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Inborn Errors in Amino Acid Metabolism and Peroxisome Biogenesis and Function
Summary: David Valle is interested in identifying the genes involved in human inborn errors of metabolism, retinal degenerations, and peroxisomal biogenesis and function. His studies are aimed at understanding the causes of these disorders, how to treat them, and what they tell us about normal biology.
Human biochemical genetics has been a fruitful area of study since its beginning with the work of Sir Archibald Garrod early in the 20th century. Inherited defects in our body's chemistry—or, as Garrod called them, inborn errors of metabolism—are intrinsically interesting and serve as important models for all genetic diseases. We have been involved in the study of several aspects of these disorders, including clinical diagnosis, biochemical characterization, delineation of pathophysiologic mechanisms, development of new therapeutic approaches, and molecular studies of the involved genes.
We have focused on disorders of amino acid metabolism, particularly those involving two fundamentally important and interrelated areas of metabolism: the urea cycle, which converts excess nitrogen from a toxic to a nontoxic, readily excreted form, and the tricarboxylic acid cycle, an essential component of energy metabolism. We have also extended our interests to inborn errors of peroxisome biogenesis and function. Peroxisomes are ubiquitous subcellular organelles containing 50 or more matrix enzymes that participate in a variety of anabolic and catabolic processes.
Amino Acid Disorders
We continue to study an inborn error of ornithine metabolism known as gyrate atrophy of the choroid and retina (GA). This progressive, blinding chorioretinal degeneration with associated cataract formation is inherited as an autosomal-recessive trait. The primary biochemical defect is deficiency of the enzyme ornithine-δ-aminotransferase (OAT), which results in an ~10-fold accumulation of ornithine in all bodily fluids. We and others have defined more than 60 mutations in the
OAT genes of GA patients.
Despite this progress at the molecular level, much remains to be learned about GA. In particular, we would like to understand why the retina is especially sensitive to this systemic metabolic disorder and what we can do to treat GA patients. To these ends, we used gene targeting to produce an Oat-deficient mouse. Postweaning Oat-deficient mice exhibit hyperornithinemia to an extent similar to human GA patients and a progressive retinal degeneration. Thus these animals are an excellent model for the human disorder.
Using an arginine-restricted diet in these animals, we have shown that reduction in ornithine accumulation completely prevents the electroretinographic, histologic, and ultrastructural abnormalities in Oat-deficient animals at 12 months. These results indicate that systemic reduction in ornithine completely prevents the retinal degeneration. Current studies are focusing on alternate methods to reduce ornithine and on delineation of the intracellular pathophysiologic mechanisms.
A second inborn error of ornithine metabolism involves the fact that enzymes using ornithine are located in two subcellular compartments, the cytosol and the mitochondrial matrix. Previous biochemical studies showed that movement of ornithine between these two compartments is carrier mediated and that the putative transporter might be defective in an inborn error known as hyperammonemia-hyperornithinemia-homocitrullinuria (HHH) syndrome, an autosomal-recessive disorder characterized by mental retardation and progressive spasticity. Using homology to fungal transporters, we identified the gene encoding a human mitochondrial ornithine transporter and showed that it is defective in the HHH syndrome. We also identified a second human ornithine transporter, and we are exploring the possibility that stimulation of the expression of this second gene might provide an effective treatment for the HHH syndrome.
We have also been interested in understanding the relationship of proline metabolism and its disorders to the pathophysiology of GA and the HHH syndrome. We have cloned the genes encoding the enzymes of proline metabolism (δ1-pyrroline-5-carboxylate [P5C] synthase, P5C dehydrogenase, two P5C reductases, and two proline oxidases) and are exploring their involvement in several inborn errors of proline metabolism. (Grants from the National Institutes of Health and the Foundation Fighting Blindness provided partial support for these projects.)
Peroxisome Biogenesis and Function
We are also interested in inborn errors of peroxisome biogenesis and function. Zellweger syndrome (ZS), a neurodevelopmental disorder fatal in infancy, is the paradigm for biogenesis disorders. X-linked adrenoleukodystrophy is the model for disorders resulting from deficiency of a single peroxisomal function. The peroxisome biogenesis disorders are genetically heterogeneous with at least 12 complementation groups.
We have used homology probing to identify genes responsible for ZS. The proteins necessary for peroxisome biogenesis are now termed peroxins, and their genes are called PEX genes. To identify human PEX genes, we search the expressed sequence tag databases for sequence homologues to yeast proteins known to be necessary for peroxisome biogenesis. We have identified seven human peroxisome biogenesis genes, including those encoding the receptors for the two major import mechanisms by which matrix proteins enter the peroxisome. Molecular and cellular studies of these peroxins have led to a better understanding of the assembly of peroxisomes and of the pathophysiology of defects in peroxisome biogenesis. (A grant from the National Institutes of Health provided partial support for this project.)
Last updated December 06, 2002
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