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Translational Control in Bone Marrow Failure

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Technical Report,01 May 2013,30 Apr 2016

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University of Washington Seattle United States

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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 originally hypothesized, and have now shown in patient-derived induced pluripotent stem cells iPSC, that ELANE can encode amino-terminally truncated polypeptides initiating from internal translational start sites. 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. In the year since our last report, significant progress has been made in using new tools to model granulopoiesis, including generation of patient-derived iPSC and CRISPR-Cas9 genome-editing technology to introduce site specific repair or mutation into the ELANE locus, allowing for more relevant modeling of ELANE and HAX1 interactions in vitro.

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  • Medicine and Medical Research

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