A novel co-segregating DCTN1 splice site variant in a family with Bipolar Disorder may hold the key to understanding the etiology

Abstract

A novel co-segregating splice site variant in the Dynactin-1 (DCTN1) gene was discovered by Next Generation Sequencing (NGS) in a family with a history of bipolar disorder (BD) and major depressive diagnosis (MDD). Psychiatric illness in this family follows an autosomal dominant pattern. DCTN1 codes for the largest dynactin subunit, namely p150^Glued. This protein plays an essential role in retrograde axonal transport and in neuronal autophagy. Neuronal autophagy deficits are implied in BD as prophylactic medications, as well as most antipsychotics and antidepressants, have been shown to enhance it. A GT→TT transversion in the DCTN1 gene, uncovered in the present work, is predicted to disrupt the invariant canonical splice donor site IVS22+1G>T and result in intron retention and a premature termination codon (PTC). Thus, this splice site variant is predicted to trigger RNA nonsense-mediated decay (NMD) and/or result in a C-terminal truncated p150^Glued protein (ct-p150^Glued), thereby negatively impacting retrograde axonal transport and neuronal autophagy. This variant is analogous to the dominant-negative GLUED Gl¹ mutation in Drosophila. The newly identified variant may reflect an autosomal dominant cause of psychiatric pathology in this affected family. Factors that affect alternative splicing of the DCTN1 gene, leading to NMD and/or ct-p150^Glued, may be of fundamental importance in contributing to our understanding of the etiology of BD as well as MDD.