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Translational Control in Bone Marrow Failure

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Annual rept. 1 May 2013-30 Apr 2014

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Severe congenital neutropenia SCN is an inherited bone marrow failure syndrome most often resulting from autosomal dominant or de novo transmission of heterozygous mutations in the gene, ELANE, encoding neutrophil elastase. Other causes of SCN include autosomal recessive inheritance of HAX1 mutations. The purpose of this research is to understand how mutations in both ELANE and HAX1 lead to neutropenia, in order to gain further understanding into normal homeostatic regulation of granulopoiesis and how it is disrupted in a variety of bone marrow failure syndromes. Based on identification of a new class of mutations in ELANE that disrupt the translational start site and recent findings that HAX1 may be an RNA-binding protein, we have hypothesized that ELANE has the potential to encode amino-terminally truncated polypeptides initiating from internal translational start sites and that mutations in either ELANE or HAX1 may deregulate normal translational control of ELANE. In scope, we have proposed a series of experiments to be performed in cell culture systems to identify RNA sequences bound by HAX1, to determine if ELANE mutations influence HAX1 binding to ELANE mRNA and influence use of alternate translational start sites, and to biochemically characterize amino-terminally truncated neutrophil elastase. After the first year of funding we have preliminary identified mRNA sequences to which HAX1 protein may bind. More significantly, in a published study, using both cultured cells as well as SCN patient-derived induced pluripotent stem cells iPSC, we have determined that mutations disrupting the translation initiation site of ELANE can lead to production of amino-terminally truncated polypeptides. One or more of the aberrantly translated forms of neutrophil elastase mislocalizes within the cell and retains proteolytic activity, thereby suggesting a potential mechanism for how mutations throughout the length of neutrophil elastase may prove pathogenic.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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