AUTHOR=Jankowska Katarzyna I. , McGill Joseph , Pezeshkpoor Behnaz , Oldenburg Johannes , Sauna Zuben E. , Atreya Chintamani D. 

TITLE=Further Evidence That MicroRNAs Can Play a Role in Hemophilia A Disease Manifestation: F8 Gene Downregulation by miR-19b-3p and miR-186-5p

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=8

YEAR=2020

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2020.00669

DOI=10.3389/fcell.2020.00669

ISSN=2296-634X

ABSTRACT=<p>Hemophilia A (HA) is a <italic>F8</italic> gene mutational disorder resulting in deficiency or dysfunctional FVIII protein. However, surprisingly, in few cases, HA is manifested even without mutations in <italic>F8</italic>. To understand this anomaly, we recently sequenced microRNAs (miRNAs) of two patients with mild and moderate HA with no <italic>F8</italic> gene mutations and selected two highly expressing miRNAs, miR-374b-5p and miR-30c-5p, from the pool to explain the FVIII deficiency that could be mediated by miRNA-based <italic>F8</italic>/FVIII suppression. In this report, an established orthogonal <italic>in vivo</italic> RNA-affinity purification approach was utilized to directly identify a group of <italic>F8</italic>-interacting miRNAs and we tested them for <italic>F8</italic>/FVIII suppression. From this pool, two miRNAs, miR-19b-3p and miR-186-5p, were found to be upregulated in a severe HA patient with a mutation in the <italic>F8</italic> coding sequence and two HA patients without mutations in the <italic>F8</italic> coding sequence were selected to demonstrate their role in <italic>F8</italic> gene expression regulation in mammalian cells. Overall, these results provide further evidence for the hypothesis that by targeting the 3′UTR of <italic>F8</italic>, miRNAs can modulate FVIII protein levels. This mechanism could either be the primary cause of HA in patients who lack <italic>F8</italic> mutations or control the severity of the disease in patients with <italic>F8</italic> mutations.</p>