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The investigations in the branch cover a wide range of genetic disorders and approaches. Some common themes have involved: the use of murine models to elucidate the biology of a disorder, approaches to the gene therapy of heritable disorders, and clinical treatment trials for rare disorders. In addition, Ida Owens has completed the description of the novel UGT1 complex locus, which encodes 13 transferase isoforms critical for the removal of bilirubin and other exogenous metabolites, and William Gahl’s group has delineated a defect in the _3A subunit of the AP3 adaptor complex in HPS-2 patients and found a new gene defect in Puerto Rican patients with HPS-3.
Several groups in the branch have generated murine models for their investigations. Janice Chou’s group has generated a knock-out murine model for GSD-1a and is engaged in generating a murine model for glycogen storage disease type 1b. The group is using the mice to understand the underlying mechanisms for the hypoglycemia, hyperlipidemia, and neutropenia experienced by patients. Anil Mukherjee’s group generated a uteroglobin-deficient mouse that is a model for IgA-nephropathy. Joan Marini’s section generated a knock-in model for nonlethal osteogenesis imperfecta, the Brittle mouse, and is investigating the mechanisms by which defective matrix causes osteoporosis. Forbes Porter has generated mice with disruptions in two of the genes encoding enzymes in the cholesterol biosynthesis pathway. Disruption of the Dhcr 7 gene creates a model for Smith-Lemli-Opitz syndrome while disruption of the Sc5d gene results in micrognathia, cleft palate, and limb patterning defects.
Investigators have approached the gene therapy of both autosomal recessive and autosomal dominant disorders. Dr. Chou has successfully used recombinant adenovirus to deliver the G6Pase transgene to the liver of knock-out mice for long-term correction of their metabolic deficiency. Before undertaking murine trials, Dr. Marini is using hammerhead ribozymes to suppress expression of mutant collagen in cultured osteogenesis imperfecta cells.
Current clinical protocols of special interest include those of Dr. Gahl on the pulmonary fibrosis of Hermansk-Pudlak syndrome and the use of cysteamine eye drops to treat corneal crystals in cystinosis patients. Dr. Mukherjee is using a Bench-to-Bedside Award from the NIH Clinical Center to determine the effects of cystagon on patients with severe infantile neuronal ceroid lipofuscinosis. The work is based on his success in using nucleophilic drugs such as cysteamine to deplete ceroid deposits in the lysosomes of cultured cells from these patients.