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Identification of Genetic Co-Modifiers in Shwachman-Diamond Syndrome

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Annual rept. 30 Jul 2011-29 Jul 2012

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The goal of this proposal was to develop a powerful model for Shwachman-Diamond Syndrome that could ultimately be used to identify genetic co-factors for the development of myelodysplastic syndromeacute myeloid leukemia MDSAML. We have hypothesized that SBDS damages hematopoietic stem cell andor stroma, and that through the power of zebrafish modeling, we can identify the cellular and genetic lesions that promote MDSAML. This model will allow us to 1 to carry out large scale screening for genetic co-modifiers that promote leukemogenesis followed by their validation, and 2 to carry out drug screening for compounds to modify SBDS-positive cells. We have generated transgenic zebrafish line harboring SBDS gene promoter fused with fluorescent protein Cherry and demonstrated that the gene is broadly expressed during embryonic development in various tissues, including hematopoietic and digestive systems while the expression is sparsely distributed stem cells in juvenile and adult animals. We have also initiated a study on generation of ZFN-induced mutations in SBDS gene. Currently, we have been able demonstrate that sbds-specific ZFN does induced mutation in the targeted gene and that this mutation is lethal in early embryos which, however, can be rescued by SBDS-specific mRNA. This study creates a foundation for establishment of a unique animal model of SBDS.

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  • Genetic Engineering and Molecular Biology
  • Biology
  • Medicine and Medical Research

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