Dr. Nussbaum works in the Genetic Disease Research Branch. Research in his laboratory is focused on using genetic methods to elucidate the function of disease genes identified through positional cloning. Nussbaum and his colleagues use embryonic stem-cell technology to create cells or entire animals lacking gene function for these genes. In this way, model systems can be developed for studying the mechanism by which altered gene function results in genetic disease. The laboratory has concentrated on two disorders: the oculocerebrorenal syndrome of Lowe (OCRL) and Parkinson's Disease. Both of these disease genes have been identified through positional cloning in patients and so their normal function is unknown. The challenge now is to delineate the pathogenesis of these disorders by studying these genes and the proteins they encode.

OCRL is an X-linked disorder characterized by prenatal onset of neurological defects leading to mental deficiency and cataracts. Postnatally, the children develop renal tubular reabsorption defects and, over a period of 2-3 decades, renal insufficiency. We isolated the gene for OCRL by positional cloning from a translocation breakpoint in a female with OCRL. We have shown that the OCRL gene is a phosphatidylinositol bisphosphate 5-phosphatase that is deficient in cells from Lowe Syndrome patients. The thrust of our research now is to determine how a defect in this enzymatic activity leads to the particular triad seen in the Lowe syndrome. As one important tool for studying OCRL, a mouse carrying a targeted knock-out of the OCRL gene has been constructed. Surprisingly, these mice show no signs of the disease. There are other genes in the human and mouse genome with strongly conserved domains that we believe encode phosphatidylinositol bisphosphate 5-phosphatases. The current hypothesis in the lab is that one or more of these genes may be compensating for the lack of OCRL activity in mice, but not in humans. We are investigating this possibility by making mice deficient in these other genes as well and then crossing them to create double knock-outs as a genetic screen for functional overlap. More broadly, embryonal stem cell technology is a powerful tool for analyzing and dissecting other signal transduction pathways, including the inositol signaling pathway.

Parkinson's Disease is a very common neurodegenerative disease in man that afflicts 500,000-1,000,000 people in the United States. A team led by Dr. Mihael Polymeropoulos, a colleague in the Genetic Diseases Research Branch, Nussbaum's team mapped and then found the gene and the mutation responsible for Parkinson's Disease in a large family of Italian descent with the disease. The mutation in this family, and in three other unrelated families with autosomal dominant Parkinson's Disease, turned out to be a subtle missense mutation in the alpha-synuclein gene. Dr. Nussbaum's lab is exploring biochemical and cell biological mechanisms for how alpha-synuclein mutations cause Parkinson's disease using in vitro and whole animal model systems.