A Novel Cosegregating Splice Site Variant in a Family with Bipolar Disorder May Hold the Key to Understanding the Etiology.

A novel cosegregating splice site variant in the () 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. codes for the largest dynactin subunit, namely p150, which plays an essential role in retrograde axonal transport and in neuronal autophagy. A GT→TT transversion in the 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 protein (ct-p150), thereby negatively impacting retrograde axonal transport and neuronal autophagy. BD prophylactic medications, and most antipsychotics and antidepressants, are known to enhance neuronal autophagy. This variant is analogous to the dominant-negative mutation in , which is responsible for a neurodegenerative phenotype. The newly identified variant may reflect an autosomal dominant cause of psychiatric pathology in this affected family. Factors that affect alternative splicing of the gene, leading to NMD and/or ct-p150, may be of fundamental importance in contributing to our understanding of the etiology of BD as well as MDD.