C D Atreya
U S Food and Drug Administration, USA
Title: MicroRNA-1246 is a potential regulator of factor 8 gene
Biography
Biography: C D Atreya
Abstract
Hemophilia A (HA) is a bleeding disorder caused by deficiency of functional plasma clotting factor VIII (FVIII). Over a thousand different mutations have been reported in the F8 gene. Nonetheless, a CDC database (CHAMP, sample size 677 genotyped HA patients) illustrates that over 4% of HA patients with normal F8 do manifest the disease, suggesting that other molecular mechanisms such as suppression of normal F8 expression may also be involved in HA pathobiology. In the past decades, non-coding RNAs (ncRNAs), i.e., RNA transcripts not translated into proteins such as microRNAs (miRs), have emerged as key players that mediate post-transcriptional regulation of gene expression. Here we evaluated the role of miRs in HA disease manifestation. Global small ncRNA expression profiling analysis of whole blood from HA patients and controls was performed using high-throughput ncRNA microarrays. Patients were further sub-divided into those that developed neutralizing-anti-FVIII antibodies (inhibitors) and those that did not. We identified several ncRNAs and among them miR-1246 was significantly up-regulated in HA patients. In addition, miR-1246 showed a six-fold higher expression in HA patients without inhibitors. We further identified a miR-1246 target site in the non coding region of F8 mRNA and were able to demonstrate the suppressor role of miR-1246 on F8 expression in a stable lymphoblastoid cell line expressing FVIII. This study with HA patient blood samples indicates that besides the coding sequence of F8, non coding regions and other regulatory elements should also be studied to fully understand the causes and consequences of dysregulation of F8 gene expression.