| Summary: | A novel cosegregating splice site variant in the <i>Dynactin-1</i> (<i>DCTN1</i>) 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. <i>DCTN1</i> codes for the largest dynactin subunit, namely p150<sup>Glued</sup>, which plays an essential role in retrograde axonal transport and in neuronal autophagy. A GT→TT transversion in the <i>DCTN1</i> 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<sup>Glued</sup> protein (ct-p150<sup>Glued</sup>), 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 <i>GLUED Gl</i><sup>1</sup> mutation in <i>Drosophila</i>, 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 <i>DCTN1</i> gene, leading to NMD and/or ct-p150<sup>Glued</sup>, may be of fundamental importance in contributing to our understanding of the etiology of BD as well as MDD.
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