Our goals are to identify genes that cause Mendelian neurologic disorders, determine the effect of mutations on the functions of the genes, delineate the effect of mutations on the spectrum of clinical manifestations and generate models for studies of disease pathogenesis. Each new gene discovery for an inherited neurologic disorder, no matter how rare that disorder, provides an opportunity to learn about the function of the human nervous system and the processes that lead to its malfunction and degeneration. We take advantage of a rich sample set of patients with neurogenetic diseases of unknown etiology, amassed through decades of ascertainment and clinical characterization. In addition to gene discovery, these families are invaluable resources for investigation of genotype effects on the phenotype. Our studies not only shed light on the biological effects of mutations, but also provide clinically useful diagnostic and prognostic information for these patients and their physicians, and have the potential to influence therapy. The speed of disease-gene discovery has increased tremendously in recent years mainly because of advances in sequencing technology that allow broad investigation of the genome with or without linkage information. Using these methods, during the current cycle, we discovered causative genes for multiple neurogenetic disorders, and demonstrated effects of mutations on the function of the genes and their contribution to disease pathogenesis. In some cases our findings have implications beyond the nervous system. One of these disorders is the first human disease definitively tied to an adenylate cyclase gene and has potential cardiac implications. Another disorder with hematologic manifestations as well as ataxia has implications for myeloid leukemias and myelodysplasia. We will continue to apply gene localization methods and exome sequencing to identify additional genes for neurogenetic disorders in our large, well-characterized collection of families. We will use a variety of cell-based systems to verify the pathologic effect of mutations on gene function and initiate studies on other genes as we discover them. We incorporate new approaches, such as molecular inversion probe panels to aid in categorizing families for further study, GIGI-Pick to select the optimal family members to sequence, and induced pluripotential stem cell generation to obtain patient- derived neuronal cells. This new proposal builds on the strength of established collaborations among all four Investigators with expertise in diagnosis and characterization of neurologic disorders, human and molecular genetics, and cell biology, and with ongoing and new collaborations with scientists at the forefronts of their fields we strengthen our ability to apply new and emerging technologies to our research.
The goal of this proposal is to identify novel genes that are responsible for inherited neurologic disorders. The research builds upon a large collection of samples from many families that have been extensively characterized and followed for as long as 30 years. We use a combination of linkage analysis and sequencing of the protein-coding portion of the genome to discover candidate disease-causing mutations. Panels of subjects with similar clinical manifestations will be screened for mutations in the relevant gene as one way to gain evidence that it is the cause of disease. In addition, the functional effect of the mutations n gene function will be explored to confirm their pathogenic nature, to improve understanding of the biology of the disease and to gain knowledge helpful for designing interventions. For a particular disorder, the mutation spectrum, their functional effects and the variation in clinical manifestations will provide clinically useful information about the relationships between specific genotypes and the disease manifestations. Beyond the implication of gene discovery for patients who suffer from a particular disorder, each new gene contributes to our understanding of the complex protein-protein interactions involved in development and maintenance of the human neurologic system. The findings of this research will be an important part of a systematic approach to diagnosis and the eventual treatment and prevention of these diseases.
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