Molecular defect in activation of a mutant Stat5b

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A recent report identified a patient presenting with clinical features of growth hormone insensitivity, who harbored a homozygous mis-sense mutation in the Stat5b gene that resulted in an alanine to proline substitution at amino acid 630, adjacent to the SH2 domain. The precise molecular defect caused by the mutant Stat5b protein has not been elucidated. Preliminary experiments have demonstrated that the mutant Stat5b protein is detected upon transient transfection in cultured mammalian cells, however at consistently <50% the level of wild-type Stat5b protein. In reconstitution experiments, mutant Stat5b failed to enhance reporter gene activity upon growth hormone stimulation. This research proposal attempts to identify the specific molecular defect of the mutant Stat5b in its inactivation cycle, highlighting two hypothesized areas of dysfunction. The first specific aim addresses protein stability and subcellular location of mutant Stat5b. The second specific aim focuses on whether the function of the nearby SH2 domain is disrupted, such that the mutant Stat5b can not interact with the activated growth hormone receptor/Jak2 complex or with other Stat5b molecules in the dimerization process.