidase subunits and apocytochrome b in strains carrying the oxa1-79 mutation. The ox1-79 strains exhibit a total absence of cytochrome aa3 and a decrease in cytochrome b, even in a strain devoid of mitochondrial introns, in which cox1 and cytb mRNAs normally accumulate. The three mitochondrial-encoded subunits of cytochrome oxidase are still detectable although their amount is reduced, and apocytochrome b is synthesized normally. These results suggest that the OXA1 gene is primary required at a post-translational step in cytochrome oxidase biogenesis, probably at the level of assembly, although the oxa1-79 mutation leads to some pleiotropic secondary defects in earlier steps of mitochondrial gene expression. The OXA1 gene has been cloned, sequenced, and disrupted. The phenotypes of the oxa1::LEU2 and oxa1-79 alleles are similar. Interestingly, the OXA1 gene, located on the yeast chromosome VIII, is adjacent to the gene PET 122, which controls the initiation of cox3 mRNA translation. In addition, the predicted OXA1 protein is homologous to several putative prokaryotic and eukaryotic proteins, suggesting that the function of the OXA1 protein is important for respiration in all living cells.

Amino Acid Sequence↗
PubMed1997

Molecular and immunological analysis of an ABC transporter complex required for cytochrome c biogenesis.

The helABC genes are predicted to encode an ATP-binding cassette (ABC) transporter necessary for heme export for ligation in bacterial cytochrome c biogenesis. The recent discoveries of homologs of the helB and helC genes in plant mitochondrial genomes suggest this is a highly conserved transporter in prokaryotes and some eukaryotes with the HelB and HelC proteins comprising the transmembrane components. Molecular genetic analysis in the Gram-negative bacterium Rhodobacter capsulatus was used to show that the helABC and helDX genes are part of an operon linked to the secDF genes. To facilitate analysis of this transporter, strains with non-polar deletions in each gene, epitope and reporter-tagged HelABCD proteins, and antisera specific to the HelA and HelX proteins were generated. We directly demonstrate that this transporter is present in the cytoplasmic membrane as an HelABCD complex. The HelB and HelC but not HelD proteins are necessary for the binding and stability of the HelA protein, the cytoplasmic subunit containing the ATP-binding region. In addition we show that the HelA protein co-immunoprecipitates with either the HelC or HelD proteins. Thus, the HelABCD heme export complex is distinguished by the presence of four membrane-associated subunits and represents a unique subfamily of ABC transporters.

ATP-Binding Cassette Transporters↗
PubMed1997

A thioreduction pathway tethered to the membrane for periplasmic cytochromes c biogenesis; in vitro and in vivo studies.

The c-type cytochromes are distinguished from other heme proteins by the covalent ligation of two heme vinyl groups to two cysteine residues on the apoprotein (at a CXXCH domain). The present study was undertaken to elucidate the roles and topological locations of two of the proteins necessary for cytochrome c biogenesis, the HelX and Ccl2 proteins in the Gram-negative bacteria Rhodobacter capsulatus. From their primary sequence, each of these proteins has a CXXC motif that could be involved in the reduction of the cysteine residues of the apocytochromes c, a prerequisite for covalent ligation to the heme. Results of site-directed mutagenesis of HelX and Ccl2 demonstrate that each cysteine residue is required for the in vivo function of the protein. We demonstrate that the native HelX in R. capsulatus is tethered to the cytoplasmic membrane via its uncleaved signal sequence. Ccl2 is tethered by a single transmembrane domain present in the C terminus with the N-terminal two-thirds of the protein in the periplasm. Thus, both CXXC motifs are exposed to the periplasm. The complete HelX protein and the soluble N-terminal portion of Ccl2 (called Ccl2*) were overproduced and purified from periplasmic fractions. The Ccl2* signal sequence is efficiently processed. In vitro studies with these purified proteins indicate that although neither can reduce insulin, HelX can reduce the Ccl2 cysteine residues and the Ccl2 cysteine residues are oxidized by an apocytochrome c peptide containing the CXXCH domain. Revertants of an helX deletion mutant were isolated that regain the ability to make c-type cytochromes (and thus grow photosynthetically); some of these suppressor strains are enhanced for photosynthetic growth by the addition of thio-reducing agents. In contrast, revertants of a ccl2 deletion strain could not be isolated under any condition. These results suggest that the HelX and Ccl2 proteins form a thioreduction pathway (HelX-->Ccl2-->apocytochrome c) whereby Ccl2 function may be highly specific for apocytochromes c while HelX may act as a more general reductant of proteins with vicinal cysteines.

Amino Acid Sequence↗
PubMed2000

Roles of the ccoGHIS gene products in the biogenesis of the cbb(3)-type cytochrome c oxidase.

In many bacteria the ccoGHIS cluster, located immediately downstream of the structural genes (ccoNOQP) of cytochrome cbb(3) oxidase, is required for the biogenesis of this enzyme. Genetic analysis of ccoGHIS in Rhodobacter capsulatus demonstrated that ccoG, ccoH, ccoI and ccoS are expressed independently of each other, and do not form a simple operon. Absence of CcoG, which has putative (4Fe-4S) cluster binding motifs, does not significantly affect cytochrome cbb(3) oxidase activity. However, CcoH and CcoI are required for normal steady-state amounts of the enzyme. CcoI is highly homologous to ATP-dependent metal ion transporters, and appears to be involved in the acquisition of copper for cytochrome cbb(3) oxidase, since a CcoI-minus phenotype could be mimicked by copper ion starvation of a wild-type strain. Remarkably, the small protein CcoS, with a putative single transmembrane span, is essential for the incorporation of the redox-active prosthetic groups (heme b, heme b(3 )and Cu) into the cytochrome cbb(3) oxidase. Thus, the ccoGHIS products are involved in several steps during the maturation of the cytochrome cbb(3) oxidase.

Bacterial Chromatophores↗
PubMed2000

Functions of the subunits in the FlhD(2)C(2) transcriptional master regulator of bacterial flagellum biogenesis and swarming.

In enterobacteria like Salmonella, biogenesis of cell surface flagella needed for motility is dependent upon the master operon flhDC at the apex of the flagellar gene hierarchy. The operon products FlhD and FlhC act together in a FlhD(2)C(2 )heterotetramer to induce flagellar gene transcription, while FlhD also represses cell septation. The flhDC operon is pivotal to differentiation into elongated hyperflagellated swarm cells that undergo multicellular migration, most strikingly in Proteus. We set out to establish the mechanism of action of the FlhD(2)C(2) multimer. In Proteus swarm cell extracts, all the FlhC was assembled into the FlhD(2)C(2 )transcription activator, but FlhD additionally formed approximately equimolar amounts of a FlhD(2) homodimer. Both FlhD and FlhC subunits homodimerised in vivo and in vitro, suggesting that self-interactions stabilise the FlhD(2)C(2 )complex. The FlhC and FlhD subunit proteins were separately expressed and purified, and the FlhD(2)C(2)heterotetramer was reconstituted in vitro. Purified FlhC bound specifically and cooperatively to the promoter region of the flhDC-regulated flhB flagellar gene in the absence of FlhD. Purified FlhD was unable to bind this target DNA, but binding by the FlhD(2)C(2)complex was approximately tenfold greater than the FlhC subunit alone, suggesting that FlhD potentiated the FlhC/DNA interaction. In support of this possibility, pre-incubation of FlhC with FlhD reduced the apparent dissociation constant, K(D), for the FlhC/DNA complex from 100 nM to 13 nM. Furthermore, in competition assays, FlhD substantially increased the specificity of DNA recognition by FlhC, and also stabilised the resultant labile protein/DNA complex, prolonging its half-life from around two minutes to more than 40 minutes. FlhD(2)C(2)is therefore an atypical prokaryotic transcription activator in which interaction of the FlhC subunit with DNA target sequences is enhanced by the coexpressed helper subunit FlhD.

Allosteric Site↗
PubMed1994

Let there be life. Thermodynamic reflections on biogenesis and evolution.

The question of how life emerged from inanimate matter is closely related to the more fundamental question, namely: What is life? Both issues yield novel insights when discussed in the light of thermodynamics. The model proposed here is based on a simple assumption, namely, that life began with the accidental assembly of a self-replicating molecule. From this assumption the emergence of life naturally follows, enabling a new understanding of evolution as a whole. The evolution of any type of self-replicating systems, even the simplest ones, is shown to be highly efficient in extracting, recording and processing information about the environment. A variety of related issues yield some surprising conclusions when discussed in the thermodynamic context. New processes of order-increase are pointed out, a novel measure of information is proposed, and Lamarckianism is proved to be inconsistent with thermodynamics. Recent works on biogenesis and evolution are critically reviewed.

Animals↗
PubMed1998

The use of permeabilized cells to investigate secretory granule biogenesis.

To investigate the mechanism of secretory granule biogenesis in endocrine cells, our laboratory used rat anterior pituitary GH3 cells which secrete growth hormone and prolactin. Here we describe a simple and rapid procedure for generating permeabilized cells to dissect molecular mechanisms involved in nascent secretory vesicle budding from the trans-Golgi network (TGN). Using this system, we demonstrate that vesicle budding is temperature, energy, and cytosol dependent; in addition, cytosol from a variety of cells, including yeast (Saccharomyces cerevisiae), can support vesicle release. The budding of nascent secretory vesicles from the TGN is stimulated by a phospholipase D activity that is associated with Golgi membranes. Our results suggest that phospholipid metabolism plays an important role in the release of nascent secretory vesicles from the TGN.

ADP-Ribosylation Factors↗
PubMed1998

Reconstitution of synaptic vesicle biogenesis from PC12 cell membranes.

Neuroendocrine PC12 cells contain small microvesicles that closely resemble synaptic vesicles in their physical and chemical properties. Two defining characteristics of synaptic vesicles are their homogeneous size and their unique protein composition. Since synaptic vesicles arise by endocytosis from the plasma membrane, nerve terminals and PC12 cells must contain the molecular machinery to sort synaptic vesicles from other membrane proteins and pinch off vesicles of the correct diameter from a precursor compartment. A cell-free reconstitution system was developed that generates vesicles from PC12 membrane precursors in the presence of ATP and brain cytosol and is temperature dependent. At 15 degrees C, surface-labeled synaptic vesicle proteins accumulate in a donor compartment, while labeled synaptic vesicles cannot be detected. The block of synaptic vesicle formation at 15 degrees C enables the use of the monoclonal antibody, KT3, a specific marker for the epitope-tagged synaptic vesicle protein, VAMP-TAg, to label precursors in the synaptic vesicle biogenesis pathway. From membranes labeled in vivo at 15 degrees C, vesicles generated in vitro at 37 degreesC had the sedimentation characteristics of neuroendocrine synaptic vesicles on glycerol velocity gradients, and excluded the transferrin receptor. Therefore, vesiculation and sorting can be studied in this cell-free system.

Adenosine Triphosphate↗
PubMed1999

Genotype-phenotype correlations in disorders of peroxisome biogenesis.

Genetically determined human peroxisomal disorders are subdivided into two major categories: disorders of peroxisome biogenesis (PBD), in which the organelle is not formed normally, and those that involve a single peroxisomal enzyme. Twelve PBD have been identified, and the molecular defects have been defined in 10. All involve defects in the import of proteins into the organelle. Factors required for this import are now referred to as peroxins (PEX) and form the basis of a new and preferred classification system. The PBD are associated with four clinical phenotypes, named before their association with the organelle was recognized: Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and rhizomelic chondrodysplasia punctata (RCDP). The first three are associated with 9 of the 10 PEX defects that have been defined so far, and represent a clinical continuum with variant severity, with ZS the most severe, NALD intermediate, and IRD the least severe. RCDP is associated with PEX7. Genotype-phenotype correlations are complicated by the fact that the clinical manifestations of the ZS-NALD-IRD continuum can be mimicked by disorders that affect single enzymes of peroxisomal fatty acid oxidation, and PEX7 by disorders of plasmalogen synthesis enzymes. Furthermore, clinical manifestations of each of the PEX disorders may vary. Phenotypic expression varies with the nature of the mutation, the milder phenotypes being associated with mutations that do not abolish function completely, or with mosaicism. Definition of the molecular defects is of great value for genetic counseling and may be of aid in establishing prognosis.

Genotype↗