A novel co-segregatingDCTN1splice site variant in a family with Bipolar Disorder may hold the key to understanding the etiology

Abstract

<jats:title>Abstract</jats:title><jats:p>A novel co-segregating splice site variant in the <jats:italic>Dynactin-1</jats:italic> (<jats:italic>DCTN1</jats:italic>) 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. <jats:italic>DCTN1</jats:italic> codes for the largest dynactin subunit, namely p150<jats:sup>Glued</jats:sup>, which plays an essential role in retrograde axonal transport and in neuronal autophagy. A GT→TT transversion in the <jats:italic>DCTN1</jats:italic> gene, uncovered in the present work, is predicted to disrupt the invariant canonical splice donor site IVS22+1G&gt;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<jats:sup>Glued</jats:sup> protein (ct-p150<jats:sup>Glued</jats: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 <jats:italic>GLUED Gl</jats:italic><jats:sup><jats:italic>1</jats:italic></jats:sup> mutation in <jats:italic>Drosophila</jats:italic> 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 <jats:italic>DCTN1</jats:italic> gene, leading to NMD and/or ct-p150<jats:sup>Glued</jats:sup>, may be of fundamental importance in contributing to our understanding of the etiology of BD as well as MDD.</jats:p>