ABT1 modifies SMARD1 pathology via interactions with IGHMBP2 and stimulation of ATPase and helicase activity.

SMA with respiratory distress type 1 (SMARD1) and Charcot Marie Tooth type 2S (CMT2S) are a result of mutations in immunoglobulin mu DNA binding protein 2 (IGHMBP2). IGHMBP2 is an UPF1-like helicase with proposed roles in several cellular processes including translation. This study examines activator of basal transcription (ABT1), a modifier of the FVB-Ighmbp2nmd/nmd phenotype. Microscale thermophoresis and dynamic light scattering demonstrate IGHMBP2 and ABT1 proteins directly interact with high affinity. The association of ABT1 with IGHMBP2 significantly increases the ATPase and helicase activity as well as the processivity of IGHMBP2. The IGHMBP2-ABT1 complex interacts with the 5' external transcribed spacer and U3 snoRNA suggesting that the IGHMBP2-ABT1 complex is important for pre-rRNA processing. Intracerebroventricular injection of scAAV9-Abt1 decreases FVB-Ighmbp2nmd/nmd disease pathology, significantly increases lifespan and substantially decreases neuromuscular junction denervation. ABT1 is the first disease modifying gene identified for SMARD1. We provide a mechanism that proposes ABT1 decreases disease pathology in FVB-Ighmbp2nmd/nmd mutants by optimizing IGHMBP2 biochemical activity (ATPase and helicase activity). Our studies provide important insight into SMARD1 pathogenesis suggesting ABT1 modifies IGHMBP2 activity as a means to regulate pre-rRNA processing.