Harry T. Orr
Molecular Nneurogenetics, Spinocerebellar Ataxia, Major Histocompatibility Complex GeneticsDr. Orr's research program is focused on the molecular genetics of mammalian development and neurodegenerative diseases. He and his colleagues recently cloned the gene for an autosomal dominant form of spinocerebellar ataxia (SCA 1). They showed that the disease is due to expansion of an unstable trinucleotide repeat (CAG) within the SCA 1 gene, which they have mapped to the short arm of human chromosome. They are examining the role of the SCA 1 gene in normal CNS function and how this mutation disrupts this function. The investigators will be working with protein biochemists to characterize the normal and abnormal SCA 1 protein.
Studies of SCA 1 are related to Orr's broader interest in the molecular genetics of development of the cerebellum, the region of the brain involved in motor control. Researchers in his laboratory have cloned several genes specifically expressed by Purkinje neurons. One of these, Pcp-2, is expressed only by Purkinje neurons and retinal bipolar neurons. Collaborative transgenic studies have been used to demonstrate that the 5_ upstream region of the Pcp-2 gene contains sequences capable of directing (both spatially and temporally) expression to Purkinje cells. Most recently, these sequences have been used to direct expression of SV40 T antigen (TAG) to Purkinje cells in transgenic mice. Expression of TAG results in the death and degeneration of Purkinje cells. These studies with neuropathologist Brent Clark are continuing to determine the molecular mechanism of SV40 TAG-induced cell death and to characterize the role of Purkinje cells in the early stages of cerebellar development. Insights from these basic biological investigations could be important for developing genetic and other therapies for patients with neurodegenerative diseases.
Orr has a long-standing interest in the genetics of the human major histocompatibility complex (MHC). Researchers in his laboratory are studying the expression of a member of the MHC class I gene family designated HLA-G. This gene, unlike other members of the HLA gene complex, is non-polymorphic and is expressed only in the extraembryonic tissue during fetal development. Orr and his colleagues are interested in why the fetus does not reject the tissue, since half of the MHC antigens come from the father.. To determine whether HLA-G plays a role in this phenomenon, they are exploring the molecular basis of HLA-G expression using hybrid reporter gene constructs transfected into choriocarcinoma cells. HLA-G expression is also being pursued in situ using transgenic mice.