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Inherited Perturbations in Heavy Metal Metabolism
Summary: Jane Gitschier studies how heavy metals are transported in mammalian cells and tissues, and how aberrations in these patterns can lead to disease. She uses genetic approaches to discover key proteins involved in these pathways.
All living organisms require heavy metals, such as copper, zinc, manganese, and iron, which are vital for the function of a wide variety of cellular processes. Excessive amounts of these metals can, however, prove toxic to organisms. Thus, the transport and compartmentalization of metals in and between cells must be tightly controlled, and perturbations in these pathways can lead to disease.
Our laboratory is attempting to discover components of the metal transport pathways in humans. Our starting point for discovery usually lies with patients who suffer from an inherited imbalance in metal metabolism. By analyzing the DNA of such individuals, we are able to identify the genetic basis for their disease. Often this research results in description of new and sometimes unexpected metabolic mechanisms.
An example of this approach involves an ongoing collaboration with Susan Hayflick and her laboratory (Oregon Health & Science University). Together we identified the gene responsible for a devastating pediatric neurodegenerative disease, formerly referred to as Hallervorden-Spatz syndrome (HSS), in which iron accumulates in one particular brain structure, the globus pallidus. Children suffering from this rare disease, now referred to as PKAN (pantothenate kinase–associated neurodegeneration), have progressive difficulty in walking, talking, and swallowing, and eventually die. By collecting blood samples from approximately 150 families, we identified the gene in which defects lead to PKAN. Contrary to our expectation, the gene does not appear to be directly involved in iron metabolism.
Instead, the PKAN gene encodes an enzyme, a pantothenate kinase, responsible for the first step in the metabolism of vitamin B5 to coenzyme A, a key molecule required for such diverse functions as fatty acid synthesis and oxidation and energy metabolism. We are attempting to understand why a defect in pantothenate kinase in PKAN should lead to specific degeneration of the globus pallidus and its concomitant iron accumulation.
One insight into these questions was gained by our discovery that the pantothenate kinase defective in PKAN is one of four such enzymes in humans and that, of these, it is uniquely targeted to mitochondria. Indeed, by electron microscopy, the enzyme appears to be located within the cristae. This suggests a role for this particular pantothenate kinase in energy metabolism, consistent with the vulnerability of the globus pallidus to oxygen deprivation. The mitochondrion is also instrumental in lipid and amino acid metabolism, and perturbations in these pathways must be considered in understanding the etiology of disease.
A defect in vitamin B5 metabolism might also lead indirectly to iron accumulation and tissue destruction as follows: Normally, cysteine is a substrate for the enzyme following pantothenate kinase in the biosynthesis of coenzyme A, and thus a deficiency of pantothenate kinase could result in an accumulation of the substrate cysteine. Indeed, cysteine levels are reportedly elevated in the affected brain structures of PKAN patients. Cysteine can bind iron, which is normally abundant in the globus pallidus, potentially augmenting iron stores as a consequence. Moreover, the iron-cysteine complex is highly reactive, capable of damaging lipids, proteins, and DNA.
To develop an animal model for PKAN, we have knocked out the pantothenate kinase gene in mice and have analyzed these mice over the course of two years for defects. To our surprise, these animals did not manifest the movement disorder characteristic of the human patients, nor did they accumulate iron in the basal ganglia. We are experimenting with a variety of dietary, chemical, and genetic manipulations that should help us to provoke and ultimately understand the genesis of the movement disorder.
Remarkably, however, the mutant mice did manifest two pathologies of great interest: First, the male mice proved to be infertile and completely devoid of mature sperm. Second, the mutant animals exhibit progressive retinal degeneration, specifically a loss in photoreceptors. We find the mitochondria in these cells to be fewer in number. (Part of this research was supported by a grant from the National Institutes of Health to Susan Hayflick.)
Recently we have begun to consider whether genetic vulnerability to environmental toxins might give rise to neurological damage in some children. Of particular interest is organic mercury, which is commonly found in fish as well as in some vaccines. Public concern over the possibility of neurological damage has mounted with the unexplained rising incidence of diseases such as autism and attention deficit disorder.
To address this hypothesis, we are pursuing a number of genetic approaches for the study of mercury metabolism. First, we have screened inbred strains of mice for sensitivity to organic mercury and have identified one strain that is particularly resistant. Our preliminary findings suggest that mercury exposure in organs from this strain is reduced compared to other strains. We plan to map and identify the gene(s) underlying this resistance. Second, we have conducted similar experiments in yeast, as yeast and humans use similar pathways for heavy metal metabolism, and we have found a number of genes, particularly in chromosomal modification and gene regulation, that confer sensitivity. Third, we are asking whether individuals with autism might have abnormalities in one or more aspects of metal metabolism.
Genetic susceptibility to mercury toxicity is not without precedent. In the early part of the 20th century, many infants in England, Australia, and the United States were given teething powder containing mercury. A small number of these children responded with pink disease, also known as acrodynia, a painful condition of the palms and soles of the feet. Affected children were also irritable and extremely sensitive to light and many died. Survivors often had lifelong medical problems. Pink disease is an excellent model of genes interacting with the environment and a stimulating example of how mercury toxicity can be overlooked when it affects only a small fraction of the population.
In completely separate collaborative work with Nelson Freimer (University of California, Los Angeles), we study the inherited basis for absolute pitch perception, the ability to identify the pitch of a tone without a reference tone. We have demonstrated that absolute pitch perception runs in families and have enrolled families with at least two affected siblings into our genetic study. If successful, this long-term study should shed light into the molecular mechanisms for neuroplasticity in the auditory cortex.
One aspect of this study has been an enhanced appreciation of pitch perception in individuals with absolute pitch. By analyzing data derived from 700 such subjects enrolled through our Web site (www.perfectpitch.ucsf.edu), we have discovered two perceptual “warps.� First, we found a previously unappreciated tendency to misidentify G-sharp as A; we hypothesize that use of A as the universal tuning standard could underlie this “perceptual magnet� effect. Second, we demonstrated that pitch perception shifts in the "sharp" direction as subjects age, a phenomenon that likely reflects shift in the acoustical properties of the cochlea with age.
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