In this review, we describe the current state of knowledge about the biochemistry of mammalian peroxisomes, especially human peroxisomes. The identification and characterization of yeast mutants defective either in the biogenesis of peroxisomes or in one of its metabolic functions, notably fatty acid beta-oxidation, combined with the recognition of a group of genetic diseases in man, wherein these processes are also defective, have provided new insights in all aspects of peroxisomes. As a result of these and other studies, the indispensable role of peroxisomes in multiple metabolic pathways has been clarified, and many of the enzymes involved in these pathways have been characterized, purified, and cloned. One aspect of peroxisomes, which has remained ill defined, is the transport of metabolites across the peroxisomal membrane. Although it is clear that mammalian peroxisomes under in vivo conditions are closed structures, which require the active presence of metabolite transporter proteins, much remains to be learned about the permeability properties of mammalian peroxisomes and the role of the four half ATP-binding cassette (ABC) transporters therein.

We report on a newborn girl with microcephaly, abnormal brain development, optic atrophy and hypoplasia, persistent lactic acidemia, and a mildly elevated plasma concentration of very-long-chain fatty acids. We found a defect of the fission of both mitochondria and peroxisomes, as well as a heterozygous, dominant-negative mutation in the dynamin-like protein 1 gene (DLP1). The DLP1 protein has previously been implicated, in vitro, in the fission of both these organelles. Overexpression of the mutant DLP1 in control cells reproduced the fission defect. Our findings are representative of a class of disease characterized by defects in both mitochondria and peroxisomes.

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Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS; MIM 260920) is an autosomal recessive disorder characterized by recurrent episodes of fever associated with lymphadenopathy, arthralgia, gastrointestinal dismay and skin rash. Diagnostic hallmark of HIDS is a constitutively elevated level of serum immunoglobulin D (IgD), although patients have been reported with normal IgD levels. To determine the underlying defect in HIDS, we analysed urine of several patients and discovered increased concentrations of mevalonic acid during severe episodes of fever, but not between crises. Subsequent analysis of cells from four unrelated HIDS patients revealed reduced activities of mevalonate kinase (MK; encoded by the gene MVK), a key enzyme of isoprenoid biosynthesis. Sequence analysis of MVK cDNA from the patients identified three different mutations, one of which was common to all patients. Expression of the mutant cDNAs in Escherichia coli showed that all three mutations affect the activity of the encoded proteins. Moreover, immunoblot analysis demonstrated a deficiency of MK protein in patient fibroblasts, indicating a protein-destabilizing effect of the mutations.