Advisory Board

Robert J. Desnick, PhD, MD
Chairman & Professor, Department of Human Genetics Mt Sinai School of Medicine, New York, New York

Training and Education
Ph.D. (1970) Genetics University of Minnesota, Minneapolis, MN, USA
M.D. (1971) University of Minnesota Medical School, Minneapolis, MN, USA
B.A. (1965) University of Minnesota, Minneapolis, MN, USA

Current Research
Dr. Desnick's group is involved in several areas of research in human genetics and is experienced in the techniques of molecular biology, protein chemistry, enzymology, and cell biology. Their active research programs include the molecular genetics of inborn errors of the lysosome and of heme biosynthesis, gene discovery and genomic medicine, and gene therapy.

Of particular importance to individuals with porphyria is the research he and his colleagues are doing on the Molecular Genetics of the Inherited Porphyrias .

Of the metabolic pathways in man, only a few are known to be tightly regulated (e.g., cholesterol and heme biosynthesis). The biosynthesis of heme in man requires eight enzymatic steps to convert succinyl-CoA and glycine to the final product, heme. All eight enzymes are encoded by nuclear genes and four of the reactions occur in the cytosol, while four take place in the mitochondrion. The focus of this research opportunity is the investigation of the inborn errors of heme biosynthesis, the inherited porphyrias. Each of these disorders results from the deficient activity of a particular heme biosynthetic enzyme. The inborn errors of heme biosynthesis provide the opportunity to investigate the effects of dominant mutations and the action of environmental factors, since most of these diseases are latent until exacerbated by an environmental or pharmacologic stress.

Past accomplishments of his laboratory in the study of the human porphyrias have included the following: 1) Development of specific assays for the first four enzymes in the pathway, ALA-synthase, ALA-dehydratase, HMB-synthase and URO-synthase, 2) purification to homogeneity and characterization of the physical and kinetic properties of human ALA-dehydratase, HMB-synthase and URO-synthase, 3) isolation and characterization of the full-length cDNAs encoding human ALA-synthase (erythroid and hepatic cDNAs, ALA-dehydratase, HMB-synthase and URO-synthase, 4) regional chromosomal assignment of the genes encoding ALA-synthase (erythroid and hepatic), ALA-dehydratase, HMB-synthase and URO-synthase, 5) demonstration of normal isozymes for ALA-dehydratase and identification of their role in the susceptibility to lead poisoning, 6) demonstration of the genetic heterogeneity in unrelated families with acute intermittent porphyria (AIP) by the immunologic identification of differen! t mutations resulting in the presence or absence of the non-functional enzyme proteins, 7) identification of a feline model with AIP and establishment of a breeding colony, and 8) characterization of the molecular defects causing congenital erythropoietic porphyria.

Current efforts in his laboratory are focused at: 1) the characterization of the genomic structure and regulatory elements of the human URO-synthase and URO-decarboxylase genes, 2) identification of the molecular lesions in patients with ALA-dehydratase deficiency, acute intermittent porphyria, congenital erythropoietic porphyria and porphyria cutanea tarda, 3) expression of high levels of the full-length ALA-dehydratase, HMB-synthase, URO-synthase and URO-decarboxylase cDNA in E. coli, 4) establishment of a murine knock-out models for acute intermittent porphyria and for congenital erythropoietic porphyria (CEP), the latter using a double replacement strategy, and 5) retroviral-mediated gene transfer in erythroid progenitor cells from patients with congenital erythropoietic porphyria.

These studies are designed to develop and evaluate various strategies for the treatment of inherited metabolic diseases. For certain disorders resulting from the deficiency of a specific enzyme, the cDNA encoding the normal enzyme is isolated and used to produce large amounts of the recombinant enzyme for animal, and then human trials of enzyme replacement therapy. For other diseases in which gene replacement is feasible, efforts are being directed to insert the cDNA into various vectors for gene transfer studies. The availability of models with certain porphyrias provides the unique opportunity to develop and evaluate new methods of gene therapy, including the use of neurotropic vectors for the treatment of neurologic disease.

Although the scienceis complicated to read about the result is simple. Our lives are greatly improved by Dr. Desnick's work and the work of his colleagues.